JP2013060370A - 6-(4-HYDROXYPHENYL)-3-STYRYL-1H-PYRAZOLO[3,4-b]PYRIDINE-4-CARBOXYLIC ACID AMIDE DERIVATIVE AS KINASE INHIBITOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a kinase inhibitor useful for treatment of diseases related to diabetes and diabetic complications.SOLUTION: There is provided a 6-(4-hydroxyphenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivative represented by formula I (wherein Ris an aralkyl group optionally substituted with a heteroatom, or the like; and R, R, Rand Rare each a group selected from among a hydrogen atom, a halogen atom, an alkyl group optionally substituted with a heteroatom, and the like).

Description

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、及びＲ⁵は下記のように定義される）のピラゾロ［３,４−ｂ］ピリジン化合物に関する。式Ｉの化合物は、キナーゼ阻害剤であり、そして例えば糖尿病及び糖尿病性合併症に関連する疾患、例えば糖尿病性腎症、糖尿病性神経障害及び糖尿病性網膜症の治療に有用である。さらに、本発明は、特に薬剤中の活性成分としての式Ｉの化合物、及びそれを含む薬学的組成物の使用に関する。 The present invention provides compounds of formula I

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are defined as follows) and a pyrazolo [3,4-b] pyridine compound. The compounds of formula I are kinase inhibitors and are useful, for example, in the treatment of diseases associated with diabetes and diabetic complications such as diabetic nephropathy, diabetic neuropathy and diabetic retinopathy. Furthermore, the invention relates in particular to the use of compounds of formula I as active ingredients in medicaments and pharmaceutical compositions comprising them.

Protein kinase C (PKC) comprises a family of several related isoenzymes that function as serine / threonine kinases. PKC plays an important role in the control of intercellular and intracellular signaling, gene expression, and cell differentiation and proliferation. At present, at least 10 PKC isoforms are known and they differ in regulation, tissue distribution, and enzyme specificity (Non-patent Document 1; Non-patent Document 2; Non-patent Document 3; Non-patent Document 4). The PKC family of isoenzymes is based on three subclasses based on the domain composition of the regulatory moiety: (1) conventional PKCs (alpha, beta-II, and beta-I), (2) novel PKCs (delta, epsilon, gamma) And eta and theta) and (3) atypical PKCs (zeta and iota / lambda) (Non-Patent Document 1; Non-Patent Document 5). PKC is a membrane-related enzyme that is regulated by several distinct factors, such as membrane phospholipids, calcium, and membrane lipids such as diacylglycerol (Non-patent Document 1; Non-patent Document 2; Non-patent Document 5; Non-patent document 6; Non-patent document 7). All PKC isoforms have a self-inhibiting pseudosubstrate sequence that is N-terminal to the C1 domain, which functions as a diacylglycerol sensor. Atypical PKC has a diacylglycerol non-reactive C1 domain. Conventional PKCs have a C2 domain that acts as a Ca ²⁺ -regulated phospholipid-binding module. The C2 domain in the novel PKC does not bind to either Ca ²⁺ or membrane phospholipids. Based on structural differences, conventional PKCs require membrane phospholipids, calcium and diacylglycerol for full activation. The new PKC does not require calcium for activation, but does require diacylglycerol. The zeta and iota / lambda forms of PKC are not affected by either calcium or diacylglycerol for their activation (Non-Patent Document 1; Non-Patent Document 8).

PKC is involved in the regulation of smooth muscle contractility. Upon stimulation, PKC phosphorylates the regulatory myosin light chain (MLC ₂₀ ) and inhibits myosin-related phosphatase (MYPT). MLC ₂₀ phosphorylation and inhibition of MYPT increase the activity of the actomyosin complex and cause vasoconstriction in various vascular beds, for example, causing resistance in the retina, cerebrum, coronary artery, duct artery and vein (Resistance-sized) (Non-patent document 9; Non-patent document 10). Overexpressed or overactivated PKC adversely affects cardiac function. Upon activation, PKC affects intracellular calcium homeostasis, which decreases myocardial contractility and relaxes myocardium. Overall, this effect leads to myocardial contraction failure (Non-patent Document 11). Furthermore, activated PKC can cause organ damage during ischemia in, for example, the heart (Non-Patent Document 11; Non-Patent Document 12) or the kidney (Non-Patent Document 13; Non-Patent Document 14) during end organ damage. Bring. PKC and especially PKC-beta II isoforms are overexpressed or overactivated in a variety of different types of tissues in diabetes, and cells, tissues and end organs such as the kidney (Non-Patent Document 13; Non-Patent Document 14; Non-patent document 15; Non-patent document 16), heart (non-patent document 11; non-patent document 17), or tissue such as retina (non-patent document 18; non-patent document 19; non-patent document 20) or neuronal tissue (Non-patent document 21; Non-patent document 22; Non-patent document 23; Non-patent document 24) or adverse effects on platelets (Non-patent document 25; Non-patent document 26; Patent document 20; Non-patent document 27) Or induces endothelial dysfunction (Non-patent document 28; Non-patent document 29; Non-patent document 30; Non-patent document 31). Furthermore, PKC signaling is associated with tumor formation (Non-Patent Document 32; Non-Patent Document 33), such as hematological tumors (Non-Patent Document 34; Non-Patent Document 35; Non-Patent Document 36), glioma formation (Non-Patent Document 33). Patent Document 37; Non-Patent Document 38; Non-Patent Document 39), Gastric and Intestinal Cancer (Non-Patent Document 40; Non-Patent Document 41), Skin Cancer (Non-Patent Document 42; Non-Patent Document 43), Lung Cancer (Non-Patent Document 43) It is suggested to be involved in Patent Document 44; Non-Patent Document 45) and others. PKC is involved in autoimmune reactions, such as T cells (Non-Patent Document 46; Non-Patent Document 47) or B-cells (Non-Patent Document 48; Non-Patent Document 49) associated with autoimmune signaling and in inflammatory processes. It is an important signal transducer for events. The above-mentioned effects of PKC-mediated signaling are the induction or promotion of asthma progression (non-patent document 50), chronic obstructive pulmonary disease (non-patent document 51; non-patent document 52; non-patent document 53; non-patent document 54; Non-patent document 55), pulmonary hypertension (non-patent document 56; non-patent document 57), retinopathy, retinal ischemia, and neovascularization (non-patent document 58; non-patent document 59), nephropathy including hypertension induction (Non-patent document 60; Non-patent document 61; Non-patent document 62), Non-hypertension-induced and diabetic nephropathy (Non-patent document 63; Non-patent document 64), Renal failure (Non-patent document 65; Non-patent document) 66) and myocardial infarction (Non-patent document 67; Non-patent document 68; Non-patent document 69; Non-patent document 70) Cardiac hypertrophy and failure (Non-patent document 71; Non-patent document 72), coronary heart disease, atherosclerotic artery Sclerosis, restenosis (non-patent document) 73; non-patent document 74), diabetes, diabetic complications, glucose utilization and metabolic syndrome (non-patent document 75; non-patent document 76; non-patent document 77), immune disease (non-patent document 78; non-patent document 79) Non-patent document 80; Non-patent document 81), psoriasis and the like (non-patent document 82; non-patent document 83; non-patent document 84), rheumatoid arthritis (non-patent document 85; non-patent document 86; non-patent document 87), Or other autoimmune disorders (non-patent document 88), central nervous system disorders (non-patent document 89; non-patent document 90), cerebral ischemia or cerebral vasospasm (non-patent document 91), neuropathy and pain, such as Neuropathic pain (Non-patent document 92; Non-patent document 93), cancer development and progression, protein kinase C inhibition is known to inhibit tumor cell growth and metastasis (Non-patent document 94; Patent 95; non-patent document 96), angiogenesis (non-patent document 97; non-patent document 98; non-patent document 99; non-patent document 100), platelet disorder leading to thrombosis (non-patent document 101; non-patent document 102; Non-patent document 103; Non-patent document 104; Non-patent document 105; Non-patent document 106; Non-patent document 107) and leukocyte aggregation (Non-patent document 108; Non-patent document 109; Non-patent document 110).

  So far, mainly staurosporine derivatives have been used in the prior art as PKC inhibitors such as ruboxistaurin (eg Patent Document 1), enzastaurine (eg Patent Document 2), midstaurine (eg Patent Document 3) or sotrastaurine. (For example, Patent Document 4). PKCβ inhibitors not derived from staurosporine, such as 3-amido-pyrrolo [3,4-c] pyrazole-5 (1H, 4H, 6H) carbaldehyde in US Pat. There is only. However, there is a continuing need for further effective low molecular weight PKCβ inhibitors, especially in view of safety and selectivity. The present invention meets this need by providing pyrazolo [3,4-b] pyridine compounds of formula I. Pyrazolo [3,4-b] pyridine derivatives useful for pharmaceutical use include, for example, Patent Document 6 (Neurogen Corp. and Aventis Pharmaceuticals Inc.), Patent Document 7 (Exelixis Inc.), and Patent Document 8 (Neurogen Corp.). Has already been described.

EP 657458 WO 9517182 EP 296110 WO 2002038561 WO 200825945 WO 2005028480 WO 2005009389 WO 2000058307

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Glycoprotein IIb / IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity.J Thromb Haemost 2003; 1 (8): 1805-1812 Kotovuori A, Pessa-Morikawa T, Kotovuori P, Nortamo P, Gahmberg CG.ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity. J Immunol 1999; 162 (11): 6613-6620 Lorenz HM, Lagoo AS, Hardy KJ. The cell and molecular basis of leukocyte common antigen (CD45) -triggered, lymphocyte function-associated antigen-1- / intercellular adhesion molecule-1-dependent, leukocyte adhesion. Blood 1994; 83 (7 ): 1862-1870

〔式中、
Ｒ¹は、 Accordingly, the subject of the present invention is the formula I of any stereoisomeric form thereof, or a mixture of stereoisomeric forms in any proportion.

[Where,
R ¹ is

［式中、
Ｒ⁶は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₃）−アルキル又はＯ−（Ｃ₁−Ｃ₃）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは、非置換であるか又は１〜５個のＦによって置換されており；
Ｒ⁷は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₃）−アルキル若しくはＯ−（Ｃ₁−Ｃ₃）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは非置換であるか若しくは１〜５個のＦによって置換されており、又はＣＮ、（Ｃ₀−Ｃ₂）−アルキレン−ＳＯ₂（Ｃ₁−Ｃ₃）−アルキル、（Ｃ₀−Ｃ₂）−アルキレン−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、１−ピロリジニル、１−ピペリジニル、１−ピロリジニル−２−オン、１−ピペリジニル−２−オン、若しくは４−モルホリニルであり；
Ｒ⁸は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₅）−アルキル若しくはＯ−（Ｃ₁−Ｃ₅）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは非置換であるか若しくは１〜５個のＦによって置換されており、又はＣＮ、ＯＨ、Ｏ−フェニル、ＳＯ₂（Ｃ₁−Ｃ₃）−アルキル、ＣＯ−（Ｃ₁−Ｃ₄）−アルキル、ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、ＣＯ−１−ピペリジニル、ＣＯ−１−ピロリジニル、若しくはＣＯ−４−モルホリニルであり；
Ｒ⁹は、Ｈ、Ｆ、ＣＨ₃、又はＯ−ＣＨ₃であり；
Ｒ¹⁰は、Ｈであり；又は
Ｒ⁶及びＲ⁷は、それらが結合している２個の炭素原子と一緒になって５〜６員ヘテロシクロアルキル環を形成し、それは窒素及び酸素から選ばれる１又は２個の同一又は異なるヘテロ原子を含み、そしてここにおいて該ヘテロシクロアルキルは、非置換であるか又は（Ｃ₁−Ｃ₄）−アルキル若しくはオキソ（＝Ｏ）によって一置換されており；又は
Ｒ⁷及びＲ⁸は、それらが結合している２個の炭素原子と一緒になって５〜６員ヘテロシクロアルキル環を形成し、それは窒素及び酸素から選ばれる１又は２個の同一又は異なるヘテロ原子を含み、そしてここにおいて該ヘテロシクロアルキルは、非置換であるか又は（Ｃ₁−Ｃ₄）−アルキル若しくはオキソ（＝Ｏ）によって一置換されている］
の残基； a) Formula Ia

[Where:
R ⁶ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted Is or is substituted by 1 to 5 F;
R ⁷ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. Or substituted by 1 to 5 F, or CN, (C ₀ -C ₂ ) -alkylene-SO ₂ (C ₁ -C ₃ ) -alkyl, (C ₀ -C ₂ ) -alkylene-N ((C ₁ -C ₄ ) -alkyl) ₂ , CO-N ((C ₁ -C ₄ ) -alkyl) ₂ , 1-pyrrolidinyl, 1-piperidinyl, 1-pyrrolidinyl-2-one, 1-piperidinyl-2 -One or 4-morpholinyl;
R ⁸ is H, F, Cl, (C ₁ -C ₅ ) -alkyl or O- (C ₁ -C ₅ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. is substituted or or by 1-5 F, or CN, OH, _{O-phenyl, SO 2 (C 1 -C 3} ) - _{alkyl, CO- (C 1 -C 4)} - alkyl, CO-N ((C ₁ -C ₄ ) -alkyl) ₂ , CO-1-piperidinyl, CO-1-pyrrolidinyl, or CO-4-morpholinyl;
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁶ and R ⁷ together with the two carbon atoms to which they are attached form a 5-6 membered heterocycloalkyl ring, which is selected from nitrogen and oxygen In which the heterocycloalkyl is unsubstituted or monosubstituted by (C ₁ -C ₄ ) -alkyl or oxo (═O) Or R ⁷ and R ⁸ together with the two carbon atoms to which they are attached form a 5-6 membered heterocycloalkyl ring, which is 1 or 2 identical selected from nitrogen and oxygen Or containing different heteroatoms, wherein the heterocycloalkyl is unsubstituted or monosubstituted by (C ₁ -C ₄ ) -alkyl or oxo (═O)]
Residues of;

b) ethylene - phenyl, phenyl or unsubstituted wherein _{F, Cl, CH 3, O} -CH 3, CF 3, O-CF 3, CN, SO 2 CH 3, CO-CH 3, and CO Substituted by 1 or 2 identical or different substituents selected from —N ((CH ₃ ) ₂ ;
c) 2-phenyl-cyclopropyl, phenyl or unsubstituted wherein _{F, Cl, CH 3, O} -CH 3, CF 3, O-CF 3, CN, SO 2 CH 3, CO-CH 3, And CO—N ((CH ₃ ) ₂ ) substituted with one or two identical or different substituents;
d) ethylene - (C ₅ -C ₇₎ cycloalkyl;
Is;
R ² is H, F, Cl, or CH ₃ ;
R ³ is H, F, or O—CH ₃ ;
R ⁴ is piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, which are unsubstituted or (C ₁ -C ₃ ) -alkyl (which is unsubstituted or 1 Monosubstituted by ˜5 F);
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them

［式中、
Ｒ¹¹は、Ｈ、（Ｃ₃−Ｃ₅）−シクロアルキル、（Ｃ₁−Ｃ₄）−アルキレン−ＯＨ又は（Ｃ₁−Ｃ₄）−アルキルであり、それは非置換であるか又は１〜５個のＦによって置換されており；
Ｒ¹²は、Ｈ、又は（Ｃ₁−Ｃ₄）−アルキルであり、
Ｒ¹³は、Ｈ、（Ｃ₁−Ｃ₄）−アルキル、又は（Ｃ₃−Ｃ₅）−シクロアルキルであり；
Ｒ¹⁴は、Ｈ、又は（Ｃ₁−Ｃ₄）−アルキルであるか；又は
Ｒ¹³及びＲ¹⁴は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロ−（Ｃ₃−Ｃ₆）−アルキルであり；そして
Ｒ¹⁵は、Ｈ、ＣＨ₂−ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、ＣＯ−（Ｃ₁−Ｃ₆）−アルキル、ＣＯ−（Ｃ₁−Ｃ₄）−アルキレン−ＯＨ、ＣＯ−（Ｃ₁−Ｃ₄）−アルキレン−Ｏ−ＣＨ₃、ＣＯ−ＣＨ₂−４−モルホリニル、ＣＯ−Ｏ−（Ｃ₁−Ｃ₄）−アルキル、ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、（Ｃ₃−Ｃ₆）−シクロアルキル、又はピリジルであり；
Ｒ¹⁶は、Ｈ、又は（Ｃ₁−Ｃ₄）−アルキルであり；
Ｒ¹⁷は、Ｈ、又はＣＨ₃であり；
Ｒ¹⁸は、Ｈ、又はＣＨ₃であり；
Ｒ¹⁹は、Ｈである］
の残基；
ｂ）窒素原子を介して結合される、２個の窒素原子を含む９〜１１員スピロ−ヘテロシクロアルキル；
を表す〕
の化合物、又はその生理学的に許容しうる塩、又はそれらのすべての生理学的に許容しうる溶媒和物である。 a) Formula Ib

[Where:
R ¹¹ is H, (C ₃ -C ₅ ) -cycloalkyl, (C ₁ -C ₄ ) -alkylene-OH or (C ₁ -C ₄ ) -alkyl, which is unsubstituted or Substituted by 5 F;
R ¹² is H or (C ₁ -C ₄ ) -alkyl;
R ¹³ is H, (C ₁ -C ₄ ) -alkyl, or (C ₃ -C ₅ ) -cycloalkyl;
R ¹⁴ is H or (C ₁ -C ₄ ) -alkyl; or R ¹³ and R ¹⁴ together with the carbon atom carrying them are 1′-spiro-cyclo- (C ₃ -C ₆ ) -alkyl; and R ¹⁵ is H, CH ₂ —CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , CO— (C ₁ -C ₆ ) -alkyl, CO— (C ₁ -C ₄₎ - _{alkylene--OH, CO- (C 1 -C 4} ) - _{alkylene--O-CH 3, CO-CH} 2 -4- _{morpholinyl, CO-O- (C 1 -C} 4) - Alkyl, CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , (C ₃ -C ₆ ) -cycloalkyl, or pyridyl;
R ¹⁶ is H or (C ₁ -C ₄ ) -alkyl;
R ¹⁷ is H or CH ₃ ;
R ¹⁸ is H or CH ₃ ;
R ¹⁹ is H]
Residues of;
b) a 9-11 membered spiro-heterocycloalkyl containing two nitrogen atoms linked via a nitrogen atom;
Represents)
Or a physiologically acceptable salt thereof, or all physiologically acceptable solvates thereof.

［式中、
Ｒ⁶は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₃）−アルキル又はＯ−（Ｃ₁−Ｃ₃）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは非置換であるか又は１〜５個のＦによって置換されており；又はＲ⁶は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、若しくはＯ−ＣＨ₃であり；又はＲ⁶は、Ｈであり；
Ｒ⁷は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₃）−アルキル若しくはＯ−（Ｃ₁−Ｃ₃）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは非置換であるか若しくは１〜５個のＦによって置換されており、又はＣＮ、ＳＯ₂（Ｃ₁−Ｃ₃）−アルキル、Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、１−ピペリジニル、若しくは４−モルホリニルであり；又はＲ⁷は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、ＣＮ、Ｏ−ＣＨ₃、ＳＯ₂ＣＨ₃、Ｎ（ＣＨ₃）₂、１−ピペリジニル、若しくは４−モルホリニルであり；又はＲ⁷は、Ｈであり；
Ｒ⁸は、Ｈ、Ｆ、Ｃｌ、（Ｃ₁−Ｃ₅）−アルキル若しくはＯ−（Ｃ₁−Ｃ₅）−アルキルであり、ここにおいて（Ｃ₁−Ｃ₃）−アルキルは非置換であるか若しくは１〜５個のＦによって置換されており、又はＯＨ、Ｏ−フェニル、ＳＯ₂（Ｃ₁−Ｃ₃）−アルキル、ＣＯ−（Ｃ₁−Ｃ₄）−アルキル、ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂であり；又はＲ⁸は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＨ₂ＣＨ₃、ＣＨ（ＣＨ₃）₂、Ｃ（ＣＨ₃）₃、ＣＦ₃、ＯＨ、Ｏ−ＣＨ₃、Ｏ−Ｃ₂Ｈ₅、Ｏ−ＣＨＦ₂、Ｏ−ＣＦ₃、Ｏ−フェニル、ＳＯ₂ＣＨ₃、ＣＯ−ＣＨ₃、若しくはＣＯ−Ｎ（ＣＨ₃）₂であり；又はＲ⁸は、Ｈであり；
Ｒ⁹は、Ｈ、Ｆ、ＣＨ₃、Ｏ−ＣＨ₃であり；又はＲ⁹は、Ｈであり；
Ｒ¹⁰は、Ｈであり；又は
Ｒ⁷及びＲ⁸は、一緒になって

である］
の残基；
ｂ）エチレン−フェニル、ここにおいてフェニルは、非置換であるか又はＦ、Ｃｌ、ＣＨ₃、Ｏ−ＣＨ₃、ＣＦ₃、Ｏ−ＣＦ₃、ＣＮ、ＳＯ₂ＣＨ₃、ＣＯ−ＣＨ₃、及びＣＯ−Ｎ（（ＣＨ₃）₂から選ばれる１〜２個の同一若しくは異なる置換基によって置換されている；であるか又はＲ¹がフェネチルである、
式Ｉの化合物である。 Another group of embodiments is:
R ¹ is a) Formula Ia

[Where:
R ⁶ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. Or is substituted by 1 to 5 F; or R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ; or R ⁶ is H;
R ⁷ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. It is substituted or or by 1-5 F, or _{CN, SO 2 (C 1 -C} 3) - _{alkyl, N ((C 1 -C 4} ) - alkyl) _2, 1-piperidinyl, or 4- Or R ⁷ is H, F, Cl, CH ₃ , CF ₃ , CN, O—CH ₃ , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-piperidinyl, or 4-morpholinyl. Or R ⁷ is H;
R ⁸ is H, F, Cl, (C ₁ -C ₅ ) -alkyl or O- (C ₁ -C ₅ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. to or is substituted by 1-5 F, or OH, _{O-phenyl, SO 2 (C 1 -C 3} ) - _{alkyl, CO- (C 1 -C 4)} - alkyl, CO-N (( C ₁ -C ₄ ) -alkyl) ₂ ; or R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , OH , O—CH ₃ , O—C ₂ H ₅ , O—CHF ₂ , O—CF ₃ , O-phenyl, SO ₂ CH ₃ , CO—CH ₃ , or CO—N (CH ₃ ) ₂ ; or R ⁸ is H;
R ⁹ is H, F, CH ₃ , O—CH ₃ ; or R ⁹ is H;
R ¹⁰ is H; or R ⁷ and R ⁸ are taken together

Is]
Residues of;
b) Ethylene-phenyl, where phenyl is unsubstituted or F, Cl, CH ₃ , O—CH ₃ , CF ₃ , O—CF ₃ , CN, SO ₂ CH ₃ , CO—CH ₃ , and Is substituted by 1 to 2 identical or different substituents selected from CO—N ((CH ₃ ) ₂ ; or R ¹ is phenethyl.
A compound of formula I.

Another group of embodiments is:
R ² is H, F, CH ₃ or R ² is H, CH ₃ or R ² is H, F, or R ² is H.
A compound of formula I.

Another group of embodiments is:
R ³ is H, O—CH ₃ or R ³ is H,
A compound of formula I.

Another group of embodiments is:
R ⁴ is piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, which are unsubstituted or unsubstituted or substituted by 1 to 5 F (C ₁ -C ₃₎ - alkyl which is monosubstituted by; or R ⁴ is 4-methyl - piperidin-4-yl, and R ⁵ is H,
A compound of formula I.

［式中、
Ｒ¹¹は、Ｈ、ＣＨ₃、（Ｃ₃−Ｃ₄）−アルキル、又は（Ｃ₃−Ｃ₄）−シクロアルキルであり；又はＲ¹¹は、ＣＨ₃、若しくは（ＣＨ₂）₃−ＣＨ₃であり；又はＲ¹¹は、Ｈであり；
Ｒ¹²は、Ｈであり；
Ｒ¹³は、Ｈ、（Ｃ₁−Ｃ₄）−アルキル、又は（Ｃ₃−Ｃ₄）−シクロアルキルであり；又はＲ¹³は、Ｈ、ＣＨ₃、若しくはＣＨ₂−ＣＨ（ＣＨ₃）₂であり；又はＲ¹³は、Ｈ若しくはＣＨ₃であり；又はＲ¹³はＨであり；
Ｒ¹⁴は、Ｈ、又はＣＨ₃であり；又はＲ¹⁴はＨであり；又は
Ｒ¹³及びＲ¹⁴は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロ−（Ｃ₃−Ｃ₆）−アルキル；好ましくは１'−スピロ−シクロペンチルであり；そして
Ｒ¹⁵は、Ｈ、ＣＨ₂−ＣＯ−Ｎ（（Ｃ₁−Ｃ₄）−アルキル）₂、ＣＯ−（Ｃ₁−Ｃ₆）−アルキル、ＣＯ−（Ｃ₁−Ｃ₄）−アルキレン−ＯＨ、ＣＯ−（Ｃ₁−Ｃ₄）−アルキレン−Ｏ−ＣＨ₃、ＣＯ−ＣＨ₂−４−モルホリニル、ＣＯ−Ｏ−（Ｃ₁−Ｃ₄）−アルキル、ＣＯ−Ｎ（−（Ｃ₁−Ｃ₄）−アルキル）₂−（Ｃ₃−Ｃ₆）−シクロアルキル、又はピリジルであり；又はＲ¹⁵は、Ｈ、ＣＨ₂−ＣＯ−Ｎ（ＣＨ₃）₂、ＣＯ−ＣＨ（Ｃ₂Ｈ₅）₂、ＣＯ−Ｃ（ＣＨ₃）２−ＯＨ、ＣＯ−Ｃ（ＣＨ₃）₂−ＣＨ₂−ＯＨ、ＣＯ−（ＣＨ₂）₂−Ｏ−ＣＨ₃、ＣＯ−ＣＨ₂−４−モルホリニル、ＣＯ−ＯＣＨ₃、ＣＯ−Ｎ（ＣＨ₃）₂、シクロプロピル、若しくは３−ピリジルであり；又はＲ¹⁵は、Ｈであり；
Ｒ¹⁶は、Ｈ、又は（Ｃ₁−Ｃ₄）−アルキルであり；又はＲ¹⁶は、Ｈ、若しくはＣＨ₃であり；又はＲ¹⁶は、Ｈであり；
Ｒ¹⁷は、Ｈであり；
Ｒ¹⁸は、Ｈであり；
Ｒ¹⁹は、Ｈである］
の残基；
ｂ）窒素原子を介して結合された、２個の窒素原子を含む９〜１１員スピロ−ヘテロシクロアルキルを表わすか、又はＲ¹が（２,７−ジアザ−スピロ［４．４］ノナ−２−イル）である、
式Ｉの化合物である。 Another group of embodiments is:
R ⁴ and R ⁵ together with the nitrogen carrying them a) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , (C ₃ -C ₄ ) -alkyl, or (C ₃ -C ₄ ) -cycloalkyl; or R ¹¹ is CH ₃ or (CH ₂ ) ₃ —CH _3. Or R ¹¹ is H;
R ¹² is H;
R ¹³ is H, (C ₁ -C ₄ ) -alkyl, or (C ₃ -C ₄ ) -cycloalkyl; or R ¹³ is H, CH ₃ , or CH ₂ -CH (CH ₃ ) _2. Or R ¹³ is H or CH ₃ ; or R ¹³ is H;
R ¹⁴ is H or CH ₃ ; or R ¹⁴ is H; or R ¹³ and R ¹⁴ together with the carbon atom carrying them are 1′-spiro-cyclo- (C ₃ -C ₆ ) -alkyl; preferably 1′-spiro-cyclopentyl; and R ¹⁵ is H, CH ₂ —CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , CO— (C ₁ -C ₆₎ - _{alkyl, CO- (C 1 -C 4)} - _{alkylene--OH, CO- (C 1 -C 4} ) - _{alkylene--O-CH 3, CO-CH} 2 -4- morpholinyl, CO-O - (C ₁ -C ₄₎ - alkyl, CO-N (- (C 1 -C 4) - _{alkyl) 2 - (C 3 -C 6} ) - cycloalkyl, or pyridyl; or R ¹⁵ is, H _{, CH 2 -CO-N (CH} 3) 2, CO-CH (C 2 H 5) 2, CO-C (CH 3) 2-OH, CO-C (CH 3 _{2 -CH 2 -OH, CO- (CH} 2) 2 -O-CH 3, CO-CH 2 -4- _{morpholinyl, CO-OCH 3, CO-} N (CH 3) 2, cyclopropyl, or 3-pyridyl Or R ¹⁵ is H;
R ¹⁶ is H or (C ₁ -C ₄ ) -alkyl; or R ¹⁶ is H or CH ₃ ; or R ¹⁶ is H;
R ¹⁷ is H;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) represents a 9-11 membered spiro-heterocycloalkyl containing two nitrogen atoms bonded via a nitrogen atom, or R ¹ is (2,7-diaza-spiro [4.4] non- 2-yl),
A compound of formula I.

［式中
Ｒ⁶は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、又はＯ−ＣＨ₃であり；
Ｒ⁷は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＨ₂−ＳＯ₂−ＣＨ₃、ＣＦ₃、ＣＮ、ＣＨ₂−Ｎ（ＣＨ₃）₂、ＣＯ−Ｎ（ＣＨ₃）₂、Ｏ−ＣＨ₃、ＳＯ₂ＣＨ₃、Ｎ（ＣＨ₃）₂、１−ピロリジニル、１−ピペリジニル、４−モルホリニル、又は１−ピロリジニル−２−オンであり；
Ｒ⁸は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＨ₂ＣＨ₃、ＣＨ（ＣＨ₃）₂、Ｃ（ＣＨ₃）₃、ＣＦ₃、ＣＮ、ＯＨ、Ｏ−ＣＨ₃、Ｏ−Ｃ₂Ｈ₅、Ｏ−ＣＨＦ₂、Ｏ−ＣＦ₃、Ｏ−フェニル、ＳＯ₂ＣＨ₃、ＣＯ−ＣＨ₃、ＣＯ−Ｎ（ＣＨ₃）₂、又はＣＯ−１−ピペリジニルであり；
Ｒ⁹は、Ｈ、Ｃｌ、Ｆ、ＣＨ₃、又はＯ−ＣＨ₃であり；
Ｒ¹⁰は、Ｈであり；又は
Ｒ⁶及びＲ⁷は、一緒になって

であり；又は
Ｒ⁷及びＲ⁸は、一緒になって

である］
の残基； Another group of embodiments is:
R ¹ is
a) Formula Ia

[Wherein R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CH ₂ —SO ₂ —CH ₃ , CF ₃ , CN, CH ₂ —N (CH ₃ ) ₂ , CO—N (CH ₃ ) ₂ , O—CH _3. , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, or 1-pyrrolidinyl-2-one;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , CN, OH, O—CH ₃ , O—C ₂ H _{5. , O-CHF 2, O-} CF 3, O- _{phenyl, SO 2 CH 3, CO-} CH 3, CO-N (CH 3) 2, or CO-1-be-piperidinyl;
R ⁹ is H, Cl, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁶ and R ⁷ are taken together

Or R ⁷ and R ⁸ are taken together

Is]
Residues of;

b) phenethyl;
c) 2-phenylcyclopropyl;
d) 2-cyclohexylethyl;
Or R ² is H, F, Cl, or CH ₃ ; or R ³ is H, F, or O—CH ₃ ; or R ⁴ is 4-methyl-piperidine-4- Ill;
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them

［式中、
Ｒ¹¹は、Ｈ、ＣＨ₃、Ｃ₂Ｈ₅、（ＣＨ₂）₃−ＣＨ₃、又はＣＨ₂−ＯＨであり；
Ｒ¹²は、Ｈ、又はＣＨ₃であり；
Ｒ¹³は、Ｈ、ＣＨ₃、又はＣＨ₂−ＣＨ（ＣＨ₃）₂であり；
Ｒ¹⁴は、Ｈ、又はＣＨ₃であり；又は
Ｒ¹³及びＲ¹⁴は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロペンチルであり；そして
Ｒ¹⁵は、Ｈ、ＣＨ₂−ＣＯ−Ｎ（ＣＨ₃）₂、ＣＯ−ＣＨ（Ｃ₂Ｈ₅）₂、ＣＯ−Ｃ（ＣＨ₃）₂−ＯＨ、ＣＯ−Ｃ（ＣＨ₃）₂−ＣＨ₂−ＯＨ、ＣＯ−（ＣＨ₂）₂−Ｏ−ＣＨ₃、ＣＯ−ＣＨ₂−４−モルホリニル、ＣＯ−ＯＣＨ₃、ＣＯ−Ｎ（ＣＨ₃）₂、シクロプロピル、又はＣＯ−３−ピリジルであり；
Ｒ¹⁶は、Ｈ、又はＣＨ₃であり；
Ｒ¹⁷は、Ｈであり；
Ｒ¹⁸は、Ｈであり；
Ｒ¹⁹は、Ｈである］
の残基；
ｂ）（２,７−ジアザ−スピロ［４．４］ノナ−２−イル）（＝Ｂｓｐ６０）
を表す、
式Ｉの化合物である。 a) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , C ₂ H ₅ , (CH ₂ ) ₃ —CH ₃ , or CH ₂ —OH;
R ¹² is H or CH ₃ ;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ together with the carbon atom carrying them is 1′-spiro-cyclopentyl; and R ¹⁵ is H, CH _{2 -CO-N (CH 3)} 2, CO-CH (C 2 H 5) 2, CO-C (CH 3) 2 -OH, CO-C (CH 3) 2 -CH 2 -OH, CO- ( _{CH 2) 2 -O-CH 3} , CO-CH 2 -4- _{morpholinyl, CO-OCH 3, CO-} N (CH 3) 2, cyclopropyl, or CO-3- pyridyl;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) (2,7-diaza-spiro [4.4] non-2-yl) (= Bsp60)
Represents
A compound of formula I.

［式中、
Ｒ⁶は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、又はＯ−ＣＨ₃であり；
Ｒ⁷は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、ＣＮ、Ｏ−ＣＨ₃、ＳＯ₂ＣＨ₃、Ｎ（ＣＨ₃）₂、１−ピペリジニル、又は４−モルホリニルであり；
Ｒ⁸は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＨ₂ＣＨ₃、ＣＨ（ＣＨ₃）₂、Ｃ（ＣＨ₃）₃、ＣＦ₃、ＯＨ、Ｏ−ＣＨ₃、Ｏ−Ｃ₂Ｈ₅、Ｏ−ＣＨＦ₂、Ｏ−ＣＦ₃、Ｏ−フェニル、ＳＯ₂ＣＨ₃、ＣＯ−ＣＨ₃、又はＣＯ−Ｎ（ＣＨ₃）₂であり；
Ｒ⁹は、Ｈ、Ｆ、ＣＨ₃、又はＯ−ＣＨ₃であり；
Ｒ¹⁰は、Ｈであり；又は
Ｒ⁷及びＲ⁸は、一緒になって

である］
の残基； Another group of embodiments is:
R ¹ is
a) Formula Ia

[Where:
R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CF ₃ , CN, O—CH ₃ , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-piperidinyl, or 4-morpholinyl;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , OH, O—CH ₃ , O—C ₂ H ₅ , O _{-CHF 2, O-CF 3,} O- _{phenyl, SO 2 CH 3, CO-} CH 3, or CO-N (CH _{3) 2;}
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁷ and R ⁸ are taken together

Is]
Residues of;

b) phenethyl;
Is;
R ² is H or CH ₃ ;
R ³ is H or O—CH ₃ ;
R ⁴ is 4-methyl-piperidin-4-yl;
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them

［式中、
Ｒ¹¹は、Ｈ、ＣＨ₃、又は（ＣＨ₂）₃−ＣＨ₃であり；
Ｒ¹²は、Ｈであり；
Ｒ¹³は、Ｈ、ＣＨ₃、又はＣＨ₂−ＣＨ（ＣＨ₃）₂であり；
Ｒ¹⁴は、Ｈ、又はＣＨ₃であり；又は
Ｒ¹³及びＲ¹⁴は、それらを担持している炭素原子と共に１'−スピロ−シクロペンチルであり；そして
Ｒ¹⁵は、Ｈ、ＣＨ₂−ＣＯ−Ｎ（ＣＨ₃）₂、ＣＯ−ＣＨ（Ｃ₂Ｈ₅）₂、ＣＯ−Ｃ（ＣＨ₃）₂−ＯＨ、ＣＯ−Ｃ（ＣＨ₃）₂−ＣＨ₂−ＯＨ、ＣＯ−（ＣＨ₂）₂−Ｏ−ＣＨ₃、ＣＯ−ＣＨ₂−４−モルホリニル、ＣＯ−ＯＣＨ₃、ＣＯ−Ｎ（ＣＨ₃）₂、シクロプロピル、又は３−ピリジルであり；
Ｒ¹⁶は、Ｈ、又はＣＨ₃であり；
Ｒ¹⁷は、Ｈであり；
Ｒ¹¹及びＲ¹²は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロペンチルであり；
Ｒ¹⁸は、Ｈであり；
Ｒ¹⁹は、Ｈである］
の残基；
ｂ）（２,７−ジアザ−スピロ［４．４］ノナ−２−イル）
を表す、
式Ｉの化合物である。 a) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , or (CH ₂ ) ₃ —CH ₃ ;
R ¹² is H;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ are 1′-spiro-cyclopentyl together with the carbon atom carrying them; and R ¹⁵ is H, CH ₂ —CO—. _{N (CH 3) 2, CO} -CH (C 2 H 5) 2, CO-C (CH 3) 2 -OH, CO-C (CH 3) 2 -CH 2 -OH, CO- (CH 2) 2 _{-O-CH 3, CO-CH} 2 -4- _{morpholinyl, CO-OCH 3, CO-} N (CH 3) 2, cyclopropyl, or 3-pyridyl;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹¹ and R ¹² together with the carbon atom carrying them are 1′-spiro-cyclopentyl;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) (2,7-diaza-spiro [4.4] non-2-yl)
Represents
A compound of formula I.

［式中、
Ｒ⁶は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、又はＯ−ＣＨ₃であり；
Ｒ⁷は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＦ₃、ＣＮ、Ｏ−ＣＨ₃、ＳＯ₂ＣＨ₃、Ｎ（ＣＨ₃）₂、１−ピペリジニル、又は４−モルホリニルであり；
Ｒ⁸は、Ｈ、Ｆ、Ｃｌ、ＣＨ₃、ＣＨ₂ＣＨ₃、ＣＨ（ＣＨ₃）₂、Ｃ（ＣＨ₃）₃、ＣＦ₃、ＯＨ、Ｏ−ＣＨ₃、Ｏ−Ｃ₂Ｈ₅、Ｏ−ＣＨＦ₂、Ｏ−ＣＦ₃、Ｏ−フェニル、ＳＯ₂ＣＨ₃、ＣＯ−ＣＨ₃、又はＣＯ−Ｎ（ＣＨ₃）₂であり；
Ｒ⁹は、Ｈ、Ｆ、ＣＨ₃、又はＯ−ＣＨ₃であり；
Ｒ¹⁰は、Ｈである）
の残基であり； Another group of embodiments is:
R ¹ is of formula Ia

[Where:
R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CF ₃ , CN, O—CH ₃ , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-piperidinyl, or 4-morpholinyl;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , OH, O—CH ₃ , O—C ₂ H ₅ , O _{-CHF 2, O-CF 3,} O- _{phenyl, SO 2 CH 3, CO-} CH 3, or CO-N (CH _{3) 2;}
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H)
Residues of;

［式中、
Ｒ¹¹は、Ｈ、ＣＨ₃、又は（ＣＨ₂）₃−ＣＨ₃であり；
Ｒ¹²は、Ｈであり；
Ｒ¹³は、Ｈ、ＣＨ₃、又はＣＨ₂−ＣＨ（ＣＨ₃）₂であり；
Ｒ¹⁴は、Ｈ、又はＣＨ₃であり；又は
Ｒ¹³及びＲ¹⁴は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロペンチルであり；そして
Ｒ¹⁵は、Ｈであり；
Ｒ¹⁶は、Ｈ、又はＣＨ₃であり；
Ｒ¹⁷は、Ｈであり；
Ｒ¹¹及びＲ¹²は、それらを担持している炭素原子と一緒になって１'−スピロ−シクロペンチルであり；
Ｒ¹⁸は、Ｈであり；
Ｒ¹⁹は、Ｈである］
の残基を表す、
式Ｉの化合物である。 R ² is H;
R ³ is H;
R ⁴ and R ⁵ together with the nitrogen carrying them have the formula Ib

[Where:
R ¹¹ is H, CH ₃ , or (CH ₂ ) ₃ —CH ₃ ;
R ¹² is H;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ together with the carbon atom carrying them are 1′-spiro-cyclopentyl; and R ¹⁵ is H ;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹¹ and R ¹² together with the carbon atom carrying them are 1′-spiro-cyclopentyl;
R ¹⁸ is H;
R ¹⁹ is H]
Represents a residue of
A compound of formula I.

Another group of embodiments is:
1
[3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 2
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 3
(2,2-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -methanone 4
(3,3-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Methanone 5
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -3-isobutyl-piperazine-1 -Yl) -methanone 6
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl-piperazine-1 -Yl) -methanone 7
[6- (4-Hydroxy-2-methyl-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 8
((2S, 5R) -2,5-dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 9
[6- (4-Hydroxy-3-methoxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 10
((S) -2-Ethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -Methanone

11
[6- (2-Fluoro-4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl -Piperazin-1-yl) -methanone 12
[6- (3-Fluoro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 13
[6- (2-Chloro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 14
[3- [2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- Il-methanone 15
{6- (4-hydroxy-phenyl) -3- [2- (3-methanesulfonylmethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine-
1-yl-methanone 16
((R) -2-hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine- 4-yl] -methanone 17
[6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 18
[6- (4-Hydroxy-phenyl) -3-((1R, 2R) -2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl -Methanone 19
(6- (4-Hydroxy-phenyl) -3- {2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1H-pyrazolo [3,4-b] pyridin-4-yl)- Piperazin-1-yl-methanone 20
1- (3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -phenyl ) -Pyrrolidin-2-one

21
[6- (4-Hydroxy-phenyl) -3-((E) -2-p-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 22
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 23
[3-[(E) -2- (3-Dimethylamino-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone 24
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 25
3-{(E) -2- [6- (4-Hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- Benzonitrile 26
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-piperidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 27
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-morpholin-4-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 28
{6- (4-Hydroxy-phenyl) -3- [2- (3-pyrrolidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 29
4- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- Benzonitrile 30
[3- [2- (3-Chloro-5-piperidin-1-yl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone

31
3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -N, N- Dimethyl-benzamide 32
5- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 33
[3- [2- (2,3-Dihydro-1H-indol-7-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 34
3- {2- [4- (2,2-Dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl } -N, N-dimethyl-benzamide 35
6- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 36
[3- (2-Cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 37
[3-[(E) -2- (4-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 38
[6- (4-Hydroxy-phenyl) -3-((E) -2-m-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 39
[3-[(E) -2- (2,4-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 40
[3-[(E) -2- (3,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone

41
[3-[(E) -2- (4-Difluoromethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone 42
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 43
[3-[(E) -2- (2,4-Dimethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 44
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-phenoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 45
[3-[(E) -2- (3,4-dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 46
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 47
[3-[(E) -2- (4-Hydroxy-3-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 48
[3-[(E) -2- (3-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 49
[3-[(E) -2- (2,4-Dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 50
[3-[(E) -2- (2,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone

51
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-isopropyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 52
[3-[(E) -2- (2-Chloro-4-fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 53
[3-[(E) -2- (4-Ethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 54
[3-[(E) -2- (4-tert-butyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 55
[3-[(E) -2- (3-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 56
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 57
1- (4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl]- Vinyl} -phenyl) -ethanone 58
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 59
[3-[(E) -2- (3,4-Difluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 60
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (2-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone

61
[3-[(E) -2- (4-Fluoro-2-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 62
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3,4,5-trimethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 63
[3-[(E) -2- (2-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 64
[3-[(E) -2- (2,3-Dihydro-benzofuran-5-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-4 -Yl] -piperazin-1-yl-methanone 65
[3-((E) -2-Benzo [1,3] dioxol-5-yl-vinyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 66
4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- N, N-dimethyl-benzamide 67
[3-[(E) -2- (4-Ethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 68
{6- (4-hydroxy-phenyl) -3-[(E) -2- (2-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 69
[6- (4-Hydroxy-phenyl) -3-((E) -2-o-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 70
[3- [2- (3,5-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- Il-methanone

71
[3-[(E) -2- (3-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 72
[3-[(E) -2- (2-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 73
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methoxy-3-methyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 74
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide 75
6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (4-methyl-piperidin-4-yl) -amide 76
((S) -2-Butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -Methanone 77
((R) -2-butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -methanone 78
(2,7-diaza-spiro [4.4] non-2-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 79
(6,9-diaza-spiro [4.5] dec-9-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 80
2-ethyl-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Il} -butan-1-one

81
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- 2-morpholin-4-ylethanone 82
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid methyl ester 83
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-[4- (pyridine-3-carbonyl) -piperazine -1-yl] -methanone 84
2- {4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- N, N-dimethyl-acetamide 85
(4-Cyclopropyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -Methanone 86
2-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2-methyl-propan-1-one 87
3-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2,2-dimethyl-propan-1-one 88
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- It is a compound selected from the group consisting of 3-methoxy-propan-1-one.

Another group of embodiments is:
[6- (4-Hydroxyphenyl) -3- (2-phenylethenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] (4-methyl-1-piperazinyl) -methanone (4, 7-diaza-spiro [2.5] oct-4-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine- 4-yl] -methanone is a compound selected from the group consisting of.

Another group of embodiments is:
1
[3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 2
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 4
(3,3-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Methanone 5
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -3-isobutyl-piperazine-1 -Yl) -methanone 6
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl-piperazine-1 -Yl) -methanone 7
[6- (4-Hydroxy-2-methyl-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 8
((2S, 5R) -2,5-dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 9
[6- (4-Hydroxy-3-methoxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 17
[6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 21
[6- (4-Hydroxy-phenyl) -3-((E) -2-p-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 22
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 23
[3-[(E) -2- (3-Dimethylamino-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone

24
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 25
3-{(E) -2- [6- (4-Hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- Benzonitrile

26
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-piperidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 27
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-morpholin-4-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 37
[3-[(E) -2- (4-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 38
[6- (4-Hydroxy-phenyl) -3-((E) -2-m-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 39
[3-[(E) -2- (2,4-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 40
[3-[(E) -2- (3,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 41
[3-[(E) -2- (4-Difluoromethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone 42
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 43
[3-[(E) -2- (2,4-Dimethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone

44
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-phenoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 45
[3-[(E) -2- (3,4-dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 46
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 47
[3-[(E) -2- (4-Hydroxy-3-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 48
[3-[(E) -2- (3-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 49
[3-[(E) -2- (2,4-Dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 50
[3-[(E) -2- (2,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone

51
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-isopropyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 52
[3-[(E) -2- (2-Chloro-4-fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 53
[3-[(E) -2- (4-Ethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone

54
[3-[(E) -2- (4-tert-butyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 55
[3-[(E) -2- (3-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 56
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 57
1- (4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl]- Vinyl} -phenyl) -ethanone 58
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 59
[3-[(E) -2- (3,4-Difluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 60
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (2-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 61
[3-[(E) -2- (4-Fluoro-2-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 62
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3,4,5-trimethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 63
[3-[(E) -2- (2-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone

64
[3-[(E) -2- (2,3-Dihydro-benzofuran-5-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-4 -Yl] -piperazin-1-yl-methanone 65
[3-((E) -2-Benzo [1,3] dioxol-5-yl-vinyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 66
4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- N, N-dimethyl-benzamide 67
[3-[(E) -2- (4-Ethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 68
{6- (4-hydroxy-phenyl) -3-[(E) -2- (2-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 69
[6- (4-Hydroxy-phenyl) -3-((E) -2-o-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanone 71
[3-[(E) -2- (3-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 72
[3-[(E) -2- (2-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 73
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methoxy-3-methyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 74
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide 75
6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (4-methyl-piperidin-4-yl) -amide

76
((S) -2-Butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -Methanone 77
((R) -2-butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -methanone 78
(2,7-diaza-spiro [4.4] non-2-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 79
(6,9-diaza-spiro [4.5] dec-9-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 80
2-ethyl-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Il} -butan-1-one 81
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- 2-morpholin-4-yl-ethanone 82
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid methyl ester 83
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-[4- (pyridine-3-carbonyl) -piperazine -1-yl] -methanone 84
2- {4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- N, N-dimethyl-acetamide 85
(4-Cyclopropyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -Methanone 86
2-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2-methyl-propan-1-one 87
3-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2,2-dimethyl-propan-1-one 88
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- It is a compound selected from the group consisting of 3-methoxy-propan-1-one.

Another group of embodiments is:
3
(2,2-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -methanone 10
((S) -2-Ethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -methanone 11
[6- (2-Fluoro-4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl -Piperazin-1-yl) -methanone 12
[6- (3-Fluoro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 13
[6- (2-Chloro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 14
[3- [2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- Il-methanone 15
{6- (4-Hydroxy-phenyl) -3- [2- (3-methanesulfonylmethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine-1- Il-methanone 16
((R) -2-hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine- 4-yl] -methanone 18
[6- (4-Hydroxy-phenyl) -3-((1R, 2R) -2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl -Methanone 19
(6- (4-Hydroxy-phenyl) -3- {2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1H-pyrazolo [3,4-b] pyridin-4-yl)- Piperazin-1-yl-methanone 20
1- (3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -phenyl ) -Pyrrolidin-2-one

28
{6- (4-Hydroxy-phenyl) -3- [2- (3-pyrrolidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 29
4- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- Benzonitrile 30
[3- [2- (3-Chloro-5-piperidin-1-yl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 31
3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -N, N- Dimethyl-benzamide 32
5- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 33
[3- [2- (2,3-Dihydro-1H-indol-7-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 34
3- {2- [4- (2,2-Dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl } -N, N-dimethyl-benzamide 35
6- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 36
[3- (2-Cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 70
[3- [2- (3,5-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- It is a compound selected from the series consisting of yl-methanone.

Components such as groups, substituents, heterocycle members, numbers or other features such as alkyl groups, groups such as R ¹ , R ² , R ³ etc. that can occur several times in compounds of formula I are , All having the meanings described independently of one another, and in each case can be the same or different from one another. For example, the alkyl groups in the dialkylamino group can be the same or different.

As used herein, the terms “including” and “comprising” are used in an open, non-limiting sense. As used herein, terms such as “(C ₁ -C ₈ )” or “(C ₅ -C ₈ )” are moieties having 1 to 8 or 5 to 8 carbon atoms, respectively. That is. In terms such as “(C ₀ -C ₆ ) -alkyl” or “(C ₀ -C ₆ ) -alkylene”, “C ₀ -alkyl” or “(C ₀ ) -alkylene” refers to a bond. In the case of yes or unsubstituted “(C ₀ ) -alkyl”, it is hydrogen.

  The term “alkyl” as used herein refers to a monovalent saturated hydrocarbon group. The term “alkenyl” as used herein refers to a monovalent hydrocarbon group containing at least one carbon-carbon double bond, wherein each double bond is in the E or Z configuration. Can have. The term “alkynyl” as used herein refers to a monovalent hydrocarbon group containing at least one carbon-carbon triple bond. Alkyl, alkenyl, and alkynyl groups can be linear, i.e., linear, or branched. This is also the case when they are part of other groups such as alkyloxy groups (= alkoxy groups, O-alkyl groups), alkyloxycarbonyl groups or alkyl-substituted amino groups, or they are substituted Sometimes also applies. Depending on the respective definition, the number of carbon atoms in the alkyl group is 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5 or 6, or 1, There can be two, three or four, or one, two or three. Examples of alkyl are propyl including methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, butyl including isobutyl and tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl. Including pentyl, n-hexyl, 3,3-dimethylbutyl and isohexyl, hexyl, heptyl and octyl. Double and triple bonds in alkenyl and alkynyl groups can be present at any position. In one embodiment of the invention, the alkenyl group contains one double bond and the alkynyl group contains one triple bond. In one embodiment of the invention, the alkenyl or alkynyl group contains at least 3 carbon atoms and is attached to the remainder of the molecule through a carbon atom that is not part of a double or triple bond. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (= allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hexa-3 -Enyl, hexa-4-enyl, prop-2-ynyl (= propargyl), but-2-ynyl, but-3-ynyl, hexa-4-ynyl or hexa-5-ynyl. Substituted alkyl, alkenyl and alkynyl groups can be substituted at any position where the individual compound is sufficiently stable and appropriate for the desired purpose such as use as a drug substance. . The requirements that a particular group and a compound of formula I are sufficiently stable and suitable for the desired purpose, such as use as a drug substance, generally apply for the definition of all groups in a compound of formula I.

Independently of each other and independently of all other substituents, the alkyl group, divalent alkyl group, alkenyl group, alkynyl group, cycloalkyl group and heterocycloalkyl group can be in any position 1 Optionally substituted by one or more fluorine substituents, ie said groups are unsubstituted by fluorine substituents or by fluorine substituents, for example 1, 2, 3, 4, 5, 6 7, 8, 9, 10, 11, 12 or 13 or 1, 2, 3, 4, 5, 6, 7, 8 or 9 or 1, 2, 3, 4, 5, 6 Alternatively, it can be substituted by 7, or 1, 2, 3, 4, or 5, or 1, 2, or 3, or 1 or 2 fluorine substituents. Examples of such fluorine-substituted groups are trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3. , 3-pentafluoro-propyl, 4,4,4-trifluoro-butyl, _{heptafluoroisopropyl, -CHF -, - CF 2 -} , - CF 2 -, CH 2 -, - CH 2 -CF 2 -, - CF 2 _{-CF 2 -, - CF (CH} 3) -, - C (CF 3) 2 -, - C (CH 3) 2 -CF 2 -, - CF 2 -C (CH 3) 2 -, 1- fluorocyclopropyl Propyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl, 3,3,4,4,5,5-hexafluorocyclohexyl. Examples of alkyloxy groups in which the alkyl moiety is fluorine-substituted are trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.

The term “alkanediyl” or “alkylene” as used herein refers to a divalent saturated hydrocarbon group. The term “alkenediyl” as used herein refers to a divalent hydrocarbon group containing at least one carbon-carbon double bond, wherein each double bond has an E or Z configuration. be able to. The term “alkynediyl” as used herein refers to a divalent hydrocarbon group containing at least one carbon-carbon triple bond. Where applicable, the above description for alkyl, alkenyl and alkynyl groups applies correspondingly to alkanediyl, alkenediyl and alkynediyl groups and therefore they can be linear and branched as well. Examples of divalent alkyl groups, -CH ₂ - (= _{methylene), - CH 2 -CH 2 -} , - CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH 2 - , —CH (CH ₃ ) —, —C (CH ₃ ) ₂ —, —CH (CH ₃ ) —CH ₂ —, —CH ₂ —CH (CH ₃ ) —, —C (CH ₃ ) ₂ —CH _{2 -, - CH 2 -C (CH} 3) 2 - a. As used herein, the term “cycloalkyl”, unless stated otherwise, refers to a monovalent group of saturated or partially saturated hydrocarbon ring systems, which may be monocyclic, bicyclic or It can be tricyclic, ie it can contain 1, 2 or 3 rings. A bicyclic or tricyclic ring system can be a fused ring system in which two adjacent rings share two adjacent carbon atoms. A bicyclic or tricyclic ring system can be a spiro ring structure or a di-spiro ring structure in which two adjacent rings share one carbon atom. A tricyclic ring system can also be a bicyclic spiro ring structure fused with another ring, where the latter ring and the ring in the spiro ring structure to which it is attached are 2 Is meant to share two adjacent carbon atoms; where the latter ring can be an aromatic saturated or partially saturated ring. Bicyclic or tricyclic systems can also be non-fused or bridged ring systems in which two adjacent rings share two non-adjacent carbon atoms. Bicyclic or tricyclic rings can be linked by all ring atoms except spiro- or bridgehead atoms.

  In monocyclic cycloalkyl groups, the number of ring carbon atoms can be 3, 4, 5, 6, 7 or 8. In one embodiment of the invention, the number of ring carbon atoms in the cycloalkyl group is 3, 4, 5 or 6 independent of the number of ring carbon atoms in all other cycloalkyl groups. 3, 4 or 5 in another embodiment, 3 or 4 in another embodiment, 3 in another embodiment, 5, 6 or 7 in another embodiment, 5 or 6 in another embodiment, another 6 or 7 in this embodiment, 5 in another embodiment, 6 in another embodiment. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

から誘導されるが、それらに制限されるわけではない。 In a bicyclic cycloalkyl group, the number of ring carbon atoms can be 6, 7, 8, 9, 10, 11 or 12. In one embodiment of the invention, the number of ring carbon atoms in the bicyclic cycloalkyl group can be 7, 8, 9, 10 or 11 and in another embodiment 8, 9 or 10. . In the tricyclic cycloalkyl group, the number of ring carbon atoms can be 7, 8, 9, 10, 11, 12, 13, 14 or 15. In one embodiment of the invention, the number of ring carbon atoms in the tricyclic cycloalkyl group can be 10, 11 or 12. Typical bicyclic or tricyclic fused-ring cycloalkyls are the following ring systems: bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptane, bisicle [5.1.0] octane. , Bicyclo [3.2.0] heptane, bicyclo [4.2.0] octane, octahydro-pentalene, octahydro-indene, decahydro-azulene, decahydronaphthalene, decahydro-benzocycloheptene, dodecahydro-heptalene, 1, 2,3,3a, 4,6a-hexahydro-pentalene, 1,2,3,4-tetrahydro-pentalene, 2,3,3a, 4,5,7a-hexahydro-1H-indene, 2,3,3a, 4,7,7a-hexahydro-1H-indene, 3a, 4,5,6,7,7a-hexahydro-1H-indene, 4,5,6,7-tetrahydro-1H-indene, indane, 1,2, 3, 4, 4a , 5,6,8a-octahydro-naphthalene, 1,2,3,4,4a, 5,8,8a-octahydro-naphthalene, 1,2,4a, 5,8,8a-hexahydro-naphthalene, 1,4 , 4a, 5,8,8a-hexahydro-naphthalene, 1,2,3,4-tetrahydro-naphthalene, 2,3,4,4a, 5,6,9,9a-octahydro-1H-benzocycloheptene, 2,3,4,4a, 5,9a-hexahydro-1H-benzocycloheptene, 4,4a, 5,6,7,8,9,9a-octahydro-1H-benzocycloheptene, 6,7, 8,9-tetrahydro-5H-benzocycloheptene, 1,2,3,4,5,5a, 6,7,8,10a-decahydro-heptalene, dodecahydro-as-indacene and 2,3,3a, 4 , 9,9a-Hexahydro-1H-cyclopenta [b] naphthalene:

Is derived from, but is not limited to them.

から誘導されるが、それらに制限されるわけではない。 Typical bicyclic or tricyclic spirocyclic cycloalkyls have the following ring systems: spiro [2.4] heptane, spiro [2.5] octane, spiro [2.6] nonane, spiro [3.3. ] Heptane, Spiro [3.4] octane, Spiro [3.5] nonane, Spiro [3.6] decane, Spiro [4.4] nonane, Spiro [4.5] decane, Spiro [4.6] undecane Spiro [5.5] Undecane, Spiro [5.6] Dodecane, Spiro [6.6] Tridecane, Dipiro [2.2.2] Dodecane, Dipiro [2.3.2] Undecane, Dipiro [2.1.4.2] Undecane and Spiro [5.5] Undec-2-ene:

Is derived from, but is not limited to them.

から誘導されるが、それらに制限されるわけではない。 A typical cycloalkyl in which the ring is fused to one ring of a bicyclic spiro system is the following ring system:

Is derived from, but is not limited to them.

から誘導されるが、それらに制限されるわけではない。 A typical non-fused or bridged bicyclic or tricyclic ring cycloalkyl includes the following ring systems: bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3. 2.1] Octane, bicyclo [3.2.2] nonane and adamantane

Is derived from, but is not limited to them.

As used herein, the term “heterocycloalkyl” or “heterocyclyl”, unless stated otherwise, is used when the spiro atom is always a carbon atom and the bridgehead atom is either a carbon or nitrogen atom, and If the cycloalkyl system is stable and suitable as a subgroup for the desired purpose of the compound of formula I, such as use as a drug substance, then 1, 2, 3 or 4 carbon atoms are replaced by nitrogen, oxygen or sulfur atoms. It is a substituted cycloalkyl as defined above. Depending on the definition of each heterocyclic group, in one embodiment of the invention, the number of ring heteroatoms that can be present in the heterocyclic group is the number of ring heteroatoms in all other heterocyclic groups. 1, 2, 3 or 4 independently of the number of atoms, 1, 2 or 3 in another embodiment, 1 or 2 in another embodiment, 2 in another embodiment, another embodiment In which the ring heteroatoms can be the same or different. A heterocycloalkyl group can be attached by any ring carbon atom or saturated ring nitrogen atom except a spiro or bridgehead atom. The ring sulfur atom in the heterocycloalkyl group can carry 0, 1 or 2 oxo groups, and if it does not carry any oxo groups, it is a non-oxidized sulfur atom S, or 1 When carrying an oxo group, it is an S (O) group (= sulfoxide group, S-oxide group), or when carrying two oxo groups, an S (O) ₂ group (= sulfone group, S, S -Dioxide group).

から誘導されるが、それらに制限されるわけではない。 A typical monocyclic heterocycloalkyl has the following ring systems: aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, 4,5-dihydrothiazole, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 1,2,3,6-tetrahydropyridine, azepan, 2,3,4,7-tetrahydro-1H-azepine, 2,7-dihydro-1H-azepine, 1 1,4-diazepan, 1,4-oxazepan, 1,4-thiazepan and 1,4-dioxepane:

Is derived from, but is not limited to them.

から誘導される。 In one embodiment, the monocyclic heterocycloalkyl is azetidine, pyrrolidine, piperidine, piperazine, morpholine or 1,4-diazepane:

Derived from.

から誘導されるが、それらに制限されるわけではない。 A typical bicyclic fused-ring heterocycloalkyl includes the following ring systems: 3-aza-bicyclo [3.1.0] hexane, 2-aza-bicyclo [4.1.0] heptane, 2-oxa- 5-aza-bicyclo [5.1.0] octane, 3-aza-bicyclo [3.2.0] heptane, 2-aza-bicyclo [4.2.0] octane, octahydro-pyrrolo [3,4- c] pyrrole, octahydro-pyrrolo [3,4-b] pyrrole, octahydro-pyrrolo [3,4-b] pyridine, octahydro-thieno [3,4-b] pyrazine, octahydro-furo [3,4-b] Pyridine, octahydro-cyclopenta [1,4] oxazine, octahydro-pyrrolo [1,2-a] pyrimidine, octahydro-pyrrolo [1,2-a] pyrazine, octahydro-cyclopenta [e] [1,4] oxazepine, de Cahydro-quinoxaline, decahydro- [1,6] naphthyridine, octahydro-benzo [1,4] oxazine, octahydro-benzo [1,4] thiazine, octahydro-pyrido [1,2-a] pyrazine, octahydro-pyrano [3 , 2-b] pyridine, decahydro-1-oxa-9-aza-benzocycloheptene, 1,2,3,3a, 6,6a-hexahydro-cyclopenta [b] pyrrole, 5,6-dihydro-4H- Cyclopenta [b] thiophene, 2,3,4,4a, 7,7a-hexahydro-1H- [2] pyridine, 2,4a, 5,6,7,7a-hexahydro-1H- [1] pyridine, 2, 3,3a, 4,7,7a-hexahydro-1H-indole, 1,2,3,4-tetrahydroquinoxaline, 4,5,6,7-tetrahydrobenzofuran, benzo [1,3] dioxo 3,3,4,4a, 7,8,8a-hexahydro-2H-benzo [1,4] oxazine, 1,2,3,4,4a, 5,8, 8a-octahydro-quinoxaline, 4a, 5, 8,8a-Tetrahydro-2H-thiopyrano [3,2-b] pyridine and 1,2,3,4-tetrahydro- [1,5] naphthyridine:

Is derived from, but is not limited to them.

から誘導される。 In one embodiment, the bicyclic fused ring heterocycloalkyl is 3-aza-bicyclo [3.1.0] hexane, octahydro-pyrrolo [3,4-c] pyrrole, octahydro-pyrrolo [3,4-b. ] Pyrrole, octahydro-thieno [3,4-b] pyrazine, octahydro-pyrrolo [1,2-a] pyrazine, decahydro-quinoxaline, octahydro-pyrido [1,2-a] pyrazine or decahydro- [1,6] Naphthyridine:

Derived from.

から誘導されるが、それらに制限されるわけではない。 Typical bicyclic or tricyclic spirocyclic heterocycloalkyl are the following ring systems: 4-aza-spiro [2.4] heptane, 5-aza-spiro [3.4] octane, 1-aza- Spiro [4.4] nonane, 7-oxa-1-aza-spiro [4.4] nonane, 7-thia-1-aza-spiro [4.4] nonane, 4-aza-spiro [2.5] Octane, 5-aza-spiro [2.5] octane, 6-aza-spiro [2.5] octane, 5-aza-spiro [3.5] nonane, 6-aza-spiro [3.5] nonane, 7-aza-spiro [3.5] nonane, 4,7-diaza-spiro [2.5] octane, 5,8-diaza-spiro [3.5] nonane, 6,9-diaza-spiro [4. 5] decane, 1,4-diaza-spiro [5.5] undecane, 2-oxa-6,9-diaza-spiro [4.5] decane, 2 Oxa-6-aza-spiro [4.5] decane, 2,7-diaza-spiro [3.5] nonane, 3,9-diaza-spiro [5.5] undecane, 1-oxa-4,9- Diaza-spiro [5.5] undecane, 1-oxa-4,8-diaza-spiro [5.5] undecane, 1-thia-4,9-diaza-spiro [5.5] undecane, 1-thia- 4,8-diaza-spiro [5.5] undecane, 4,8-diaza-spiro [2.6] nonane, 5,8-diaza-spiro [3.6] decane, 2-aza-spiro [5. 5] undec-7-ene, 6,9-diaza-spiro [4.6] undecane, 4-azadispiro [2.1.4.2] undecane, 4,10-diaza-dispiro [2.2.3. 2] Undecane and 4,11-diaza-dispiro [2.2.2.4.2] dodecane:

Is derived from, but is not limited to them.

から誘導される。 In one embodiment, the bicyclic or tricyclic spirocyclic heterocycloalkyl is 4,7-diaza-spiro [2.5] octane, 6-aza-spiro [3.5] nonane, 5,8-diaza-spiro. [3.5] Nonane, 6,9-diaza-spiro [4.5] decane, 2,7-diaza-spiro [
3.5] nonane, 2,7-diaza-spiro [4.4] nonane, 2,7-diaza-spiro [4.5] decane, 2,8-diaza-spiro [4.5] decane, 6- Oxa-2,9-diaza-spiro [4.5] decane, 3,9-diaza-spiro [5.5] undecane, 1-oxa-4,9-diaza-spiro [5.5] undecane or 1- Oxa-4,8-diaza-spiro [5.5] undecane:

Derived from.

から誘導されるが、それらに制限されるわけではない。 A typical heterocycloalkyl fused to one ring of a bicyclic spiro system is the following ring system: octahydro-spiro [cyclopentane-1,2 ′ (3′H) -quinoxaline], 1 ′, 4′-dihydro-spiro [cyclopentane-1,2 ′ (3′H) -quinoxaline], 1 ′, 2 ′, 4,5-tetrahydro-spiro [furan-3 (2H), 3 ′-[3H] Indole], 1,3-dihydro-spiro [indene-2,2′-piperazine], 2,3-dihydro-spiro [1H-indene-1,4′-piperidine] and 1,2-dihydro-5-spiro [3H-indole-3,4'-piperidine]:

Is derived from, but is not limited to them.

から誘導される。 In one embodiment, the heterocycloalkyl fused to one ring of the bicyclic spiro system is 3-dihydro-spiro [indene-2,2'-piperazine], 2,3-dihydro-spiro [1H- Indene-1,4'-piperidine] or 1,2-dihydro-5-spiro [3H-indole-3,4'-piperidine]:

Derived from.

から誘導されるが、それらに制限されるわけではない。 A typical non-fused or bridged bicyclic or tricyclic ring heterocycloalkyl includes the following ring systems: 2-aza-bicyclo [2.2.1] heptane, 1-aza-bicyclo [2.2. .2] Octane, 8-aza-bicyclo [3.2.1] octane, 3-aza-bicyclo [3.2.1] octane, 9-aza-bicyclo [3.3.1] nonane, 2,5 Diaza-bicyclo [2.2.1] heptane, 2,5-diaza-bicyclo [2.2.2] octane, 3,8-diaza-bicyclo [3.2.1] octane and 3,7-diaza -Bicyclo [3.3.1] nonane:

Is derived from, but is not limited to them.

  The term “aryl” as used herein refers to a group derived by removing one hydrogen from an aromatic hydrocarbon such as phenyl or naphthyl (= naphthalenyl). As used herein, the term “heteroaryl” or “hetaryl” refers to an aromatic monocyclic or bicyclic ring in which 1, 2, 3, 4 or 5 carbon atoms are replaced by heteroatoms. A group derived from the system. The ring heteroatom is generally selected from N, O and S, where N includes a hydrogen atom or a ring nitrogen atom not bearing a substituent, as well as a ring nitrogen atom bearing a substituent. . If the heterocyclic ring system is stable and suitable as a subgroup for the desired purpose of the compound of formula I, such as use as a drug substance, the ring heteroatom can be in any position. A heteroaryl group is a 5- or 6-membered monocyclic ring or an 8-, 9- or 10-membered bicyclic ring, in another embodiment a 5- or 6-membered monocyclic ring or a 9-membered or 10-membered bicyclic ring Derived from a formula ring, in another embodiment a 5-membered or 6-membered monocyclic ring.

から誘導されるが、それらに制限されるわけではない。 Typical heteroaryl systems include the following ring systems: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole (= [1,3] oxazole), isoxazole (= [1,2] oxazole), thiazole (= [ 1,3] thiazole), isothiazole (= [1,2] thiazole), [1,2,3] triazole, [1,2,4] triazole, [1,2,4] oxadiazole, [1 , 3,4] oxadiazole, [1,2,4] thiadiazole, [1,3,4] thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, [1,2,3] triazine, [1,2 , 4] triazine, [1,3,5] triazine, indole, isoindole, benzofuran, benzothiophene [1,3] benzoxazole, [1,3] benzothiazole, Zone imidazole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, various naphthyridine, for example [1,8] naphthyridine, various thienopyridine, e.g. thieno [2,3-b] pyridine and purine:

Is derived from, but is not limited to them.

Groups such as phenyl, naphthyl (= naphthalenyl) and residues of aromatic heterocycles optionally substituted by one or more substituents can be unsubstituted or, for example, in any position 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1 substituted by the same or different substituents it can. In a five-membered ring such as a pyrrole, imidazole, indole or benzimidazole ring, an aromatic nitrogen heterocycle carrying a hydrogen atom on the ring nitrogen atom in the parent ring system is, for example, on the ring carbon atom and / or Can be substituted on any ring nitrogen atom. In one embodiment of the invention, such substituents on the ring nitrogen atom are selected from (C ₁ -C ₄ ) -alkyl groups, ie such ring nitrogen atoms in aromatic heterocycles are hydrogen Carrying atoms or (C ₁ -C ₄ ) -alkyl substituents. When referring to an aromatic heterocycle capable of carrying a hydrogen atom or substituent and ring nitrogen atoms in all other heterocycles, such ring nitrogen atoms carry either hydrogen atoms or substituents. Or carry no hydrogen atoms or substituents. Ring nitrogen atoms carrying hydrogen atoms or substituents are found, for example, in pyrrole, imidazole, indole or benzimidazole, and in nitrogen-containing aromatic five-membered rings such as are present in non-aromatic rings including saturated rings. A ring nitrogen atom that does not carry a hydrogen atom or substituent unless present in a positively charged form, including a hydrogen atom or any additional ring nitrogen atom in addition to a ring nitrogen atom carrying a substituent, is, for example, thiazole Found in aromatic rings, as in imidazole, pyridine or benzimidazole, and in non-aromatic rings in which they are part of a double bond, and they are linked through them It is found as a ring nitrogen atom. Suitable ring nitrogen atoms in aromatic heterocycles in compounds of formula I, such as ring nitrogen atoms in the pyridine ring or quinoline ring, are generally as N-oxides or quaternary salts, such as, for example, N-methyl salts. N- (C ₁ -C ₄ ) -alkyl salts may be present, wherein in one embodiment of the invention the counter anion in such a quaternary salt is physiologically acceptable. A physiologically acceptable anion derived from a salt forming acid.

  In monosubstituted phenyl groups, the substituent can be in the 2-position, the 3-position or the 4-position. In a disubstituted phenyl group, the substituent can be in the 2,3 position, 2,4 position, 2,5 position, 2,6 position, 3,4 position or 3,5 position. In the trisubstituted phenyl group, the substituent is 2,3,4,2,3,4,2,3,4,2,4,5,2,4,6 or 3,4 , Can be in fifth place. Naphthyl can be 1-naphthyl (= naphthalen-1-yl) or 2-naphthyl (= naphthalen-2-yl). In monosubstituted 1-naphthyl groups, the substituent can be in the 2, 3, 4, 5, 6, 7 or 8 position. In monosubstituted 2-naphthyl groups, the substituent can be in the 1, 3, 4, 5, 6, 7 or 8 position. In a disubstituted naphthyl group, the substituent can likewise be at any position on both the ring to which the naphthyl group is attached and / or another ring.

  Heterocyclic systems are known in the art, and ring heteroatoms are in any position provided that they are stable and suitable as a subgroup for the desired purpose of the compound of formula I, such as use as a drug substance. Can do. In one embodiment of the invention, two ring oxygen atoms cannot be present at adjacent ring positions of any heterocycle, and in another embodiment two ring heteroatoms selected from oxygen and sulfur Cannot be present in adjacent ring positions of any heterocycle. The substituents can be in any position in the heterocyclic group. For example, in the pyridin-2-yl group, the substituent can be in the 3-position and / or 4-position and / or 5-position and / or 6-position, and in the pyridin-3-yl group the substituent is in the 2-position And / or 4-position and / or 5-position and / or 6-position, and in the pyridin-4-yl group, the substituent is 2-position and / or 3-position and / or 5-position and / or 6-position Can be in

  Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention, all halogens in the compounds of formula I are independently of one another from fluorine, chlorine and bromine, in another embodiment a halogen selected from fluorine and chlorine, and In an embodiment, it is fluorine.

When an oxo group is attached to a carbon atom, it replaces two hydrogen atoms on the parent carbon atom. Thus, when a CH ₂ group in a chain or ring is replaced by oxo, ie by a double bond oxygen atom, it becomes a CO group. It is clear that an oxo group cannot be present as a substituent on a carbon atom in an aromatic ring such as in a phenyl group. When a ring sulfur atom in a heterocyclic group can carry 1 or 2 oxo groups, if it does not carry any oxo groups, it is a non-oxidized sulfur atom S, or 1 oxo group In the case of carrying two oxo groups, it is an S (O) ₂ group (= sulfone group, S, S). -Dioxide group).

  The present invention includes all stereoisomeric forms of the compounds of formula I and their salts and solvates. For each chiral center, independently of all other chiral centers, the compound of formula I may be in the S or substantially S configuration, or in the R or substantially R configuration, or in any proportion of S isomerism. Can exist as a mixture of isomers and R isomers. The present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, eg mixtures of all ratios of enantiomers and / or diastereomers. Thus, the compounds according to the invention which can exist as enantiomers are mixtures of two enantiomers in enantiomerically pure form as both levorotatory and dextrorotatory enantiomers and in all ratios including racemates Can exist in the form of In the case of E / Z isomerism, or cis-trans isomerism, for example in a ring such as a double bond or a cycloalkyl ring, the present invention relates to E and Z forms, or cis and trans forms, and these in all ratios. Including a mixture of forms. In one embodiment of the invention, the compounds that can exist in two or more stereoisomeric forms are the pure or substantially pure respective stereoisomers. The preparation of the respective stereoisomers can be carried out, for example, by separation of a mixture of isomers by conventional methods, for example by chromatography or crystallization, by using stereochemically uniform starting materials in the synthesis, or by stereoselection. Can be carried out by chemical synthesis. In some cases, derivatization can be performed prior to separation of the stereoisomers. Separation of the mixture of stereoisomers can be carried out at the stage of the compound of formula I or at the stage of starting materials or intermediates during synthesis. The present invention also includes all tautomeric forms of the compounds of formula I and salts and solvates thereof.

  Also, if the compounds of formula I contain one or more acidic and / or basic groups, ie bases, the present invention provides their corresponding physiologically or toxicologically acceptable salts, ie Non-toxic salts, especially their pharmaceutically acceptable salts.

Furthermore, the present invention includes all solvates of compounds of formula I, for example hydrates or alcohol adducts such as (C ₁ -C ₄ ) -alkanols, active metabolites of compounds of formula I, and also in vitro. Includes prodrugs and derivatives of compounds of formula I, such as esters or amides of carboxylic acid groups, which do not necessarily exhibit pharmacological activity, but are converted in vivo to pharmacologically active compounds.

  The compounds of the present invention, PKC inhibitors, are other pharmacologically active compounds, such as all antihypertensive and nephroprotective agents described in Rote Liste 2011, antidiabetics described in Rote Liste 2011, Chapter 12. Drugs; Rote Liste 2011, all weight loss / appetite suppressants listed in Chapter 1; Rote Liste 2011, all diuretics listed in Chapter 36; Rote Liste 2011, all listed in Chapter 58 Can be widely combined with other lipid-lowering drugs. They can be combined with the inventive compounds of formula I especially for synergistic improvement of action. A combination of active ingredients can be administered by separately administering the active ingredients to the patient or in the form of a combination in which a plurality of active ingredients are present in a pharmaceutical formulation. When administering the active ingredients by administering the active ingredients separately, this can be done simultaneously or sequentially. Most of the active ingredients listed below are described in the USAP USP Dictionary and International Drug Names, US Pharmacopeia, Rockville 2006.

Antidiabetics include insulin and insulin derivatives such as Luntus ^(R) (see www.lantus.com) or HMR 1964 or Levemir ^(R) (insulin detemir), Humalog ^(R) (insulin lispro), insulin deglu dec, insulin aspart was pegylated as described in WO2009152128 (polyethylene glycosidized) (pegylated) insulin ^{lispro, Humulin (R), VIAject TM} , SuliXen (R), according to VIAject ^TM or WO2005005477 (Novo Nordisk), fast acting insulin (see US 6,221,633), inhaled insulin, eg Exubera ^(R) , Nasulin ^™ , or oral insulin, eg IN-105 (Nobex) or Oral-lyn ^™ (Generex Biotechnology), or Technosphere ^(R) insulin (MannKind) or Cobalamin ^TM oral insulin or ORMD-0801 or W Insulin or an insulin precursor as described in O2007128815, WO2007128817, WO2008034881, WO2008049711, WO2008145721, WO2009041171, WO2009060071, WO2009030099, or insulin that can be administered transdermally; and further includes Their insulin derivatives linked to albumin by means of a bifunctional linker, for example as described in WO2009211884;
GLP-1 derivatives and GLP-1 agonists such as exenatide or specific formulations thereof such as those described in WO2008061355, WO2009080024, WO2009080032, liraglutide, taspoglutide (R-1583), albiglutide, lixisenatide or Novo Nordisk A / S 98/08871, WO2005027978, WO2006037811, WO2006037810, those described by Zeland in WO01 / 04156 or by Beaufour-Ipsen in WO00 / 34331, pramlintide acetate (Symlin), inhaled GLP-1 ( MannKind MKC-253) AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: Ex Sendin-4 (an exendin-4 analog covalently linked to recombinant human albumin), a biotinylated exendin (WO2009107900), a specific formulation of exendin-4 as described in US200038879, CVX-73, CVX -98 and CVx-96 (a GLP-1 analog covalently linked to a monoclonal antibody having a binding site specific for the GLP-1 peptide), CNTO-736 (a GLP-1 analog bound to a domain containing the Fc portion of the antibody) ), PGC-GLP-1 (GLP-1 bound to nanocarriers), eg agonists or modulators as described in D. Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943, WO2006124529, WO2007124461, WO2008062457, WO200808 274, WO2008101017, WO2008081418, WO2008112939, WO2008112941, WO2008113601, WO2008116294, WO2008116648, WO2008119238, WO2008148839, US2008299096, WO2008152403, WO2009030738, WO2009030771, WO2009030774, WO2009035540, WO2009058734, WO2009111700, WO2009125424, WO2009129696, those described in WO2009149148, peptides, For example, obinepitide (TM-30338), an orally active GLP-1 analog (eg NN9924 from Novo Nordisk ), For example, amylin receptor agonists as described in WO2007104789, WO2009034119, analogs of human GLP-1 as described in WO2007120899, WO20080221515, WO2008056726, e.g. Chimeric PEGylated peptides containing both GLP-1 and glucagon residues, glycosylated GLP-1 derivatives as described in WO2009153960, and orally active hypoglycemic components.

  Antidiabetic agents also include gastrin analogs such as TT-223.

  Antidiabetic agents further include, for example, poly or monoclonal antibodies against interleukin 1 beta (IL-1β), such as XOMA052.

  Antidiabetic agents further include peptides capable of binding to the human islet peptide (HIP) receptor as described, for example, in WO2009049222.

  Antidiabetic agents further include agonists of glucose-dependent insulinotropic polypeptide (GIP) receptors as described, for example, in WO200006121860.

  Antidiabetic agents also include glucose-dependent insulinotropic polypeptides (GIPs) and also similar compounds as described, for example, in WO2008021560, WO20110016935, WO2010016936, WO2010016938, WO2010016940, WO2010016944.

  Further included are analogs and derivatives of human pancreatic polypeptides as described, for example, in WO2009007714.

More antidiabetic agents, encapsulated insulin-producing porcine cells (encapsulated insulin-producing porcine cells) , include, for example DiabeCell ^(R) is.

  Antidiabetic drugs include, for example, analogs and derivatives of fibroblast growth factor 21 (FGF-21) as described in WO2009149171 and WO2020000614.

As an orally active blood sugar lowering component, preferably sulfonylurea,
Biguanidine,
Meglitinide,
Oxadiazolinedione,
Thiazolidinedione,
PPAR and RXR modulators,
Glucosidase inhibitors,
Inhibitors of glycogen phosphorylase,
Glucagon receptor antagonist,
Glucokinase activator,
An inhibitor of fructose 1,6-bisphosphatase,
A modulator of glucose transporter 4 (GLUT4),
Inhibitor of glutamine: fructose-6-phosphate amide transferase (GFAT),
A GLP-1 agonist,
Potassium channel openers such as pinacidil, cromakalim, diazoxide, diazoxide choline salt, or RD Carr et al., Diabetes 52, 2003, 2513.2518, JB Hansen et al., Current Medicinal Chemistry 11, 2004, 1595-1615, TM Tagmose et al., J Med. Chem. 47, 2004, 3202-3211 or as described in MJ Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653, or WO 97/26265 and by Novo Nordisk A / S Those described in WO 99/03861,
Active ingredients that act on ATP-sensitive potassium channels of beta cells,
Inhibitors of dipeptidyl peptidase IV (DPP-IV),
Insulin sensitizers,
Inhibitors of liver enzymes involved in stimulation of gluconeogenesis and / or glycogenolysis,
Modulators of glucose uptake, glucose transport and glucose reabsorption,
Modulator of sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2),
Inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1),
An inhibitor of protein tyrosine phosphatase-1B (PTP-1B),
A nicotinic acid receptor agonist,
Inhibitors of hormone sensitivity or endothelial lipase,
Inhibitors of acetyl-CoA carboxylase (ACC1 and / or ACC2) or inhibitors of GSK-3beta are included.

Also included are compounds that improve lipid metabolism, such as active antihyperlipidemic component and active antilipidemic component,
HMG-CoA reductase inhibitor,
Farnesoid X receptor (FXR) modulator,
Fibrates,
Cholesterol reabsorption inhibitor,
CETP inhibitor,
Bile acid absorption inhibitors,
MTP inhibitor,
Estrogen receptor gamma agonist (ERR _γ agonist),
A sigma-1 receptor antagonist,
Antagonists of somatostatin 5 receptor (SST5 receptor);
Compounds that reduce food intake and compounds that increase heat production.

  In one embodiment of the invention, the compound of the formula I is administered in combination with insulin.

  In another embodiment of the invention, the compound of the formula I is administered in combination with an insulin sensitizer (eg PN-2034 or ISI-1171315).

  In one embodiment, the compounds of formula I are active ingredients that act in the ATP-sensitive potassium channel of beta cells, such as sulfonylureas, such as tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride, or their formulations as described, for example, in EP2103302 Administered in combination.

  In one embodiment, the compound of formula I is administered in combination with a tablet comprising both rapidly released glimepiride and a longer-term released metformin (see, for example, US2007264331, WO2008050987, WO2008062733). ing).

  In one embodiment, the compound of the formula I is administered in combination with a biguanide, for example metformin or one of its salts.

  In a further embodiment, the compounds of the formula I are administered in combination with guanidines such as, for example, benzylguanidine or one of its salts, or those guanidines described in WO20090838795.

In another embodiment, the compound of formula I is
It is administered in combination with a meglitinide such as repaglinide, nateglinide or mitiglinide.

  In a further embodiment, the compound of the formula I is administered with a combination of mitiglinide and a glitazone, such as pioglitazone hydrochloride.

  In a further embodiment, the compound of the formula I is administered with a combination of mitiglinide and an alpha-glucosidase inhibitor.

  In a further embodiment, the compound of the formula I is administered in combination with an antidiabetic compound as described in WO2007095462 WO2007101060, WO2007105650.

  In a further embodiment, the compound of the formula I is administered in combination with an antihyperglycemic compound as described in WO2007137008, WO2008020607.

  In one embodiment, the compound of formula I is a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097 by Dr. Reddy's Research Foundation, in particular 5-[[4-[( It is administered in combination with 3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione.

  In one embodiment of the invention, the compound of the formula I is a PPAR gamma agonist, such as rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-011 (riboglitazone), DRL-17564, DRF-2593. (Baragritazone), INT-131, T-2384, or WO2005086904, WO2007060992, WO2007100027, WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969, WO20080802383, WO200808089, WO2008068489, WO2008080689 WO20088093639, WO2008096969, WO2008096820, WO2008096829, US2008194617, WO20080809944, WO2008108602, WO2008109334, WO200008110062, WO2008267331, WO200812632, WO2008137105, WO2009902461, WO2009908601, WO2009908601, WO2009904681 The

In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of pioglitazone hydrochloride and metformin hydrochloride, Compact ^™ .

In one embodiment of the invention, the compound of the formula I is administered in combination with Tandemact ^™ , a solid combination of pioglitazone and glimepiride.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of pioglitazone hydrochloride and an angiotensin II agonist such as TAK-536.

  In one embodiment of the invention, the compound of the formula I is a PPAR alpha agonist or a mixed PPAR alpha / PPAR delta agonist, such as GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518744, CP-900691, BMS-668753, BMS-711939, or WO20040207207, WO2002096894, WO20050997076, WO2007055671, WO2007084748, WO20070895767, WO2007082951, WO20071032007196, WO2007103684 6043, WO2008006044, WO200801470, WO2008035359, WO2008087365, WO2008087366, WO2008087367, WO2008017982, JP20099023975, WO2009092581, WO2009019248, WO20090819, The

  In one embodiment of the invention, the compound of the formula I is a mixed PPAR alpha / gamma agonist, such as nabeglitazar, aleglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, AVE 0897, CKD-501 (Robeglitazone sulfate), MBX-213, KY-201, BMS-759509, or WO 00/64888, WO 00/64876, WO 03/020269, WO2004024726, WO20070999553, US20000728541, WO2007088541 WO20070885136, WO2007141423, WO2008016175, WO20088053311, WO2008109697, WO20 8109700, WO2008108735, WO2009026657, WO2009026658, WO2009149819, WO2009149820 or J.P.Berger like, TRENDS in Pharmacological Sciences 28 (5), 244-251, is administered in combination with those described in 2005.

  In one embodiment of the invention, the compound of the formula I is a PPAR delta agonist such as GW-501516, or WO2008071311, WO2008084962, US200008178661, WO2009016650, US200137671, WO2009080223, WO2009149819, WO2009149820, WO20100003 It is administered in combination with those described in 3.

  In one embodiment of the invention, the compounds of the formula I are described in pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as GFT-505, indeglitazar, or WO2008035959, WO2009072581. Administered in combination with

  In one embodiment, the compound of the formula I is administered in combination with metaglidacene or MBX-2044 or other partial PPAR gamma agonist / antagonist.

  In one embodiment, the compound of the formula I is administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose, or for example those described in WO2007114532, WO2007140230, US2007287744, US2008103201, WO2008065796, WO2008082017, US2009076129.

  In one embodiment, the compound of formula I is an inhibitor of glycogen phosphorylase, such as PSN-357 or FR-258900, or , In combination with those described in WO2009045831, WO2009127723.

  In another embodiment, the compound of formula I comprises an inhibitor of the interaction between liver glycogen phosphorylase and protein PPP1R3 (GL subunit of glycogen-related protein phosphatase 1 (PP1)), for example as described in WO2009030715 Administered in combination.

  In one embodiment, the compound of the formula I is a glucagon receptor antagonist such as A-770077 or NNC-25-2504, or WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120283, WO200713857, It is administered in combination with those described in WO2008098244, WO2009057784, WO2009055862, WO2009058734, WO2009152020, WO2009120530, WO2009140342, WO2010019828.

  In a further embodiment, the compound of the formula I is administered in combination with an antisense compound that inhibits the production of glucagon receptor, for example ISIS-325568.

  In one embodiment, the compound of formula I is an activator of glucokinase, such as LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or such as WO2004072031, WO20040772066, WO2005080360, WO2005048011, WO2006016194, WO2006058923, WO212512549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO200 041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847, WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103, WO2007125105, US2007281942, WO2008005914, WO2008005964, WO2008043701, WO2008044777, WO2008047821, US2008096877, WO2008050117, WO2008050101, WO2008059625, S2008146625, WO2008078674, WO2008079787, WO2008084043, WO2008084044, WO2008084872, WO2008089892, WO2008091770, WO2008075073, WO2008084043, WO2008084044, WO2008084872, WO2008084873, WO2008089892, WO2008091770, JP2008189659, WO2008104994, WO2008111473, WO2008116107, WO2008118718, WO2008120754, US2008280875, WO2008136428, WO2008136444, WO2008149382, WO20000814 563, WO2008156174, WO2008156757, US2009030046, WO2009018065, WO2009023718, WO2009039944, WO2009042435, WO2009046784, WO2009046802, WO2009047798, WO2009063821, WO2009081782, WO2009082152, WO2009083553, WO2009091014, US2009181981, WO2009092432, WO2009099080, WO2009106203, WO2009106209, WO2009109270, WO2009125873, WO2009127544, WO2009127546, WO2009128481, WO20 9133687, WO2009140624, WO2010013161, WO2010015849, is administered in combination with those described in WO2010018800.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of gluconeogenesis, for example as described in FR-225654, WO2008053446.

  In one embodiment, the compound of formula I is an inhibitor of fructose 1,6-bisphosphatase (FBPase), such as MB-07729, CS-917 (MB-06322) or MB-07803, or WO2006023515, WO2006104030, WO2007014619, It is administered in combination with those described in WO2007137962, WO2008019309, WO2008037628, WO200901012039, EP2058308, WO2009068467, WO2009068468.

  In one embodiment, the compound of formula I is a modulator of glucose transporter 4 (GLUT4), such as KST-48 (D.-O. Lee et al: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004). )) In combination.

  In one embodiment, the compound of the formula I is administered in combination with an inhibitor of glutamine: fructose-6-phosphate amide transferase (GFAT) as described, for example, in WO2004101528.

  In one embodiment, the compound of formula I is an inhibitor of peptidase IV (DPP-IV) dipeptidyl, such as vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptin phosphate, saxagliptin (BMS-477118), GSK. -823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200 (melogliptin), GW-825964X, KRP-104, DP-893, ABT-341, ABT -279 or another salt thereof, S-40010, S-40755, PF-00734200, BI-1356, PHX-1149, DSP-7238, alogliptin benzoate, linagliptin, melogliptin, carmeg Ripuchin or WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828, WO2005058901, WO2005012312, WO2005 / 012308, WO2006039325, WO2006058064, WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117, WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826, WO2006078676, WO2006073167, WO2006068163 , WO2006088565, WO2006090915, W 2006104356, WO2006127530, WO2006111261, US2006890898, US2006803357, US2006303661, WO2007015767 (LY-2463665), WO2007024993, WO2007029086, WO2007063928, WO2007070434, WO2007071738, WO2007071576, WO2007077508, WO2007087231, WO2007097931, WO2007099385, WO2007100374, WO2007112347, WO2007112669, WO2007113226, WO2007113634, WO2007115821 , WO2007116092, US20072599 0, EP1852108, US2007270492, WO2007126745, WO2007136603, WO2007142253, WO2007148185, WO2008017670, US2008051452, WO2008027273, WO2008028662, WO2008029217, JP2008031064, JP2008063256, WO2008033851, WO2008040974, WO2008040995, WO2008060488, WO2008064107, WO2008066070, WO2008077597, JP2008156318, WO2008087560, WO2008089636, WO2008093960, WO2008096841, WO2008101 953, WO2008118848, WO2008119005, WO2008119208, WO2008120813, WO2008121506, WO2008130151, WO2008131149, WO2009003681, WO2009014676, WO2009025784, WO2009027276, WO2009037719, WO2009068531, WO2009070314, WO2009065298, WO2009082134, WO2009082881, WO2009084497, WO2009093269, WO2009099171, WO2009099172, WO2009111239, WO2009113423, WO2009116067, US2009247532, WO20 0000469, is administered in combination with those compounds described in WO2010015664.

In one embodiment, the compound of the formula I is administered in combination with Janumet ^™ , a solid combination of sitagliptin phosphate and metformin hydrochloride.

In one embodiment, the compound of the formula I is administered in combination with Eucreas ^(R) , a solid combination of vildagliptin and metformin hydrochloride.

  In a further embodiment, the compound of the formula I is administered in combination with a solid combination of alogliptin benzoate and pioglitazone.

  In one embodiment, the compound of the formula I is administered in combination with a solid combination of a salt of sitagliptin and metformin hydrochloride.

  In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor and an omega-3 fatty acid or omega-3 fatty acid ester, for example as described in WO2007128801.

  In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor and metformin hydrochloride, as described, for example, in WO200921945.

  In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor and a GPR-119 agonist, as described, for example, in WO2009233992.

  In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor and miglitol, as described, for example, in WO200939362.

  In one embodiment, the compound of the formula I is administered in combination with a solid combination of a salt of sitagliptin and metformin hydrochloride.

  In one embodiment, the compound of the formula I is administered in combination with a solid combination of alloliptin benzoate and pioglitazone hydrochloride.

  In one embodiment, the compound of the formula I is administered in combination with substances that enhance insulin secretion, such as those described in KCP-265 (WO20030997064), or WO2007026761, WO2008045484, US2008194617, WO2009109259, WO2009109341.

  In one embodiment, the compound of the formula I is administered in combination with an agonist of the glucose-dependent insulinotropic receptor (GDIR), such as APD-668.

  In one embodiment of the invention, the compound of the formula I is administered in combination with an ATP citrate lyase inhibitor such as SB-204990.

  In one embodiment, the compound of formula I is a modulator of sodium-dependent glucose transporters 1 and / or 2 (SGLT1, SGLT2), such as KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL. -5083, SGL-5085, SGL-5094, ISI-388626, sergliflozin, dapagliflozin or remogliflozin etabonate, canagliflozin, or eg WO2004007517, WO200452903, WO200452902, PCT / EP2005 / 005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, W 2006062224, WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895, WO2007080170, WO2007093610, WO2007126117, WO2007128480, WO2007129668, US2007275907, WO2007136116, WO2007143316, WO2007147478, WO2008001864, WO2008002824, WO2008013277, WO2008013280, WO2008013321, WO2008013322, WO2008016132, WO2008020011, JP20080311 61, WO2008034859, WO2008042688, WO2008044762, WO2008046497, WO2008049923, WO2008055870, WO2008055940, WO2008069327, WO2008070609, WO2008071288, WO2008072726, WO2008083200, WO2008090209, WO2008090210, WO2008101586, WO2008101939, WO2008116179, WO2008116195, US2008242596, US2008287529, WO2009026537, WO2009049731, WO2009076550, WO2009084531, WO20090965503, WO200 100936, WO2009121939, WO2009124638, WO2009128421, WO2009135673, WO2010009197, WO2010018435, in WO2010018438 or A. L. Handlon in Expert Opin. Ther. Patents (2005) 15 (11), it is administered in combination with those described by 1531-1540.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of an SGLT inhibitor and a DPP-IV inhibitor as described in WO20099091082.

  In one embodiment, the compound of the formula I is administered in combination with a glucose transport stimulator as described, for example, in WO200836392, WO200836393.

  In one embodiment, the compound of formula I is an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1), such as BVT-2733, JNJ-25918646, INCB-13739, INCB-20817, DIO-92. ((-)-Ketoconazole) or, for example, WO200190090-94, WO200343999, WO2004112778, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO210012784, WO2003065983, WO2003104208, WO200311410, 20040 WO2004037251, WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877, WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329, WO2006066109, WO200 6074244, WO2006078006, WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508, WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584, WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768, WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150, WO2007092435, WO2007089683, O2007101270, WO2007105753, WO2007107470, WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935, WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254, WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763, WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898, WO2007135427, WO2007139992, WO2007714 394, WO2007145834, WO2007145835, WO2007146761, WO2008000950, WO2008000951, WO2008003611, WO2008005910, WO2008006702, WO2008006703, WO2008011453, WO2008012532, WO2008024497, WO2008024892, WO2008032164, WO2008034032, WO2008043544, WO2008044656, WO2008046758, WO2008052638, WO2008053194, WO2008071169, WO2008074384, WO2008076336, WO2008076862, WO2008807725, WO20 08087654, WO2008088540, WO2008099145, WO2008101885, WO2008101886, WO2008101907, WO2008101914, WO2008106128, WO2008110196, WO2008119017, WO2008120655, WO2008127924, WO2008130951, WO2008134221, WO2008142859, WO2008142986, WO2008157752, WO2009001817, WO2009010416, WO2009017664, WO2009020140, WO2009023180, WO2009023181, WO2009023664, WO2009026422, WO20099038064 WO2009045753, WO2009056881, WO2009059666, WO2009061498, WO2009063061, WO2009070497, WO2009074789, WO2009075835, WO2009088997, WO2009090239, WO2009094169, WO2009098501, WO2009100872, WO2009102428, WO2009102460, WO2009102761, WO2009106817, WO2009108332, WO2009112691, WO2009112845, WO2009114173, WO2009117109, US2009264401, WO2009118473, WO2009131669, WO20091 2986, WO2009134384, WO2009134387, WO2009134392, WO2009134400, WO2009135581, WO2009138386, WO2010006940, WO2010010157, WO2010010174, is administered in combination with those described in WO2010011917.

  In one embodiment, the compound of the formula I is, for example, Described in WO2008033455, WO2008033931, WO2008033932, WO20080333934, WO2008089581, WO2008087444, WO2009033211, WO2009109999, WO2009109998 Administered in combination with an inhibitor of tyrosine phosphatase-1B (PTP-1B).

  In a further embodiment, the compound of the formula I is administered in combination with a stimulant of tyrosine kinase B (Trk-B) as described, for example, in WO20130014613.

  In a further embodiment, the compound of formula I is, for example, Physiol. Behav. 15 September 2004; 82 (2-3): 489-96, J Clin Invest (1998) 101: 2387-93, Curr. Pharma Des. 2001 Sep; 7 (14): 1433-49., Bioorganic & Medicinal Chemistry Letters Vol. 14, No. 13, July 5, 2004, 3525-3529 (BMS-201620) In combination with a beta 3 agonist (also referred to as a beta-3 adrenergic receptor agonist).

  In one embodiment of the invention, the compound of the formula I comprises a GPR109A agonist (HM74A receptor agonist; NAR agonist (nicotinic acid receptor agonist)), for example MK0524A (laropiprant) or nicotinic acid or sustained release in combination with MK0524 Niacin, or WO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006024490, WO2006013150, WO2007002557, WO2007017261, WO2007017265, WO2007017572, WO200701574 64, WO2007120575, WO2007134986, WO2007150025, WO2007150026, WO2008016968, WO2008051403, WO2008086949, WO2008091338, WO2008097535, WO2008099448, US2008234277, is administered in combination with those compounds described in WO2008127591.

  In another embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of niacin and simvastatin.

  In another embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or “sustained release niacin” in combination with MK-0524A (laropiprant).

  In a further embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or “sustained release niacin” in combination with MK-0524A (laropiprant) and simvastatin.

  In one embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or another nicotinic acid receptor agonist and a prostaglandin DP receptor antagonist, such as those described in WO2008039882.

  In another embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of niacin and meloxicam as described, for example, in WO2009149905.

  In another embodiment of the invention, the compound of the formula I is administered in combination with an agonist of GPR116 as described, for example, in WO2006067531, WO2006067532.

  In one embodiment, the compounds of formula I are for example WO2007013689, WO2007703002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131622, US2007265332, WO2007136622, WO2008075, WO200305, WO2009038204, WO2009903994, WO2009903994, WO2009048527, WO20090544479, O2009058237, WO2009111056, is administered in combination with modulators of GPR40 as are described in WO2010012650.

  In one embodiment, the compound of formula I is a modulator of GPR119 (G protein-coupled glucose-dependent insulinotropic receptor) such as PSN-119-1, PSN-821, PSN-119-2, MBX-2982 or such as WO2004065380, WO2005061489 (PSN-632408), WO2006083491, WO2007003960-62 and WO2007003964, WO2007703355, WO2007116229, WO2007116230, WO2008005569, WO2008005576, WO2008008887, WO2008080569, WO2000802569, WO200802569, WO200802569 008076243, WO200807692, WO2008081204, WO2008081205, WO2008081206, WO2008081207, WO2008081208, WO2008083238, WO2008085316, WO2008109702, WO2008130581, WO2008130584, WO2008130615, WO2008137435, WO2008137436, WO2009012275, WO2009012277, WO2009014910, WO2009034388, WO2009038974, WO2009050522, WO2009050523, WO2009055331, WO2009105715, WO2009105717, WO200910572 , It is described in WO2009106561, WO2009106565, WO2009117421, WO2009125434, WO2009126535, WO2009129036, US2009286812, WO2009143049, WO2009150144, WO2010001166, WO2010004343, WO2010004344, WO2010004345, WO2010004346, WO2010004347, WO2010004348, WO2010008739, WO2010006191, WO2010009183, WO2010009195, WO2010009207, WO2010009208, in WO2010014593 Administered in combination with

  In a further embodiment, the compound of the formula I is administered in combination with a modulator of GPR120 as described, for example, in EP1688138, WO2008066131, WO20088066611, WO2008103500, WO2008103501, WO2008139879, WO2008038204, WO2009147990, WO2010008831.

  In another embodiment, the compound of the formula I is administered in combination with an antagonist of GPR105 as described, for example, in WO2009000087, WO2009090873.

  In a further embodiment, the compound of the formula I is administered in combination with an agonist of GPR43, such as ESN-282.

  In one embodiment, the compound of formula I is an inhibitor of hormone-sensitive lipase (HSL) and / or phospholipase as described, for example, in WO20050773199, WO2006074957, WO20060887309, WO2006111321, WO2007042178, WO2007119837, WO200122352, WO2008122357, WO2009009287. Administered in combination.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of endothelial lipase as described, for example, in WO2007110216.

  In one embodiment, the compound of the formula I is administered in combination with a phospholipase A2 inhibitor, such as dalaprazib or A-002, or those described in WO20080848866, WO20080488867, US200906269.

  In one embodiment, the compound of the formula I is administered in combination with a mycitrin, a lipase inhibitor (WO2007119827).

  In one embodiment, the compound of formula I is for example US200222222, WO2005085230, WO2005111018, WO2200378403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009797, WO200401764, WO2001764, WO20017,4 WO2007120102, WO200712634, WO2007125109, WO2007125110, US2007281949, WO2 08002244, WO2008002245, WO2008016123, WO200880239, WO2008080239, WO2008056266, WO2008057940, WO2008077138, EP1939191, EP1939192, WO208078196, WO208019492, WO2100261EP, WO210026EP WO2009007029, EP2020232, WO2009017452, WO2009035634, WO2009035684, WO2 09038385, WO2009095787, WO2009095788, WO2009095789, WO2009095789, WO2009145814, US20000925882, WO20091546597, WO2009156857, WO2009156686, WO2001561683, WO2001566843, WO20091566863, WO20091566863, WO2009156684 Administered in combination with beta) inhibitors.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), such as those described in WO2004074288.

  In one embodiment, the compound of formula I is an inhibitor of phosphoinositide kinase-3 (PI3K), such as described in WO2008027584, WO200870150150, WO2008125833, WO2008125835, WO2008125839, WO2009090530, WO2009026345, WO2009071890, WO2009071895, WO2009071895. Administered in combination.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of serum / glucocorticoid-regulated kinase (SGK) as described, for example, in WO2006072354, WO2007093264, WO2008009335, WO2008088544, WO20000813844.

In one embodiment, the compound of formula I is, for example, WO2008078755, WO2008057856, WO2008057857, WO2008057859, WO2008057862, WO20080809867, WO2008059866, WO2008080965, WO2008048736, WO200804765, It is administered in combination with a modulator of the glucocorticoid receptor.

  In one embodiment, the compound of the formula I is administered in combination with a mineralocorticoid receptor (MR) modulator, such as drospirenone, or those described in WO2008104306, WO2000081918.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of protein kinase C beta (PKC beta), such as ruboxistaurin, or those described in WO2008096260, WO200825945.

  In one embodiment, the compound of the formula I is administered in combination with an inhibitor of protein kinase D, for example doxazosin (WO2008088006).

  In a further embodiment, the compound of the formula I is, for example, WO2007062568, WO2008006432, WO2008016278, WO20088016730, WO2008080607, WO20080883124, WO2000081642, WO20099089445, WO200900914, WO20099019600, WO20090631, WO2009063, Administered in combination with an activator / modulator of AMP-activated protein kinase (AMPK).

  In one embodiment, the compound of the formula I is administered in combination with inhibitors of ceramide kinase as described, for example, in WO2007112914, WO2007149865.

  In a further embodiment, the compound of the formula I is administered in combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1 or 2) as described, for example, in WO2007104053, WO2007115822, WO2008008547, WO2008075741.

  In one embodiment, the compound of formula I is, for example, described in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005013544, US20072444140, WO20088099073, WO2008099073, WO2000909074, WO2000909075, WO2000909075, WO2000909075, It is administered in combination with an inhibitor of “I-kappa B kinase” (IKK inhibitor).

  In another embodiment, the compound of the formula I is administered in combination with an inhibitor of NF-kappa B (NFKB) activation, for example salsalate.

  In a further embodiment, the compound of the formula I is administered in combination with an inhibitor of ASK-1 (apoptosis signal-regulating kinase 1) as described, for example, in WO2008016131, WO200923986.

  In one embodiment of the invention, the compound of the formula I is an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950, NCX -6560, or administered in combination with those described in US2007249583, WO2008083551, WO2009055682.

  In a further embodiment of the invention, the compound of the formula I is a farnesoid X receptor (FXR) modulator, such as WAY-362450 or WO2003099821, WO2005056554, WO2007052843, WO207070796, WO2007092751; JP2007230909; WO2008025539, WO2008025540, JP200008214222, JP200008273847, WO2008157270, US20089999118, US20080000235, WO2009005998, WO20090112125, WO2009027 64, WO2009062874, US2009131409, US2009137554, US2009163552, WO2009127321, is administered in combination with those described in EP2128158.

  In another embodiment of the invention, the compounds of the formula I are for example WO2007092965, WO200804003, WO2008049047, WO2008065754, WO2008073825, US2008242677, WO20090902063, US200990386, WO200990186, 20090246,200, Of the liver X receptor (LXR) as described in US2007458787, WO2001363692, WO20013838438, WO2001494961, WO200150109 It is administered in combination with ligand.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a fibrate such as fenofibrate, clofibrate, bezafibrate or those described in WO2008093655.

In one embodiment of the invention, the compound of the formula I is administered in combination with a fibrate, for example the choline salt of fenofibrate (SLV-348; Trilipix ^™ ).

In one embodiment of the invention, the compound of the formula I is administered in combination with a fibrate such as the choline salt of fenofibrate (Trilipix ^™ ) and an HMG-CoA reductase inhibitor such as rosuvastatin.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with bezafibrate and diflunisal.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of fenofibrate or a salt thereof and simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin, pitavastatin or atorvastatin.

In a further embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of fenofibrate and metformin, Synordia ^(R) .

  In another embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of metformin and an MTP inhibitor as described in WO2009090210.

  In one embodiment of the invention, the compound of the formula I comprises a cholesterol reabsorption inhibitor, such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol alcoholyl phosphate; Forbes Medi- Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005502497, WO2005021495) or WO2002064644, WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO20050444256 or WO2005062624 (Merck & Co.) or WO200506151 AB WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG) As described in, or WO2002050060, WO2002050068, WO2004000803, WO2004000804, WO2004000805, WO2004087655, WO2004097265, WO2005047248, WO20060370061, WO20061370061, WO20061270061, WO20061220061, WO20061220061, , WO2006137792, WO2006138163, WO2007059871, US2007 32688, WO2007126358, WO2008033431, WO2008033465, WO2008052658, WO2008057336, WO2008085300, WO2008104875, US2008280836, is administered in combination with compounds as described in WO2008108486.

  In one embodiment of the invention, the compound of the formula I is administered in combination with NPC1L1 antagonists, such as those described in WO20080333464, WO20080333465.

In one embodiment of the invention, the compound of the formula I is administered in combination with Vytorin ^™ , a solid combination of ezetimibe and simvastatin.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of ezetimibe and atorvastatin.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of ezetimibe and fenofibrate.

  In one embodiment of the invention, the further active ingredient is a diphenylazetidinone derivative as described, for example, in US 6,992,067 or US 7,205,290.

  In a further embodiment of the invention, the further active ingredient is combined with a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin or rosuvastatin, for example US 6,992,067 or US 7,205, Diphenyl azetidinone derivatives as described in 290.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of rapakistat, a squalene synthase inhibitor and atorvastatin.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with a conjugate consisting of the HMG-CoA reductase inhibitor atorvastatin and the renin inhibitor aliskiren (WO2009090158).

  In one embodiment of the invention, the compound of the formula I is a CETP inhibitor, such as torcetrapib, anacetrapib or JTT-705 (dalcetrapib), or US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007020621, US2007265252, US2007265304, WO2200285568, WO2007132 06, WO2008006257, WO2008009435, WO2008018529, WO2008058961, WO2008058967, WO2008059513, WO2008070496, WO2008115442, WO2008111604, WO2008129951, WO2008141077, US2009118287, WO2009062371, is administered in combination with those described in WO2009071509.

  In one embodiment of the invention, the compound of the formula I is a bile acid reabsorption inhibitor (inhibitor of intestinal bile acid transporter (IBAT)) (eg US 6,245,744, US 6,221,897 or WO 00/61568), for example, HMR 1741, or DE 10 2005 03099.1 and DE 10 2005 03310.00.9, DE 10 2006 053635, DE 10 2006 053637, WO2007009655-56, WO2008058628, WO2008058630, WO2005805861 Administered in combination with

  In one embodiment, the compound of formula I is an agonist of GPBAR1 (G protein-coupled bile acid receptor 1; TGR5), eg INT-777 or eg , US200905304304, WO2009026241, WO2009146772, WO2010014739, WO20110014836.

  In one embodiment, the compound of the formula I is administered in combination with a modulator of histone deacetylase, for example ursodeoxycholic acid as described in WO2009011420.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors / modulators of the TRPM5 channel (TRP cation channel M5) as described, for example, in WO2008097504, WO20090387722.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors / modulators of the TRPA1 channel (TRP cation channel A1), as described, for example, in US2007696883, WO20099089083, WO2009144548.

  In one embodiment, the compound of the formula I is administered in combination with inhibitors / modulators of the TRPV3 channel (TRP cation channel V3) as described, for example, in WO20090884034, WO2009130560.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a polymeric bile acid adsorbent such as cholestyramine, colesevelam hydrochloride.

  In one embodiment of the invention, the compound of the formula I is administered in combination with colesevelam hydrochloride and metformin or sulfonylurea or insulin.

  In one embodiment of the invention, the compound of the formula I is administered in combination with tocotrienol and insulin or insulin derivatives.

In one embodiment of the invention, the compound of the formula I is administered in combination with a chewing gum (Reductol ^™ ) comprising phytosterols.

  In one embodiment of the invention, the compound of the formula I is an inhibitor of a microsomal triglyceride transfer protein (MTP inhibitor), such as impritapid, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, It is administered in combination with JTT-130, or those described in WO2005085226, WO2005121091, WO2006010423, WO2006013910, WO2007143164, WO208049806, WO208049808, WO2008090198, WO2008000423, WO2009014674.

  In a further embodiment of the invention, the compound of the formula I is a combination of a cholesterol absorption inhibitor, such as ezetimibe, and a triglyceride transfer protein inhibitor (MTP inhibitor), such as imputapide, as described in WO2008080382 or WO2008079398 Administered in combination.

  In one embodiment of the invention, the compound of the formula I is administered in combination with an active anti-hypertriglyceridemia component, such as those described in WO2008033980.

  In another embodiment of the invention, the compound of the formula I is administered in combination with antagonists of the somatostatin 5 receptor (SST5 receptor), such as those described in WO2006094682.

  In one embodiment of the invention, the compound of the formula I is an ACAT inhibitor such as avasimib, SMP-797 or KY-382, or Are administered in combination with those described in.

  In a further embodiment of the invention, the compound of the formula I is a liver carnitine palmitoyltransferase-1 as described, for example, in WO2007063012, WO2007096251 (ST-3473), WO200808015081, US2008103182, WO2008074692, WO2008145559, WO200915199, WO2009156479, WO2010008473. It is administered in combination with an inhibitor of (L-CPT1).

  In another embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of carnitine O-palmitoyltransferase II (CPT2), as described, for example, in US20097070500, US2009707055, WO2009132978, WO2009132979.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with modulators of serine palmitoyltransferase (SPT) as described, for example, in WO2008031032, WO2008060771, WO2008083280, WO20080884300.

  In one embodiment of the invention, the compounds of the formula I are described in squalene synthetase inhibitors, such as BMS-188494, TAK-475 (rapakistat acetate), or Administered in combination with

  In one embodiment of the invention, the compound of the formula I is administered in combination with ISIS-301012 (Mipomersen), an antisense oligonucleotide capable of regulating the apolipoprotein B gene.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a therapeutic product comprising apolipoprotein (ApoB) SNALP, siRNA (for the ApoB gene).

  In one embodiment of the invention, the compound of the formula I is administered in combination with stimulators of the ApoA-1 gene, as described, for example, in WO2008092231.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a modulator of apolipoprotein C-III synthesis, such as ISIS-APOCIIIRx.

  In one embodiment of the invention, the compounds of the formula I are combined with LDL receptor inducers (see US Pat. No. 6,342,512), such as those described in HMR1171, HMR1586, or WO2005097738, WO208020607. Be administered.

  In another embodiment of the invention, the compound of the formula I is administered in combination with HDL cholesterol-elevating agents, such as those described in WO20080804061, WO2008099278, WO2009071099, WO2009086096, US200009247550.

  In one embodiment of the invention, the compound of the formula I is administered in combination with an ABCA1 expression potentiator as described, for example, in WO20060772393, WO2008062830, WO200009100326.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a lipoprotein lipase modulator, such as, for example, ibrolipim (NO-1886).

  In one embodiment of the invention, the compound of the formula I is administered in combination with a lipoprotein (a) antagonist, such as gemcabene (CI-1027).

  In one embodiment of the invention, the compound of the formula I is administered in combination with a lipase inhibitor such as orlistat or cetiristat (ATL-962).

  In one embodiment of the invention, the compounds of the formula I are described in adenosine A1 receptor agonists (adenosine A1 R), for example CVT-3619 or for example EP1258247, EP1375508, WO2008028590, WO20080777050, WO2009050199, WO2009080197, WO2009100827, WO2009112155. Administered in combination with

  In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor agonist (adenosine A2BR), such as ATL-801.

  In another embodiment of the invention, the compound of the formula I is administered in combination with a modulator of adenosine A2A and / or adenosine A3 receptor as described, for example, in WO200711194, WO2007121918, WO2007121921, WO2007121923, WO2008070661, WO20090108771 The

  In a further embodiment of the invention, the compound of the formula I is administered in combination with a ligand for the adenosine A1 / A2B receptor, as described, for example, in WO2008064788, WO2008080989, WO2009080198, WO2009100827, WO2009143992.

  In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2BR) as described in US2007047043, WO2008027585, WO2008080461, WO20090904633, WO200909037467, WO200909037468, WO200918759 .

  In one embodiment, the compound of formula I is an inhibitor of acetyl-CoA carboxylase (ACC1 and / or ACC2), such as WO199946262, WO200372197, WO20030772197, WO20050444814, WO20050101370, JP2006131559, WO20070111809, WO2007016931, WO2003016951, , WO2008065508, WO2008069500, WO2008070609, WO2008072850, WO2008079610, WO2008088888, WO2008088899, WO2008086992, US2008171761, J2008080944, J 2008179621, US2008200461, WO2008102749, WO2008103382, WO2008121592, WO2009082346, US2009253725, JP2009196966, WO2009144554, WO2009144555, WO2010003624, is administered in combination with those described in WO2010002010.

  In another embodiment, the compound of the formula I comprises a modulator of microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GPAT3, described in WO2007100789) or a modulator of microsomal acyl-CoA: glycerol-3- It is administered in combination with a modulator of mitochondrial glycerol-3-phosphate O-acyltransferase as described in phosphate acyltransferase 4 (GPAT4, described in WO2007100833) or WO2010005922.

  In a further embodiment, the compound of the formula I is administered in combination with a modulator of xanthine oxidoreductase (XOR).

  In another embodiment, the compound of formula I is for example soluble in WO2008018773, WO2008051875, WO2008073623, WO20080804869, WO2000081122, WO2009011872, WO2009049154, WO2009049157, WO2009093772, WO2009097476, WO2009111, WO It is administered in combination with an inhibitor of (sEH).

In a further embodiment, the compound of formula I is a CART modulator ("Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al: Hormone and Metabolic Research (2001), 33 (9). , 554-558);
NPY antagonists such as 4-[(4-aminoquinazolin-2-ylamino) methyl] -cyclohexylmethylnaphthalene-1-sulfonamide hydrochloride (CGP 71683A) or Berneperito or those described in WO2009110510;
NPY-5 receptor antagonist / receptor modulator, for example L-152804 or the compound “NPY-5-BY” from Banyu, or for example WO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026769, WO2008092887, WO2008092888, WO200892888 Those described in WO200834228, WO20090543434, WO2009095377, WO2009131096;
NPY-4 receptor antagonists as described, for example, in WO2007038942;
NPY-2 receptor antagonists / modulators such as those described, for example, in WO2007038943, WO2009006185, US2009099199, US2009099243, US2009099244, WO2009079593, WO2009079597;
Peptide YY 3-36 (PYY3-36) or similar compounds such as CJC-1682 (PYY3-36 bound to human serum albumin via Cys34) or CJC-1643 (derivative of PYY3-36 that binds serum albumin in vivo ), Or those described in WO2005080424, WO2006095166, WO2008003947, WO2009080608;
NPY-2 receptor agonists as described, for example, in WO2009080608;
Derivatives of the peptide obestatin as described by WO20060996847;

CB1R (cannabinoid receptor 1) antagonist / inverse agonist such as rimonabant, sulinabant (SR147778), SLV-319 (Ibipinabant), AVE-1625, taranabant (MK-0364) or their salts, otenabant (CP-945,598) , Rosonabant, V-24343 or for example EP 0656354, WO 00/15609, WO2001 / 64632-64634, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080347, WO200170700, WO20030240 WO200 3007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096994, WO2005000809, WO2004099157 US20040626845, WO2004010453, WO2004108728, WO2004000817, WO2005000820, US20050009870, WO200500974, WO210011033-34, WO200411038-39, WO20050602006, WO20056060200, WO20056060650, WO20056060, WO2006067443, WO2006087480, WO20060874 6, WO2006100208, WO2006106054, WO2006111849, WO2006113704, WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007018460, WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548, WO2007047737, WO2007057687, WO2007062193, WO2007064272, WO2007079681, WO200 7084319, WO2007084450, WO2007086080, EP1816125, US2007213302, WO2007095513, WO2007096764, US2007254863, WO2007119001, WO2007120454, WO2007121687, WO2007123949, US2007259934, WO2007131219, WO2007133820, WO2007136571, WO2007136607, WO2007136571, US7297710, WO2007138050, WO2007139464, WO2007140385, WO2007140439, WO2007146761, WO2007148061, WO20071488062, US2007 93509, WO2008004698, WO2008017381, US2008021031, WO2008024284, WO2008031734, WO2008032164, WO2008034032, WO2008035356, WO2008036021, WO2008036022, WO2008039023, WO2998043544, WO2008044111, WO2008048648, EP1921072-A1, WO2008053341, WO2008056377, WO2008059207, WO2008059335, WO2008062424, WO2008068423, WO2008068424, WO2008070305, WO2008070306, WO2008074816, W 2008074982, WO2008075012, WO2008075013, WO2008075019, WO2008075118, WO2008076754, WO2008081009, WO2008084057, EP1944295, US2008090809, US2008090810, WO2008092816, WO2008094473, WO2008094476, WO2008099076, WO2008099139, WO2008101995, US2008207704, WO2008107179, WO2008109027, WO2008112674, WO2008115705, WO2008118414, WO2008119999, WO200812000, WO20081212257, W O2008127585, WO200008129157, WO200008130616, WO200008134300, US200008262066, US200008287505, WO2009005645, WO2009005646, WO2009005671, WO2009902392, WO20099053959, WO2090290125, WO2009903125, WO200903125
4782, WO2009075691, WO2009078498, WO2009087285, WO2009074782, WO2009097590, WO2009097995, WO2009097996, WO2009097998, WO2009097999, WO2009098000, WO2009106708, US2009239909, WO2009118473, US2009264436, US2009264476, WO2009130234, WO2009131814, WO2009131815, US2009286758, WO2009141532, WO2009141533, WO2009153569, WO2010003760, WO2010012437, Described in WO2010019762 These compounds;

Cannabinoid receptor 1 / cannabinoid receptor 2 (CB1, / CB2) modulating compounds, such as delta-9-tetrahydrocannabinavalin, or, for example, WO2007001939, WO20070444215, WO2007044737, WO2007095513, WO2007096764, WO2007112399, WO21212402, WO2008122675, WO20099097, WO20099097 , WO2009093018, WO20090905752, WO2009120660, WO2010012964;
Cannabinoid receptor 2 (CB2) -modulating compounds, such as those described in WO20088063625, WO200157557500, WO2009004171, WO20099032754, WO20090565357, WO20099061652, WO20099063495, WO2009076613, WO2009141566;
For example WO2007140005, WO2008019357, WO2008021625, WO2008023720, WO2008030532, WO2008129129, WO2008145839, WO2008145843, WO2008147553, WO2008153752, WO2009011904, WO2009048101, WO2009084970, WO2009105220, WO2009109504, WO2009109743, WO2009117444, WO2009127944, WO2009138416, WO2009151991, WO2009152025, WO2009154785, WO2010005572, in WO2010017079 FAAH (Fatty Acids) as described Modulators of Dohidororaze);

Inhibitors of fatty acid synthase (FAS) as described, for example, in WO2008057585, WO2008059214, WO2008075064, WO2008075070, WO20080775077, WO2009079860;
Inhibitors of LCE (long chain fatty acid elongase) / long chain fatty acid CoA ligase as described for example in WO20000816803, WO2009038021, WO20090447788, WO2009081789, WO2009909986;
For example WO2007091948, WO2007129188, WO2007133637, WO2008007780, WO2008010061, WO2008007211, WO2008010061, WO2008015335, WO2008018827, WO2008024433, WO2008024438, WO2008032204, WO2008050199, WO2008059339, WO2008059370, WO2008066664, WO2008075150, WO2008090382, WO2008090434, WO2008093024, WO2008107543, WO2008107544, WO2008110863, WO2008125295, WO2008125296 , WO200 125,337, such WO2008125342, WO2008132600, WO2008133973, WO2009010529, WO2009010824, WO2009016241, WO2009023539, WO2009038812, WO2009050348, WO2009055629, WO2009055749, WO2009064449, WO2009081222, WO2009089057, WO2009109710WO2009112677, WO2009112678, WO2009112679, WO2009121036, WO2009124551, WO2009136625, as described in WO2010002209 Vanilloid-1 receptor modulator (TRPV1 modulator ;

Modulators, ligands, antagonists or inverse agonists of opioid receptors, such as GSK-982 or described in, for example, WO2007047397, WO2008021849, WO2008021851, WO200803156, WO2008059335, WO200825348, WO2008253494, WO2009309562, WO2009103552, WO2009103552;
Modulators of “orphan opioid (ORL-1) receptors” as described, for example, in US200829122, WO20080889201;
Agonists of prostaglandin receptors, such as bimatoprost or those compounds described in WO2007111806;
MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists such as N- [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo) [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl] -1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (WO 01 / 91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493, or WO2005060985, WO20050099950, WO20040887717, WO2004078716, WO2004078716, US20 050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, WO2004005324, WO2004037797, WO2004089307, WO2005042516, WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159, WO2004072076, WO20040720 7, WO2006021655-57, WO2007009894, WO2007015162, WO2007041061, WO2007041052, JP2007131570, EP-1842846, WO2007096186, WO2007096763, WO2007141343, WO2008007930, WO2008017852, WO2008039418, WO2008087186, WO2008087187, WO2008087189, WO2008087186-WO2008087190, WO2008090357, WO2008142319, WO2009015867, WO2009061411, US2009076029, US200911465, WO2009071011, US20 9305960, WO2009144432, WO2009151383, those described in WO2010015972;

MC4 receptor modulators (melanocortin-4 receptor modulators) as described, for example, in WO2009010299, WO20090774157;
Orexin receptor 1 antagonist (OX1R antagonist), orexin receptor 2 antagonist (OX2R antagonist) or mixed OX1R / OX2R antagonist (eg 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridine -4-ylurea hydrochloride (SB-334867-A) or, for example, WO200630302, WO200185633, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374, WO2007222591, WO2007126934, WO2008008517, WO2008008517, WO2008008517, WO2008008517 2008020405, WO2008026149, WO2008038251, US2008132490, WO2008065626, WO2008078291, WO2008087611, WO2008081399, WO2008108991, WO2008107335, US2008249125, WO2008147518, WO2008150364, WO2009003993, WO2009003997, WO2009011775, WO2009016087, WO2009020642, WO2009058238, US2009186920, US2009203736, WO2009092642, WO2009100994, WO2009104155, WO2009124956, WO20091335 2, WO2009156951, WO2010017260) those described in;

Histamine H3 receptor antagonist / inverse agonist (eg 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) propan-1- Oxalic acid salt (WO 00/63208), or WO2000064884, WO2005082893, WO2005123716, US20051711181 (e.g. PF-00389027), WO2006107661, WO2007003804, WO20070702996, WO200770570, WO200770570, WO200770570, 629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349, WO2007110364, WO2007115938, WO2007131907, WO2007133561, US2007270440, WO2007135111, WO2007137955, US2007281923, WO2007137968, WO2007138431, WO2007146122, WO2008005338, WO2008012010, WO2008015125, WO2008045371, EP1575594, WO2008 68173, WO2008068174, US20080171753, WO2008072703, WO2008072724, US2008188484, US2008188486, US2008188487, WO2008109333, WO2008109336, WO2008126886, WO2008154126, WO2008151957, US2008318952, WO2009003003, WO2009013195, WO2009036132, WO2009039431, WO2009045313, WO2009058300, WO2009063953, WO2009067401, WO2009067405, WO2009067406, US2009163464, WO2009100120, W O2009105206, WO2009121812, WO2009126782, WO2010016533, WO201001657));

A histamine H1 / histamine H3 modulator, such as betahistine or its dihydrochloride salt;
Modulators of the histamine H3 transporter or of the histamine H3 / serotonin transporter as described for example in WO2008002816, WO2008002817, WO2008002818, WO2008002820;
A modulator of vesicular monoamine transporter 2 (VMAT2) as described for example in WO200126305;
For example, a histamine H4 modulator as described in WO2007117399, US2009156613;
CRF antagonists such as [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triazafluorene] dipropylamine (WO 00/66585) or WO2007105113, WO2007133756, WO20080365541, WO2008036579, WO2008083070, WO2010015628, their CRF1 antagonists described in WO2010015655);
A CRF BP antagonist (eg urocortin);
Urocortin agonist;
Beta-3 adrenergic receptor modulators such as 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) ethylamino] ethanol hydrochloride Salt (WO 01/83451) or solavegron (GW-427353) or N-5984 (KRP-204), or JP20000611553, WO2002038543, WO2002038444, WO20070484840-843, WO2008015558, EP1947103, WO200008132162;

MSH (melanocyte stimulating hormone) agonist;
MCH (melanin-concentrating hormone) receptor antagonist (for example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71 (AMG-071, AMG-076), GW- 856464, NGD-4715, ATC-0453, ATC-0759, GW-803430, or WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO20040974200 3004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802, JP2007091649, WO2007092416; WO2007093363- 366, WO200711490 , WO2007114916, WO2007141200, WO2007142217, US2007299062, WO2007146758, WO2007146759, WO2008001160, WO2008016811, WO2008020799, WO2008022979, WO2008038692, WO2008041090, WO2008044632, WO2008047544, WO2008061109, WO2008065021, WO2008068265, WO2008071646, WO2008076562, JP2008088120, WO2008086404, WO2008086409, US2008269110, WO2008140239, WO2009021740 , US20090 11994, US2009082359, WO2009041567, WO2009076387, WO2009089482, WO2009103478, WO2009119726, WO2009120655, WO2009123194, WO2009137270, WO2009146365, WO2009154132);

CCK-A (CCK-1) modulator (eg {2- [4- (4-chloro-2,5-dimethoxyphenyl) -5- (2-cyclohexylethyl) -thiazol-2-ylcarbamoyl] -5,7 -Dimethylindol-1-yl} acetic acid trifluoroacetate (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those described in WO216016034, WO2007120655, WO2007120688, WO2007120718, WO2008091631;
A serotonin reuptake inhibitor (eg, dexfenfluramine), or those described in WO200483411, WO2008034142, WO2008081477, WO200008120761, WO20041081, WO2000081082, WO200008145135, WO2008150848, WO2008043834, WO2009907858;
Mixed serotonin / dopamine reuptake inhibitors (eg, bupropion), or those described in WO20088063673, or solid combinations of bupropion and naltrexone or bupropion and zonisamide;
Mixed reuptake inhibitors, such as those described in DOV-21947 or WO2009016214, WO2009016215, WO20090907584, WO200909098208, WO200909098209, WO2009106769, WO2009109517, WO2009109518, WO2009109958, WO2009109608, WO2009145357; WO200949258;
Mixed serotonergic and noradrenergic compounds (eg WO 00/71549);

5-HT receptor agonists such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111);
Mixed dopamine / norepinephrine / acetylcholine reuptake inhibitors (eg, Tesofensin), or those described, for example, in WO2006085118, WO2008150480;
Dopamine antagonists as described, for example, in WO2008079838, WO2008079839, WO20080798847, WO2008079848;
Norepinephrine reuptake inhibitors as described, for example, in US2008076724, WO2009062318;
5-HT1A receptor modulators such as those described, for example, in WO2009006227, WO200937679, WO200937732;
5-HT2A receptor antagonists as described, for example, in WO2007138343;
5-HT2C receptor agonists such as lorcaserine hydrochloride (APD-356) or BVT-933, or WO20070701, WO200077001-02, WO2005019180, WO20030644223, WO200242304, WO2005035533, WO2005082859, WO200628965, WO200285961, WO200285961, , WO2007028132, WO2007084622, US2007249709; WO2007132841, WO2007140213, WO2008007661, WO2008007664, WO2008009125, WO2008010073, WO20 8108445, WO2009063991, WO2009063992, WO2009063993, those described in WO2009079765);
5-HT6 receptor modulators such as E-6837, BVT-74316, PF-3246799 or PRX-07034, or, for example, WO2005058858, WO2007705547, WO2007107373, WO2007108569, WO20071087424-744, WO2008047381, WO2008808703, WO20080804 WO2008084922, WO20080926665, WO2008082666, WO2008101247, WO2008101598, WO2008168831, WO200816833, WO200817169, WO2008136017, WO20081 7812, EP2036888, WO2009013010, WO2009034581, WO2009053997, WO2009056632, WO2009073118, WO2009115515, WO2009135925, WO2009135927, WO2010000456, WO2010012806, those described in EP2145887;

Agonists of estrogen receptor gamma (ERR _γ agonists) as described for example in WO2007131005, WO2008052709;
Estrogen receptor alpha agonists (ERRα / ERR1 agonists) as described, for example, in WO2008109727;
Estrogen receptor beta agonists (ERRβ agonists) as described, for example, in WO2009055534, WO2100100355, WO2009127686;
For example, a sigma-1 receptor antagonist as described in WO2007709953, WO2007098961, WO2008015266, WO2008055932, WO2008055933, WO2009071657;
A muscarinic 3 receptor (M3R) antagonist as described, for example, in WO20000711078, WO2008041184;
Bombesin receptor agonists (BRS-3 agonists) as described, for example, in WO2008051404, WO2008051405, WO20080551406, WO2008073311;
A galanin receptor antagonist;
Growth hormone (eg, human growth hormone or AOD-9604);
Growth hormone releasing compound (tert-butyl 6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695));
Growth hormone secretagogue receptor antagonists (ghrelin antagonists), such as those described in A-778193, or WO2005030734, WO20071274457, WO2008008286, WO2009056707;
Growth hormone secretagogue receptor modulators (ghrelin modulators) such as JMV-2959, JMV-3002, JMV-2810, JMV-2951, or WO2006012577 (eg YIL-781 or YIL-870), WO20070779239, WO2008092681, WO2008145749, WO2001484853 , WO2008148854, WO2008148856, WO2009047558, WO2009071283, WO200915503;
TRH agonists (see for example EP 0 462 884);
Decoupled protein 2 or 3 modulator (eg as described in WO2009285833);
Chemical decouplers (e.g. WO2008059023, WO2008059024, WO2008059025, WO2008059026);
Leptin receptor agonists (eg, Lee, Daniel W .; Leinung, Matthew C .; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (See (9), 873-881);

Leptin receptor modulators such as those described, for example, in WO2009019427, WO2009071658, WO2009071668, WO2009071667, WO2009071678, WO2009147211, WO2009147216, WO2009147219, WO2009147221;
DA agonists (bromocriptine, bromocriptine mesylate, dooplexin) or those described in US2009143390;
Lipase / amylase inhibitors (eg WO 00/40569, WO2008107184, WO2009049428, WO200925819);
Inhibitors of diacylglycerol O-acyltransferase (DGAT), such as BAY-74-4113 or, for example, US2004 / 0224997, WO2004094618, WO2000058491, WO20050444250, WO2005072740, JP2005206492, WO2005013907, WO2006019020, WO2006019020, WO200601894 , WO2007016538, WO2007060140, JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107, WO200 138304, WO2007138311, WO2007141502, WO2007141517, WO2007141538, WO2007141545, WO2007144571, WO2008011130, WO2008011131, WO2008039007, WO2008048991, WO2008067257, WO2008099221, WO2008129319, WO2008141976, WO2008148840, WO2008148849, WO2008148851, WO2008148868, WO2009011285, WO2009016462, WO2009024821, US2009076275, WO2009040410, WO2009071483, WO2009081195, O2009119534, WO2009126624, WO2009126861, WO2010007046, those described in WO2010017040;
Inhibitors of monoacylglycerol acyltransferase (2-acylglycerol O-acyltransferase; MGAT) as described for example in WO2008038768;

Inhibitors of fatty acid synthase (FAS) such as C75, or those described in WO2004005277, WO2008006113;
For example WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746, WO2007143597, WO2007143823, WO2007143824, WO2008003753, WO2008017161, WO2008024390, WO2008029266, WO2008036715, WO2008043087, WO2008044767, WO2008046226, WO2008056687, WO2008062276, WO2008064474, WO2008074824 , WO20 8074832, WO2008074833, WO2008074834, WO2008074835, WO2008089580, WO2008096746, WO2008104524, WO2008116898, US2008249100, WO2008120744, WO2008120759, WO2008123469, WO2008127349, WO2008128335, WO2008135141, WO2008139845, WO2008141455, US20080255130, US2008255161, WO2008141455, WO2009010560, WO2009016216, WO2009012573, WO2009024287, JP2009019013, WO2009903754 , WO2009056556, WO2009060053, WO2009060054, WO2009070533, WO2009073973, WO2009103739, WO2009117659, WO2009117676, US2009253693, US2009253738, WO
Inhibitors of stearoyl-CoA delta 9 desaturase (SCD1) as described in 200009259, WO2009126123, WO200926527, WO2009129625, WO2009137201, WO2009150196, WO2009156484, WO2010006962, WO20100007482;

An inhibitor of fatty acid desaturase 1 (delta 5 desaturase) as described, for example, in WO20080889310;
Inhibitors of monoglyceride lipase (MGL) as described in WO2008145842;
Hypoglycemic / hypertriglyceridemic indoline compounds as described in WO2008039087, WO2009051119;
Inhibitors of “adipocyte fatty acid binding protein aP2”, such as those described in BMS-309403 or WO2009028248;
An activator of adiponectin secretion, as described, for example, in WO20066082978, WO2008105533, WO200836173;
An adiponectin production promoter as described, for example, in WO2007125946, WO2008038712;
For example, a modified adiponectin (modified) as described in WO2008121009
adiponectins);
Oxyntomodulin or an analog thereof (eg, TK-1225);
Oleoyl-estrone or thyroid hormone receptor agonists or partial agonists (thyroid hormone receptor agonists), eg: KB-2115 (epirotirome), QRX-431 (sobetirome) or DITPA, or Also described in WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007709913, WO20070339125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864, WO20080019959, WO2008106213, JP2001552611. Or an agonist of thyroid hormone receptor beta (TR-beta), eg MB-07811 or MB-07344, or in combination with those described in WO200806469.

  In one embodiment of the invention, the compound of the formula I is administered in combination with a combination of epirotirome and ezetimibe.

  In one embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of site-1 protease (S1P), for example PF-429242.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with modulators of “trace amine-related receptor 1” (TAAR1), as described, for example, in US2008146523, WO2008092785.

  In one embodiment of the invention, the compound of the formula I is administered in combination with inhibitors of growth factor receptor binding protein 2 (GRB2) as described, for example, in WO2008067270.

  In a further embodiment of the invention, the compound of the formula I is administered in combination with an RNAi (siRNA) therapeutic against PCSK9 (proprotein convertase subtilisin / kexin type 9).

In one embodiment, the compound of the formula I are, Omacor ^(R) or Lovaza ^TM; is administered in combination with (omega-3 fatty acid esters e and highly concentrated ethyl esters of docosahexaenoic acid eicosapentaenoic acid).

  In one embodiment, the compound of the formula I is administered in combination with lycopene.

  In one embodiment of the invention, the compounds of the formula I are described in antioxidants such as OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, β-carotene or selenium or in WO2009135918. Administered in combination with

  In one embodiment of the invention, the compound of the formula I is administered in combination with a vitamin, such as vitamin B6 or vitamin B12.

  In one embodiment, the compound of formula I is combined with more than one of the above compounds, for example sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin (PrandiMet (TM)), insulin and sulfonylurea, insulin and It is administered in combination with metformin, insulin and troglitazone, insulin and lovastatin, and the like.

  In a further embodiment, the compound of the formula I is administered in combination with an activator of soluble guanylate cyclase (sGC) as described, for example, in WO2009032249.

  In another embodiment, the compound of the formula I is administered in combination with inhibitors of carboanhydrase type 2 (carbonic anhydrase type 2), such as those described in WO2007065948, WO2009050252.

  In another embodiment, the compound of the formula I is administered in combination with topiramate or a derivative thereof as described in WO2008027557, US2009304789.

In a further embodiment, the compound of the formula I is administered in combination with a solid combination of topiramate and phentermine (Qnexa ^™ ).

  In a further embodiment, the compound of the formula I is administered in combination with an antisense compound that inhibits the production of the glucocorticoid receptor, for example ISIS-377131.

  In another embodiment, the compound of formula I is combined with an aldosterone synthase inhibitor and an antagonist of a glucocorticoid receptor, a cortisol synthesis inhibitor and / or an antagonist of a corticotropin releasing factor, as described, for example, in EP 1886695, WO200008119744 Administered.

  In one embodiment, the compound of the formula I is administered in combination with an agonist of the RUP3 receptor as described, for example, in WO2007035355, WO2008005576.

  In another embodiment, the compound of the formula I is administered in combination with an activator of the gene encoding vasodilator schizophrenia mutation (ATM) protein kinase, such as chloroquine.

  In one embodiment, the compound of the formula I is administered in combination with a tau protein kinase 1 inhibitor (TPK1 inhibitor) as described, for example, in WO2007119463, WO2009035159, WO2009035162.

  In one embodiment, the compound of the formula I is administered in combination with a “c-Jun-N-terminal kinase” inhibitor (JNK inhibitor), for example B1-78D3 or such as those described in eg WO2007125405, WO2008028860, WO2000081826. The

  In one embodiment, the compound of the formula I is administered in combination with an endothelin A receptor antagonist such as avosentan (SPP-301).

  In one embodiment, the compound of the formula I is administered in combination with an inhibitor of neutral endopeptidase (NEP inhibitor) as described, for example, in WO2009138122, WO200935526.

  In one embodiment, the compounds of the formula I are described in modulators of the glucocorticoid receptor (GR), such as KB-3305 or such as in WO2005090336, WO2006071609, WO2006135826, WO2007105766, WO200008120661, WO2009090288, WO2009058944, WO2009108525, WO20091111414. In combination with the compound.

  In one embodiment, the further active ingredient is varenicline tartrate, a partial agonist of alpha 4-beta2 nicotinic acetylcholine receptor.

  In one embodiment, the further active ingredient is an agonist of the alpha 7-nicotinic acetylcholine receptor as described, for example, in WO2009018551, WO2009071519, WO2009071576, WO2009071577.

  In one embodiment, the further active ingredient is Troduschemin.

  In one embodiment, the further active ingredient is a modulator of the enzymes SIRT1 and / or SIRT3 (NAD + dependent protein deacetylase); this active ingredient can be, for example, resveratrol in a suitable formulation or WO2007019416 (eg SRT-1720). ), WO2008074511, WO2008156866, WO2008156869, WO2009090701, WO2009904901, WO200990558348, WO2009906453, WO2009349773, WO200946358, WO2010003048.

  In one embodiment of the invention, the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanechol).

In one embodiment, the compound of the formula I is, for example,
Administered in combination with an anti-hypercholesterolemic compound as described in 302.

  In a further embodiment, the compound of the formula I is administered in combination with an inhibitor of SREBP (sterol regulatory element binding protein), for example fatostatin, or for example as described in WO2008097835.

  In another embodiment, the compound of the formula I is administered in combination with a cyclic peptide agonist of the VPAC2 receptor as described, for example, in WO2007101146, WO2007133828.

  In a further embodiment, the compound of the formula I is administered in combination with agonists of the endothelin receptor, for example as described in WO2007112069.

  In a further embodiment, the compound of the formula I is administered in combination with AKP-020 (bis (ethylmaltolato) oxovanadium (IV)).

  In another embodiment, the compound of the formula I is administered in combination with tissue selective androgen receptor modulators (SARMs) as described, for example, in WO200770999, WO2007137874.

  In a further embodiment, the compound of the formula I is administered in combination with an AGE (glycation end product) inhibitor, as described, for example, in JP2008024673.

  In one embodiment of the invention, the further active ingredient is leptin; for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001) , 2 (10), 1615-1622.

  In another embodiment of the invention, the further active ingredient is metreleptin (recombinant methionyl-leptin) in combination with pramlintide.

  In a further embodiment of the invention, the further active ingredient is the tetrapeptide ISF-402.

  In one embodiment, the further active ingredient is dexamphetamine or amphetamine.

  In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

  In another embodiment, the further active ingredient is sibutramine or a derivative thereof described in WO2008034142.

  In one embodiment, the further active ingredient is mazindol or phentermine.

  In a further embodiment, the further active ingredient is geniposide acid (WO2007100104) or a derivative thereof (JP2008106008).

  In another embodiment, the further active ingredient is a neuropeptide FF2 agonist, for example as described in WO2009038012.

  In one embodiment, the further active ingredient is a nasal calcium channel blocker such as diltiazem, or those described in US 7,138,107.

  In one embodiment, the further active ingredient is an inhibitor of sodium-calcium ion exchange, such as those described in WO2008028958, WO2008087711.

  In a further embodiment, the further active ingredient is a blocker of a calcium channel, such as CaV3.2 or CaV2.2, as described in WO2008033431, WO2008033447, WO2008033356, WO2008033460, WO20080333464, WO200803465, WO2008033468, WO2008074611.

  In one embodiment, the further active ingredient is a modulator of calcium channels, such as those described in WO2008073934, WO2008073936, WO2009107660.

  In one embodiment, the further active ingredient is an inhibitor of calcium metabolism, such as those described in US200924680.

  In one embodiment, the further active ingredient is a “T-type calcium channel” blocker as described, for example, in WO2008034311, WO20000810008, US20080800900, WO2008141446, US20092703338, WO2009146540, US2009325979, WO2009146539.

  In one embodiment, the additional active ingredient is an inhibitor of KCNQ potassium channel 2 or 3, such as those described in US2008027049, US2008027090.

  In one embodiment, the further active ingredient is a modulator of KCNN potassium channel 1, 2 or 3 (a modulator of SK1, SK2 and / or SK3 channel), such as those described in US2009036475.

  In one embodiment, the further active ingredient is an inhibitor of potassium Kv1.3 ion channel, such as those described in WO2008040057, WO2008040058, WO2008046065, WO2009041171.

  In one embodiment, the further active ingredient is a potassium channel modulator, such as those described in WO2008135447, WO2008135448, WO2008355511, WO20090998820.

  In a further embodiment, the further active ingredient is a hyperpolarized activated cyclic nucleotide-dependent (HCN) potassium-sodium channel inhibitor, such as those described in US2009090296.

  In another embodiment, the further active ingredient is an inhibitor of sodium-potassium-2 chloride (NKCCl) cotransporter, such as those described in WO20030735.

  In another embodiment, the further active ingredient is a voltage-gated sodium channel inhibitor, such as those described in WO2009049180, WO2009049181.

  In another embodiment, the further active ingredient is a modulator of the MCP-1 receptor (monocyte chemotactic protein-1 (MCP-1)), such as those described in WO2008014360, WO2008014381.

  In one embodiment, the further active ingredient is a modulator of somatostatin receptor 3 (SSTR3), such as those described in WO20090111836.

  In one embodiment, the further active ingredient is a modulator of somatostatin receptor 5 (SSTR5), such as those described in WO2008019967, US2008064697, US200008249101, WO20080006962, US20080082756, WO200008148710.

  In one embodiment, the further active ingredient is a modulator of somatostatin receptor 2 (SSTR2), such as those described in WO2008051272.

  In one embodiment, the further active ingredient is a compound capable of reducing the amount of retinol binding protein 4 (RBP4), such as those described in WO2009051244, WO2009145286.

  In one embodiment, the further active ingredient is an erythropoietin mimetic peptide that acts as an erythropoietin (EPO) receptor agonist. Such molecules are described, for example, in WO2008042800.

  In a further embodiment, the further active ingredient is an appetite suppressant / hypoglycemic compound, such as those described in WO2008033053, WO208035306, WO208035686.

  In one embodiment, the further active ingredient is a lipoic acid synthase inducer, such as those described in WO2008036966, WO2008036967.

  In one embodiment, the further active ingredient is an endothelial nitric oxide synthase (eNOS) stimulant, such as those described in WO2008086441, WO2008074413.

  In one embodiment, the further active ingredient is a modulator of carbohydrate and / or lipid metabolism, such as those described in WO2008059023, WO2008059024, WO2008059025, WO2008059026.

  In a further embodiment, the further active ingredient is an angiotensin II receptor antagonist, such as those described in WO2008062905, WO2008067378, WO2008062905.

  In one embodiment, the further active ingredient is an agonist of sphingosine 1-phosphate receptor (S1P), for example in WO2008064315, WO2008074820, WO2008048221, WO2008135522, WO20089019167, WO20099043613, WO2009086633, WO2009151529, WO2009151537, WO200915516, It has been done.

  In one embodiment, the further active ingredient is an agent that delays gastric emptying, such as 4-hydroxyisoleucine (WO20080444770).

  In one embodiment, the further active ingredient is tritophan-5-hydroxylase inhibitor-1 (TPH1 inhibitor) which modulates gastrointestinal motility, for example as described in WO2009014972.

  In one embodiment, the further active ingredient is a muscle relaxant, for example as described in WO2008090200.

  In a further embodiment, the further active ingredient is an inhibitor of monoamine oxidase B (MAO-B), such as those described in WO2008092091, WO2009066152.

  In a further embodiment, the further active ingredient is an inhibitor of monoamine oxidase A (MAO-A), such as those described in WO2009030968.

  In another embodiment, the further active ingredient is an inhibitor of the binding of cholesterol and / or triglycerides to the SCP-2 protein (sterol carrier protein-2), such as those described in US2008194658.

  In a further embodiment, the further active ingredient is a compound that binds to the β-subunit of the trimeric GTP binding protein, such as those described in WO200008192620.

  In one embodiment, the further active ingredient is a urate anion exchanger inhibitor 1 as described, for example, in WO2009070740.

  In one embodiment, the further active ingredient is a modulator of the ATP transporter as described, for example, in WO2009108657.

  In another embodiment, the further active ingredient is lysophylline which prevents autoimmune damage to insulin producing cells.

  In yet another embodiment, the further active ingredient is an extract from Bidens pilosa with the ingredient cytopyroin as described in EP 1955701.

  In one embodiment, the further active ingredient is an inhibitor of glucosylceramide synthase as described, for example, in WO2008150486.

  In a further embodiment of the invention, the further active ingredient is a glycosidase inhibitor as described, for example, in WO2009117829, WO2009155753.

  In another embodiment, the further active ingredient is an ingredient from the plant Hoodia Gordonii as described in US2009042813, EP2044852.

  In one embodiment, the further active ingredient is an antidiabetic agent, such as D-tagatose.

  In one embodiment, the further active ingredient is a zinc complex of curcumin as described in WO2009079902.

  In one embodiment, the further active ingredient is an inhibitor of “cAMP response element binding protein” (CREB) as described in WO200143391.

  In another embodiment, the further active ingredient is an antagonist of the bradykinin B1 receptor as described in WO200924746.

  In a further embodiment, the further active ingredient is a compound capable of modulating diabetic peripheral neuropathy (DPN).

  Such modulators are, for example, those described in FK-1706 or SB-509, or WO 198900304, WO20090992129, WO2010002956.

  In one embodiment, the further active ingredient is a compound capable of modulating diabetic nephropathy. Such compounds are described, for example, in WO20090889545, WO200953261.

  In one embodiment, the further active ingredient is an inhibitor of CD38 (eg anti-CD38 antibody) as described in US2009196825.

  In one embodiment, the further active ingredient is an inhibitor of human fibroblast growth factor receptor 4 (FGFR4), for example as described in WO2009046141.

  In a further embodiment of the invention, the further active ingredient is a compound that protects beta cells, such as 14-alpha-lipolyl-andrographolide (AL-1).

  In yet another embodiment of the invention, the further active ingredient is an INGAP (islet neogenesis associated protein) peptide, a peptide that restores insulin production in patients with diabetes mellitus.

  In one embodiment of the invention, the further active ingredient is a modulator of CFTR (cystic fibrosis transmembrane conductance regulator) as described, for example, in US20046146137, US2009264433, US200926441, US2009264471, US200926441, US2009264486, WO2010019239 .

  In one embodiment of the invention, the further active ingredient is a compound that stimulates / modulates insulin release, such as those described in WO2009109258, WO2009132739, US2009181057, WO2009157418.

  In one embodiment of the present invention, the further active ingredient is an extract from Snaggi as described, for example, in WO20012571.

  In one embodiment of the present invention, the further active ingredients are from Huanglian and Ku Ding Cha, for example as described in WO200913458.

  In another embodiment, the further active ingredient is a root extract from Cipadessa baccifera as described in US200009238900.

  In one embodiment of the invention, the further active ingredient is, for example, plant SDH-V, as described in US20110016213, Borapetoside A and / or Borapetoside C, which can be isolated from the species Tinospora crispa. is there.

In one embodiment, the compound of the formula I are, bulking agents, preferably administered in combination with an insoluble bulking agents ^{(e.g., Carob / Caromax (R) (} Zunft HJ; etc., Carob pulp preparation for treatment of hypercholesterolemia , ADVANCES IN THERAPY (September-October 2001), 18 (5), 230-6) See Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt / Main). Combination with Calomax ^(R) is possible in one formulation or by separately administering the compound of Formula I and Calomax. Moreover, this respect, Caro Max ^(R), for example may also be administered in the form of food products such as bakery products or muesli bars (muesli bars).

  All suitable combinations of a compound of this invention with one or more of the above compounds and optionally one or more other pharmacologically active substances are included within the scope of protection afforded by this invention. It is understood that

In addition, the following active ingredients are suitable for the combination:
All antiepileptic drugs specified in Rote Liste 2011, Chapter 15;
All antihypertensive drugs specified in Rote Liste 2011, Chapter 17;
All hypotonics specified in Rote Liste 2011, Chapter 19;
All anticoagulants specified in Rote Liste 2011, Chapter 20;
All arteriosclerotic drugs specified in Rote Liste 2011, Chapter 25;
All beta receptors, calcium channel blockers and inhibitors of the renin-angiotensin system specified in Rote Liste 2011, Chapter 27;
All diuretics and perfusion enhancers specified in Rote Liste 2011, Chapters 36 and 37;
Rote Liste 2011, all withdrawal drugs specified in Chapter 39 / drugs to treat addictive disorders;
All coronary and gastrointestinal drugs specified in Rote Liste 2011, Chapters 55 and 60;
All migraine, neuropathic and parkinsonian drugs specified in Rote Liste 2011, Chapters 61, 66 and 70.

  All suitable combinations of a compound of this invention with one or more of the above compounds and optionally one or more other pharmacologically active substances are included within the scope of protection afforded by this invention. It is understood that

  PKC inhibitors can be administered to animals, particularly mammals including humans, alone as a drug, in a mixture with others, or in the form of a pharmaceutical composition. Administration is oral, for example in the form of tablets, film-coated tablets, dragees, granules, hard and soft gelatin capsules, solutions including aqueous, alcoholic and oily solutions, juices, drops, syrups, emulsions or suspensions. For example, rectally in the form of suppositories or parenterally in the form of solutions, in particular aqueous solutions, for example for subcutaneous, intramuscular or intravenous injection or infusion.

  Pharmaceutical compounds suitable for oral administration may be in the form of discrete units such as capsules, cachets, lozenges or tablets, as powders or granules, respectively; aqueous or non-aqueous liquids As a solution or suspension in it; or as an oil-in-water or water-in-oil emulsion containing a predetermined amount of a compound of formula I. These compositions are prepared by any suitable pharmaceutical method, as described above, comprising contacting the active ingredient and a carrier, which may consist of one or more additional ingredients. Compositions are generally produced by uniformly and uniformly mixing the active ingredient with a liquid and / or finely divided solid carrier and then shaping the product as necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets are free flowing forms of compounds, such as powders or granules, for example, in a suitable device, optionally in a binder, lubricant, inert diluent and / or one (or more) interface. It can be produced by mixing with an active agent / dispersant and tableting. Wet tablets can be made by molding in a suitable device a compound that is in powder form and is moistened with an inert liquid diluent.

  Pharmaceutical compositions suitable for oral (sublingual) administration include flavoring agents, typically lozenges containing the compound of formula I with sucrose and gum arabic or tragacanth, and inert bases such as gelatin and glycerol Or pastels containing compounds in sucrose and gum arabic.

  Coated formulations and coated delayed release formulations, particularly acid and gastric juice resistant formulations, also fall within the scope of the present invention. Suitable coatings that are resistant to gastric juice include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

  Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. This can be prepared by mixing the compound of formula I with one or more conventional solid carriers, such as cocoa butter, and shaping the resulting mixture.

  Pharmaceutical compositions suitable for parenteral administration preferably include a sterile aqueous preparation of the compound of formula I, which is preferably isotonic with the blood of the intended recipient. This formulation is preferably administered intravenously, but can also be administered by subcutaneous, intramuscular or intradermal injection. These preparations can be made preferably by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

  Other suitable administration forms are, for example, transdermal or topical administration, eg in the form of ointments, emulsions, tinctures, sprays, powders or transdermal therapeutic systems, or eg in the form of nasal sprays or aerosol mixtures, or microcapsules Inhalation administration in the form of an implant or rod.

  Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, emulsion, lotion, paste, spray, aerosol or oil. The carrier used may be petrolatum, lanolin, polyethylene glycol, alcohol and combinations of two or more of these materials. The active ingredient is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.

  Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal use may be in the form of single patches which are suitable for long-term close contact with the patient's epidermis. Such patches suitably contain the active ingredient in an aqueous solution that is buffered as needed and dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably 3% to 15%. Specific options include active ingredients released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).

  In addition, the PKC inhibitor can be used in a local drug delivery system, for example in a coated stent to prevent or reduce in-stent restenosis or by applying it locally via a catheter. The appropriate dosage form depends, inter alia, on the disease to be treated and its severity.

  The dosage of the PKC inhibitor to achieve the desired therapeutic effect depends on many factors, such as the particular compound selected, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range of 0.3 mg to 100 mg (typically 3 mg to 50 mg), for example 3 to 10 mg / kg / day per day and per kilogram of body weight. Intravenous doses may range, for example, from 0.3 mg to 1.0 mg / kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram and per minute. Infusion solutions suitable for these purposes may contain, for example, 0.1 ng to 100 mg, typically 1 ng to 100 mg per milliliter. A single dose may contain, for example, 1 mg to 10 g of the active ingredient. Thus, an ampoule for injection may contain, for example, 1 mg to 100 mg, and an orally administrable single dose formulation, such as a tablet or capsule, eg contains 1.0 to 1000 mg, typically 10 to 600 mg. But you can. To treat said condition, the compound of formula I itself may be used as a compound, but it is preferably present with a carrier that is compatible in the form of a pharmaceutical composition. Of course, the carrier must be acceptable in that it is compatible with the other ingredients of the composition and is not harmful to the health of the patient. The carrier may be solid or liquid or both and is preferably formulated as a tablet with the compound as a single dose, for example, 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of formula I, may be present as well. The pharmaceutical compositions of the present invention can be manufactured by one of the known pharmaceutical methods consisting essentially of mixing the ingredients with pharmacologically acceptable carriers and / or excipients. .

  The present invention provides novel and potent PKC inhibitors. The compounds of the present invention are selective for PKC over other kinases and are isozyme selective. Selective PKC inhibitors are those associated with diabetes and diabetic complications (eg diabetic cardiomyopathy, diabetic nephropathy, diabetic microvascular and macrovascular complications, diabetic neuropathy and diabetic retinopathy, preferably Is diabetic nephropathy, diabetic neuropathy and diabetic retinopathy), cardiovascular disease, hypertension and non-hypertension related and diseases related to ischemic and non-ischemic end organ damage (eg myocardial infarction, coronary heart Diseases, atherosclerosis, heart and kidney hypertrophy, stroke), diseases related to inflammation and fibrosis, central nervous system disorders (eg neuropathic pain), skin diseases, autoimmune diseases (eg psoriasis, type I diabetes) ) And cancer (eg, hematological tumors, gliomas, stomach and intestine cancers, skin cancers and lung cancers).

  Another subject of the invention is a process for the preparation of compounds of formula I and their salts and solvates, whereby the compounds can be obtained and are described below.

  Scheme 1 shows a first method for preparing compounds of formula I,

の残基であり、そして式ＶＩ、ＶＩＩ、ＶＩＩＩ、ＩＸ、Ｘ、ＸＩ及びＸＩＩの化合物中の基Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸ Ｒ⁹及びＲ¹⁰は、式Ｉの化合物において上記定義された通りである。式ＩＸ、Ｘ及びＸＩＩの化合物中の基Ｒ^4a及びＲ^5aは、互いに独立して、式Ｉ中の基Ｒ⁴及びＲ⁵として定義されるか又は式Ｉ中の基Ｒ⁴及びＲ⁵の前駆体であり、例えば保護された形態の官能基若しくは転換して最終的な基Ｒ⁴及びＲ⁵を得ることが
できる官能基を含むことができるかのいずれかである。式ＩＩ、ＩＩａ、ＩＩＩ、ＩＶ、Ｖ及びＶＩＩの化合物中の基Ｇ¹は、例えばメチル、エチル、プロピル、ｔｅｒｔ−ブチル又はベンジルのようなカルボン酸の保護基、好ましくはメチル又はエチルである。式Ｖ、ＶＩＩ、ＶＩＩＩ、Ｘ及びＸＩＩの化合物中の基Ｇ²は、例えば、２−テトラヒドロピラニル−基、トリメチルシリルエトキシメチル−基、ベンジル基、４−メトキシベンジル、２,５−ジメトキシベンジル基、トリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基のようなピラゾール窒素の保護基として定義される。式ＶＩの化合物中の基Ｇ³は、水素、ボロン酸又はボロン酸エステル又は環式ボロン酸エステル、例えば

である。式ＸＩ及びＸＩＩの化合物中の基Ｇ⁴は、水素又は例えばトリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基、２−テトラヒドロピラニル−基、ベンジル基、４−メトキシベンジル若しくは２,５−ジメトキシベンジル基のようなフェノール性ヒドロキシル基の保護基として定義される。式ＸＩの化合物中の基Ｇ⁵は、ボロン酸又はボロン酸エステル又は上記のような環式ボロン酸エステルである。 Where R ¹ is the formula Ia

And the groups R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ R ⁹ and R in the compounds of formula VI, VII, VIII, IX, X, XI and XII ¹⁰ is as defined above for compounds of formula I. Formula IX, groups R ^4a and R ^5a in the compounds X and XII, independently of one another, the radicals R ⁴ and R ⁵ of or in Formula I are defined as radicals R ⁴ and R ⁵ in the formula I A precursor, for example, which can contain either a protected form of a functional group or a functional group that can be converted to give the final groups R ⁴ and R ⁵ . The group G ¹ in the compounds of the formulas II, IIa, III, IV, V and VII is a protecting group for a carboxylic acid such as, for example, methyl, ethyl, propyl, tert-butyl or benzyl, preferably methyl or ethyl. The group G ² in the compounds of the formulas V, VII, VIII, X and XII is, for example, a 2-tetrahydropyranyl group, a trimethylsilylethoxymethyl group, a benzyl group, a 4-methoxybenzyl, a 2,5-dimethoxybenzyl group. , Defined as a protecting group for the pyrazole nitrogen such as a trialkylsilyl group, for example a tert-butyldimethylsilyl group. The group G ³ in the compound of formula VI is hydrogen, boronic acid or boronic acid ester or cyclic boronic acid ester, for example

It is. The group G ⁴ in the compounds of the formulas XI and XII is hydrogen or for example a trialkylsilyl group, for example a tert-butyldimethylsilyl group, a 2-tetrahydropyranyl-group, a benzyl group, 4-methoxybenzyl or 2,5-dimethoxy. Defined as a protecting group for a phenolic hydroxyl group such as a benzyl group. The group G ⁵ in the compound of formula XI is a boronic acid or boronic ester or a cyclic boronic ester as described above.

  As is known to those skilled in the art, the protecting groups used in the present invention must be selected to be compatible with the desired reaction conditions for all subsequent steps. All the protection and deprotection reactions used in all the conversions above and below are well known per se to those skilled in the art and are described in the literature, for example PJ Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 or TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley, New York, 1999, or similarly under standard conditions.

  The compound of formula II is obtained by reacting 3-aminopyrazole with a 2-oxosuccinic acid derivative of formula IIa (or its tautomerism) in the presence of an acid such as aqueous hydrochloric acid or acetic acid or trifluoroacetic acid at a temperature of about 20 ° C. to about 120 ° C. Body and / or salt). The reaction can be carried out under neat conditions or in a suitable inert solvent. The reaction time is generally from 30 minutes to 48 hours, preferably from 30 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range. Depending on the solvent and the conditions applied, the preferred regioisomer of formula II can be easily isolated from the reaction mixture by precipitation.

  The compound of formula III is obtained by reacting the compound of formula II with a chlorinating agent such as phosphorus oxychloride. The reaction is heated at neat conditions or in a suitable inert solvent such as a hydrocarbon such as benzene or toluene, or a chlorinated hydrocarbon such as 1,2-dichloroethane at a temperature between 50 ° C and 110 ° C. Can be implemented.

Subsequent iodination of the compound of formula III to obtain the compound of formula IV can be carried out using a base such as Na ₂ CO ₃ , NaHCO ₃ in water or an inert organic solvent such as acetonitrile, dimethylformamide, tetrahydrofuran and dioxane or a mixture of solvents. ₃ can be carried out by treatment with iodine in the presence of tBuOK. Preferably, this iodination reaction is carried out in iodine in saturated aqueous sodium bicarbonate at room temperature for 1-3 days to give a compound of formula IV, which is a conventional chemistry well known to those skilled in the art. Can be used to protect the compound of formula V with the appropriate G ² on the pyrazole ring nitrogen. Where G ² is a cyclic ether protecting group (eg, a tetrahydropyran group), such a group may be applied under known conditions and then removed. Such cyclic ethers can be prepared from their enol ethers (eg, 3,4-) in the presence of a suitable acid (eg, p-toluenesulfonic acid monohydrate or methanesulfonic acid) and a solvent (eg, dichloromethane). It may be bonded to the nitrogen moiety and the hydroxyl group via dihydro-2H-pyran). Functionalized the C-3 position with iodine and, after protecting the pyrazole ring nitrogen with a suitable protecting group G ^2, a suitable catalyst, with a ligand, and a vinyl aryl species Suzuki - through type of reaction - type or Heck The compound of formula VII can be obtained by synthesizing the C-3 position of the pyrazole ring with the desired vinylic R ¹ group.

A Suzuki-type reaction between a compound of formula V and a compound of formula VI where G ³ is a boronic acid or boronic ester or cyclic boronic ester is carried out in an inert solvent such as a hydrocarbon such as benzene, toluene or A palladium (II) salt which can be used in the presence of a catalytic palladium compound, such as phosphine, such as tricyclohexylphosphine or triphenylphosphine, in a mixture of xylene or ether, such as THF, dioxane or DME, or water or a solvent, For example, palladium (II) acetate or palladium (II) chloride, or a palladium complex such as tetrakis (triphenylphosphine) palladium (0), palladium (0) bis (tri-tert-butylphosphine) or bis (triphenylphosphine) At temperatures from about 20 ° C. to about 200 ° C. in the presence of palladium (II) chloride and conveniently in the presence of a base such as an alkali metal carbonate or phosphate, such as sodium carbonate or tripotassium phosphate. For example, at a temperature from about 80 ° C. to about 110 ° C. The reaction time is generally from 30 minutes to 24 hours, preferably from 30 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range.

Depending on the reaction conditions chosen to carry out the Suzuki-type coupling reaction, the carboxylic acid group of the compound of formula VII can be deprotected in situ to give the compound of formula VIII directly. If the G ¹ protecting group is maintained at selected Suzuki conditions, then preferably the carboxylic acid group is deprotected in a basic medium (eg, aqueous sodium hydroxide) to convert the compound of formula VII to the compound of formula VIII Can be converted to

Alternatively, the vinyl bond can be converted through a Heck-type reaction through a catalyst such as palladium (II) acetate, a ligand such as tri-o-tolylphosphine, a suitable base such as triethylamine or N, N-diisopropylethylamine and a solvent such as The compound of formula V can be introduced by heating with a compound of formula VI where G ³ is hydrogen in the presence of acetonitrile or DMF to give a compound of formula VII. Subsequent removal of the G ¹ protecting group provides the compound of formula VIII.

  The reaction of a compound of formula VIII with an amine of formula IX to form an amide of formula X is carried out using a suitable inert solvent such as a hydrocarbon or chlorinated hydrocarbon such as benzene, toluene, chlorobenzene, dichloromethane, dichloroethane, chloroform. Or ethers such as tetrahydrofuran, 1,4-dioxane, dibutyl ether, diisopropyl ether, methyl-tert-butyl ether, dimethoxyethane, or esters such as ethyl acetate or ethyl butyrate or amides such as N, N-dimethylformamide or N, Activating agents such as CDI, DCC, EDC, HOAt, HOBt, HATU, TOTU, TBTU, BEP or combinations thereof in N-dimethylacetamide or N-methyl-pyrrolidinone or in a mixture of solvents , And additional base, for example TEA, it is generally carried out in the presence of DIPEA or N- methylmorpholine optionally.

  The reaction temperature in this case is generally 30 ° C. to 200 ° C., preferably −20 ° C. to 80 ° C., more preferably 0 ° C. to 20 ° C. The reaction time is generally from 15 minutes to 6 days, preferably from 15 minutes to 16 hours, depending on the composition of the mixture and the temperature range selected. The acid of formula VIII can be reacted in the form of its salt, for example its sodium salt. It can also be converted to activated derivatives, such as acid chlorides or acid anhydrides by standard conversion prior to coupling with amines. The amine of formula IX can be reacted in the form of its salt, for example as the hydrochloride or triflate salt, in which case usually an additional equivalent of base is added to the reaction.

  The reaction of the compound of formula X with the compound of formula XI to the compound of formula XII is a Suzuki-type reaction and, as already mentioned above, an inert solvent such as a hydrocarbon such as benzene, toluene or xylene or ether A palladium (II) salt, such as palladium acetate, which can be used in the presence of a catalytic palladium compound, such as phosphine, such as tricyclohexylphosphine or triphenylphosphine, in a mixture of water, for example THF, dioxane or DME, or a solvent. (II) or palladium chloride (II) or a palladium complex such as tetrakis (triphenylphosphine) palladium (0), palladium (0) bis (tri-tert-butylphosphine) or bis (triphenylphosphine) palladium (II In the presence of chloride and conveniently in the presence of a base such as an alkali metal carbonate or phosphate, such as sodium carbonate or tripotassium phosphate, for example at a temperature from about 20 ° C. to about 200 ° C. It is generally carried out at a temperature from 0C to about 120C. The reaction time is generally from 30 minutes to 48 hours, preferably from 30 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range.

Compounds of formula XII can be converted to compounds of formula I in one step or in several steps depending on the meaning of the groups G ² , G ⁴ , R ^4a and R ^5a . When the groups R ^4a and / or R ^5a contain protecting groups which can be cleaved by hydrogenation, for example benzyl or 4-methoxybenzyl groups, or the groups G ² and / or G ⁴ consist of these protecting groups, One step in the conversion of a compound of formula Ia to a compound of formula I can be catalytic hydrogenation or transfer hydrogenation. Protecting groups in which the radicals R ^4a and / or R ^5a can be cleaved by treatment with acids, such as 2-tetrahydropyranyl, trimethylsilylethoxymethyl, trialkylsilyl, such as tert-butyldimethylsilyl, 4 When containing a -methoxybenzyl group, a 2,4-dimethoxybenzyl group or a tert-butoxycarbonyl group, or when the groups G ² and / or G ⁴ consist of their protecting groups, from compounds of the formula XII to compounds of the formula I One step in the conversion can be acid deprotection. The radicals R ^4a and / or R ^5a are cleaved by treatment with a suitable fluoride source, for example tetrabutylammonium fluoride, for example a 2-trimethylsilylethoxymethyl group, a trialkylsilyl group, for example a tert-butyldimethylsilyl group. when the case containing the protecting group or groups G ² and / or G ^4, which may consist of those protecting groups, one step in the conversion of the compound of formula XII to the compound of formula I, with a suitable fluoride source Can be deprotected. All deprotection reactions used in the above conversion of compounds of formula XII to compounds of formula I wherein the groups R ^4a and / or R ^5a contain protecting groups or the groups G ² and / or G ⁴ consist of protecting groups are: Well known to those skilled in the art, and in the literature, e.g. PJ Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 or TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley, New York, It can be carried out according to the method described in 1999 or similarly under standard conditions.

Alternatively, the conversion of a compound of formula XII where R ^4a and / or R ^5a is a precursor to group R ⁴ and / or R ⁵ to a compound of formula I can be carried out by standard methods, for example esterification, amidation, It may also include hydrolysis, etherification, alkylation, acylation, sulfonylation, reduction, oxidation, conversion to salts, and other functionalization or modification of included functional groups. For example, a hydroxy group that can be obtained by deprotection from a protected hydroxy group can be esterified to give a carboxylic acid ester or a sulfonic acid ester, or can be etherified. The etherification of the hydroxy group can be accomplished by using a base such as an alkali metal carbonate such as potassium carbonate or carbonate in an inert solvent such as an amide such as dimethylformamide or a ketone or butan-2-one such as N-methylpyrrolidinone or acetone. It can be conveniently carried out by alkylation with individual halogen compounds, for example bromide or iodide in the presence of cesium or with individual alcohols under the Mitsunobu reaction conditions cited above. Hydroxy groups can be converted to halides by treatment with a halogenating agent. The halogen atom can be replaced with various groups in the substitution reaction, and it can be a transition metal catalyzed reaction. Nitro groups can be reduced to amino groups, for example, by catalytic hydrogenation. Amino groups obtainable by deprotection from protected hydroxy groups are obtained under standard conditions for alkylation, for example by reaction with halogen compounds or by reductive amination of carbonyl compounds, or acylation or sulfonylation. Reaction or activators with reactive carboxylic acid derivatives such as acid chlorides or anhydrides or sulfonic acid chlorides, for example CDI, DCC, EDC, HOAt, HOBt, HATU, TOTU , TBTU, BEP or combinations thereof may be modified by reaction with a carboxylic acid or under standard conditions for carbamoylation, for example by reaction with an isocyanate. Carboxylic acid ester groups can be hydrolyzed under acidic or basic conditions to give carboxylic acids. Carboxylic acid groups can be activated or converted to reactive derivatives as described above and reacted with alcohols or amines or ammonia to give esters or amides. The primary amide can be dehydrated to give the nitrile. For example, a sulfur atom in an alkyl-S-group or in a heterocyclic ring is oxidized using a peroxide such as hydrogen peroxide or peracid to sulfoxide moiety S (O) or sulfone moiety S (O) _2. Can be obtained. Carboxylic acid groups, carboxylic acid ester groups and ketone groups can be reduced to alcohols by, for example, complex hydrides such as lithium aluminum hydride, lithium borohydride or sodium borohydride. All reactions used in the above synthesis of compounds of formula I are well known per se to those skilled in the art and can be found in the literature such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, It can be carried out according to Stuttgart, or Organic Reactions, John Wiley & Sons, New York or similarly under standard conditions.

  Scheme 2 shows a second method for preparing compounds of formula I starting from compounds of formula V

の残基であり、そして式ＸＩ、ＸＩＩ、ＸＶＩ及びＸＶＩＩの化合物中の基Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸ Ｒ⁹及びＲ¹⁰は、式Ｉの化合物において上記定義された通りである。式ＩＸ、ＸＩＩ、ＸＩＶ、ＸＶ及びＸＶＩＩの化合物中の基Ｒ^4a及びＲ^5aは、互いに独立して、式Ｉ中の基Ｒ⁴及びＲ⁵として定義された通りであるか、又は式Ｉ中の基Ｒ⁴及びＲ⁵の前駆体であり、例えば保護された形態の官能基若しくは転換して最終的な基Ｒ⁴及びＲ⁵を得ることができる官能基を含むことができるかのいずれかである。式Ｖの化合物中の基Ｇ¹は、例えばメチル、エチル、プロピル、ｔｅｒｔ−ブチル又はベンジルのようなカルボン酸の保護基、好ましくはメチル又はエチルである。式Ｖ、ＸＩＩ、ＸＩＩＩ、ＸＩＶ、ＸＶ及びＸＶＩＩの化合物中の基Ｇ²は、例えば、２−テトラヒドロピラニル−
基、トリメチルシリルエトキシメチル−基、ベンジル基、４−メトキシベンジル、２,５−ジメトキシベンジル基、トリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基のようなピラゾール窒素の保護基として定義される。式ＸＩ及びＸＩＩの化合物中の基Ｇ⁴は、水素又は例えばトリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基、２−テトラヒドロピラニル−基、ベンジル基、４−メトキシベンジル若しくは２,５−ジメトキシベンジル基のようなフェノール性ヒドロキシル基の保護基として定義される。式ＸＩの化合物中の基Ｇ⁵は、ボロン酸又はボロン酸エステル又は環式ボロン酸エステルである。式ＸＶＩの化合物中の基Ｇ⁶は、例えばヨウ化物、臭化物若しくは塩化物のようなハロゲン化物又はスルホナート、例えばトリフルオロメタンスルホナートのようなヘック−タイプの反応で置き換えることができる脱離基である。 Where R ¹ is the formula Ia

And the groups R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ R ⁹ and R ¹⁰ in the compounds of formula XI, XII, XVI and XVII are of the formula I As defined above for compounds. The groups R ^4a and R ^{5a in} the compounds of the formulas IX, XII, XIV, XV and XVII are independently of one another as defined as the groups R ⁴ and R ^{5 in the} formula I or in the formula I Either of the precursor groups R ⁴ and R ⁵ , for example, which can contain protected forms of functional groups or functional groups that can be converted to give the final groups R ⁴ and R ⁵ It is. The group G ¹ in the compound of formula V is a protecting group for a carboxylic acid such as, for example, methyl, ethyl, propyl, tert-butyl or benzyl, preferably methyl or ethyl. The group G ² in the compounds of the formulas V, XII, XIII, XIV, XV and XVII is for example 2-tetrahydropyranyl-
Defined as a protecting group for the pyrazole nitrogen such as the group, trimethylsilylethoxymethyl-group, benzyl group, 4-methoxybenzyl, 2,5-dimethoxybenzyl group, trialkylsilyl group, eg tert-butyldimethylsilyl group. The group G ⁴ in the compounds of the formulas XI and XII is hydrogen or for example a trialkylsilyl group, for example a tert-butyldimethylsilyl group, a 2-tetrahydropyranyl-group, a benzyl group, 4-methoxybenzyl or 2,5-dimethoxy. Defined as a protecting group for a phenolic hydroxyl group such as a benzyl group. The group G ⁵ in the compound of formula XI is a boronic acid or boronic ester or a cyclic boronic ester. The group G ⁶ in the compound of the formula XVI is a leaving group which can be replaced by a halide or a Heck-type reaction such as a sulfonate, for example trifluoromethanesulfonate, for example iodide, bromide or chloride. .

  The compound of formula XIII is obtained by subjecting the compound of formula V to carboxylic acid deprotection, for example in aqueous sodium hydroxide. Subsequent reaction of the compound of formula XIII with the amine of formula IX to form an amide of formula XIV can be accomplished by a suitable inert solvent such as a hydrocarbon or chlorinated hydrocarbon such as benzene, toluene, chlorobenzene, dichloromethane, dichloroethane. , Chloroform, or ether such as tetrahydrofuran, 1,4-dioxane, dibutyl ether, diisopropyl ether, methyl-tert-butyl ether, dimethoxyethane, or esters such as ethyl acetate or ethyl butyrate or amides such as N, N-dimethylformamide or In N, N-dimethylacetamide or N-methyl-pyrrolidinone or in a mixture of solvents, activators such as CDI, DCC, EDC, HOAt, HOBt, HATU, TOTU, TBTU, BEP or their The combined viewing, and additional base, for example TEA, is generally carried out in the presence of DIPEA or N- methylmorpholine optionally. The reaction temperature in this case is generally 30 ° C. to 200 ° C., preferably −20 ° C. to 80 ° C., more preferably 0 ° C. to 20 ° C. The reaction time is generally from 15 minutes to 6 days, preferably from 15 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range. The acid of formula XIII can be reacted in the form of its salt, for example its sodium salt. It can also be converted to activated derivatives such as acid chlorides or acid anhydrides by standard conversion prior to coupling with amines. The amine of formula IX can be reacted in the form of its salt, for example as the hydrochloride or triflate salt, in which case usually an additional equivalent of base is added to the reaction.

Subsequently, the C-3 position of the pyrazole ring is a suitable CH ₂ ═CH—organometallic reagent in a suitable organic solvent such as tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidinone or a mixture of solvents, for example CH ₂ = CH- tin reagent, for example tributyl (vinyl) stannane or CH ₂ = CH- boron reagent, such as potassium vinyltrifluoroborate, and a suitable catalyst, such as palladium complexes such as tetrakis (triphenylphosphine) palladium (0 ) or bis (triphenylphosphine) palladium (II) chloride, or (diphenylphosphino ferrocene) palladium (II) CH ₂ = CH- boron reagent with a chloride, such as potassium vinyltrifluoroborate, such as tertiary amines, For example, Trier When using tilamine or N, N-ethyldiisopropylamine, the desired to arrive at the compound of formula XV by treating the compound of formula XIV, preferably in the presence of a base, at a temperature from about 20 ° C. to about 120 ° C. Can be synthesized into the vinyl group. The Heck-type reaction involves the presence of a catalyst such as palladium (II) acetate, a ligand such as tri-o-tolylphosphine, a suitable base such as triethylamine or N, N-diisopropylethylamine, and a solvent such as acetonitrile or dimethylformamide. This is carried out by heating a compound of formula XV with a compound of formula XVI to give a compound of formula XII. The reaction of the compound of formula XVII with the compound of formula XI to the compound of formula XII is a Suzuki-type reaction and is generally an inert solvent such as a hydrocarbon such as benzene, toluene or xylene as already described above. Or a palladium (II) salt that can be used in the presence of a catalytic palladium compound, such as a phosphine, such as tricyclohexylphosphine or triphenylphosphine, in an ether such as THF, dioxane or DME, or a mixture of water or solvent, Palladium (II) acetate or palladium (II) chloride or palladium complexes such as tetrakis (triphenylphosphine) palladium (0), palladium (0) bis (tri-tert-butylphosphine) or bis (triphenylphosphine) para In the presence of um (II) chloride and conveniently in the presence of a base, such as an alkali metal carbonate or phosphate, such as sodium carbonate or tripotassium phosphate, at a temperature from about 20 ° C. to about 200 ° C., For example, it is carried out at a temperature from about 80 ° C. to about 120 ° C. The reaction time is generally from 30 minutes to 48 hours, preferably from 30 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range. The compound of formula XII can be converted to the compound of formula I in one or several steps as already described above in the first method of the invention.

  Further, Schemes 3 and 4 show two examples of alternative methods that are also part of the present invention, where the order of the various synthetic steps shown in Scheme 2 is altered to produce compounds of Formula I. And

の残基であり、そして式ＸＩ、ＸＩＩ、ＸＶＩ、ＸＩＸ、ＸＸ、ＸＸＩ、ＸＸＩＩ、ＸＸＩＩＩ及びＸＸＩＶの化合物中の基Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸ Ｒ⁹及びＲ¹⁰は、式Ｉの化合物において上記定義された通りである。式ＩＸ、ＸＩＩ及びＸＸＩＩＩの化合物中の基Ｒ^4a及びＲ^5aは、互いに独立して、式Ｉにおいて基Ｒ⁴及びＲ⁵として定義された通りであるか又は式Ｉ中の基Ｒ⁴及びＲ⁵の前駆体であり、例えば保護された形態の官能基若しくは転換して最終的な基Ｒ⁴及びＲ⁵を得ることができる官能基を含むことができるかのいずれかである。式Ｖ、ＸＶＩＩＩ，ＸＩＸ、ＸＸ及びＸＸＩＩの化合物中の基Ｇ¹は、例えばメチル、エチル、プロピル、ｔｅｒｔ−ブチル又はベンジルのようなカルボン酸の保護基、好ましくはメチル又はエチルである。式Ｖ、ＸＩＩ、ＸＶＩＩＩ、ＸＩＸ、ＸＸ、ＸＸＩ、ＸＸＩＩ、ＸＸＩＩＩ及びＸＸＩＶの化合物中の基Ｇ²は、例えば、２−テトラヒドロピラニル−基、トリメチルシリルエトキシメチル−基、ベンジル基、４−メトキシベンジル、２,５−ジメトキシベンジル基、トリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基のようなピラゾール窒素の保護基として定義される。式ＸＩ、ＸＩＩ、ＸＸ、ＸＸＩ、ＸＸＩＩ、ＸＸＩＩＩ及びＸＩＶの化合物中の基Ｇ⁴は、水素又は例えばトリアルキルシリル基、例えばｔｅｒｔ−ブチルジメチルシリル基、２−テトラヒドロピラニル−基、ベンジル基、４−メトキシベンジル若しくは２,５−ジメトキシベンジル基のようなフェノール性ヒドロキシル基の保護基として定義される。式ＸＩの化合物中の基Ｇ⁵は、ボロン酸又はボロン酸エステル又は環式ボロン酸エステルである。式ＸＶＩの化合物中の基Ｇ⁶は、例えばヨウ化物、臭化物若しくは塩化物のようなハロゲン化物又はスルホナート、例えばトリフルオロメタンスルホナートのようなヘック−タイプの反応で置き換えることができる脱離基である。 Here, in Scheme 3 and Scheme 4, R ¹ is of formula Ia

And the groups R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^{8 in} the compounds of formula XI, XII, XVI, XIX, XX, XXI, XXII, XXIII and XXIV R ⁹ and R ¹⁰ are as defined above for compounds of formula I. The groups R ^4a and R ^{5a in} the compounds of the formulas IX, XII and XXIII are independently of one another as defined in the formula I as groups R ⁴ and R ⁵ or the groups R ⁴ and R in the formula I ⁵ precursors, for example, which can contain either a protected form of a functional group or a functional group that can be converted to give the final groups R ⁴ and R ⁵ . The group G ¹ in the compounds of the formulas V, XVIII, XIX, XX and XXII is a protecting group for a carboxylic acid such as, for example, methyl, ethyl, propyl, tert-butyl or benzyl, preferably methyl or ethyl. The group G ² in the compounds of the formulas V, XII, XVIII, XIX, XX, XXI, XXII, XXIII and XXIV is for example 2-tetrahydropyranyl-group, trimethylsilylethoxymethyl-group, benzyl group, 4-methoxybenzyl Defined as a protecting group for the pyrazole nitrogen such as a 2,5-dimethoxybenzyl group, a trialkylsilyl group, for example a tert-butyldimethylsilyl group. The group G ⁴ in the compounds of the formulas XI, XII, XX, XXI, XXII, XXIII and XIV is hydrogen or for example a trialkylsilyl group, for example a tert-butyldimethylsilyl group, a 2-tetrahydropyranyl-group, a benzyl group, Defined as a protecting group for a phenolic hydroxyl group such as 4-methoxybenzyl or 2,5-dimethoxybenzyl group. The group G ⁵ in the compound of formula XI is a boronic acid or boronic ester or a cyclic boronic ester. The group G ⁶ in the compound of the formula XVI is a leaving group which can be replaced by a halide or a Heck-type reaction such as a sulfonate, for example trifluoromethanesulfonate, for example iodide, bromide or chloride. .

  As shown in Scheme 3, and using a method similar to that described in the previous method, the compound of formula V can be directly vinylated at the C-3 position to give the compound of formula XVIII, followed by A Heck-type reaction with a suitable compound of formula XVI yields a compound of formula XIX. Using the method previously shown in the present invention, a Suzuki-type reaction with a suitable compound of formula XI yields a compound of formula XX and deprotection of the carboxylic acid group yields a compound of formula XXI, which Is converted to an amide of formula XII by coupling with an amine of formula IX. Compounds of formula XII can be converted to compounds of formula I in one or several steps as already described above in the first method of the invention (see Scheme 1).

  As shown in Scheme 4 and using the method previously described in the present invention, a compound of formula XVIII obtained through vinylation of V is subjected to a Suzuki-type reaction using a compound of formula XI. A compound of XXII can be obtained. Subsequent cleavage of the G2 protecting group to give a compound of formula XXIII followed by coupling with an amine of formula IX provides an amide of formula XXIV. Subsequent Heck-type reaction with a compound of formula XVI yields a compound of formula XII, which is then used in one or several steps as described in the first method of the invention (see Scheme 1). Convert to the desired compound of Formula I.

As another part of the invention, R ¹ is ethylene-phenyl, where phenyl is unsubstituted or F, Cl, CH ₃ , O—CH ₃ , CF ₃ , O—CF ₃ , CN, Compounds of formula I substituted by one or two identical or different substituents selected from SO ₂ CH ₃ , CO—CH ₃ and CO—N ((CH ₃ ) ₂ are the corresponding vinyls of formula I It can be obtained in one step by reduction of the compound, for example by catalytic hydrogenation, which can be prepared according to the synthetic sequence described in Schemes 1, 2, 3 and 4.

As another part of the invention, Scheme 5 shows a process for the preparation of compounds of formula I

Where R ¹ is 2-phenylcyclopropyl, where phenyl is unsubstituted or F, Cl, CH ₃ , O—CH ₃ , CF ₃ , O—CF ₃ , CN, SO ₂ CH _3, CO-CH _3, and CO-N ((CH ₃₎ which is substituted by one or two identical or different substituents selected from _2, and the group in the compound of formula XXVI, XXVII and XXVIII R ² , R ³ are as defined for compounds of formula I. The groups R ^4a and R ^{5a in} the compounds of formulas IX and XXVIII are, independently of one another, defined as groups R ⁴ and R ⁵ in formula I. Or precursors of the groups R ⁴ and R ⁵ in formula I, eg protected forms of functional groups or functionalities that can be converted to give the final groups R ⁴ and R ⁵ Whether it can contain groups . It is or formula XXVI, group G ⁴ in the compounds of XXVII and XXVIII is hydrogen or, for example a trialkylsilyl group, for example tert- butyldimethylsilyl group, 2-tetrahydropyranyl - group, benzyl group, 4-methoxybenzyl Alternatively, it is defined as a protecting group for a phenolic hydroxyl group such as a 2,5-dimethoxybenzyl group.

  The reaction of the aminopyrazole compound of formula XXV (prepared as described in WO2008021924) with the benzaldehyde of formula XXVI and pyruvic acid is carried out in the presence of an acid, preferably refluxed in glacial acetic acid. Depending on the solvent and the conditions applied, the preferred regioisomer of formula XXVII can be easily isolated by precipitation from the reaction mixture. A compound of formula XXVII is converted to an amide of formula XXVIII by coupling with an amine of formula IX using the coupling method previously described in Scheme 1 and the compound of formula VIII is converted to a compound of formula XII.

A compound of formula XXVIII can already be a compound of formula I when G ⁴ is H and R ^4a is R ⁴ and R ^5a is R ⁵ . If the compound of formula XXVIII is not yet a compound of formula I, it can be converted to a compound of formula I in one step or in several steps depending on the meaning of the groups G ⁴ , R ^4a and R ^5a . When the radicals R ^4a and / or R ^5a contain protecting groups which can be cleaved by hydrogenation, for example benzyl or 4-methoxybenzyl, or when the radical G ⁴ consists of these protecting groups, from compounds of the formula XXVIII One step in the conversion to the compound of formula I can be catalytic hydrogenation or transfer hydrogenation. Protecting groups in which the radicals R ^4a and / or R ^5a can be cleaved by treatment with acid, such as 2-tetrahydropyranyl, trialkylsilyl, such as tert-butyldimethylsilyl, 4-methoxybenzyl, 2 When the 1,4-dimethoxybenzyl group or tert-butoxycarbonyl group is included or the group G ⁴ consists of these protecting groups, one step in the conversion of the compound of formula XXVII to the compound of formula I is acid deprotection. Can be. Groups R4a and / or R5a is a protective group which can be cleaved by treatment with a suitable fluoride source, such as tetrabutylammonium fluoride, for example trialkylsilyl groups such tert- case including butyldimethylsilyl group or a group G ⁴ Can comprise one of these protecting groups, one step in the conversion of a compound of formula XXVII to a compound of formula I can be deprotection with a suitable fluoride source. All deprotection reactions used in the above conversion from compounds of formula XII to compounds of formula I, wherein the groups R ^4a and / or R ^5a contain a protecting group or the group G ⁴ consists of a protecting group, are themselves known to those skilled in the art. And described in the literature, e.g. PJ Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 or TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley, New York, 1999. It can be carried out according to the method or likewise under standard conditions.

As another part of the invention, Scheme 6 shows a process for the preparation of compounds of formula I

In which R ¹ is ethylene- (C ₅ -C ₇ ) cycloalkyl and the groups R ² and R ^{3 in} the compounds of the formulas XI, XXXIII and XXXIV are as defined above in the compounds of the formula I. is there. The groups R ^4a and R ^{5a in} the compounds of the formulas IX, XXXII, XXXIII and XXXIV, independently of one another, are as defined in the formula I as groups R ⁴ and R ⁵ or the group R in the formula I A precursor of ⁴ and R ⁵ , for example, which can contain either a protected form of a functional group or a functional group that can be converted to give the final groups R ⁴ and R ⁵ . The group G ¹ in the compounds of the formulas V and XXX is a protecting group for a carboxylic acid such as, for example, methyl, ethyl, propyl, tert-butyl or benzyl, preferably methyl or ethyl. The group G ² in the compounds of formula V, XXX, XXXI, XXXII, XXXIII and XXXIV is, for example, 2-tetrahydropyranyl-group, trimethylsilylethoxymethyl-group, benzyl group, 4-methoxybenzyl, 2,5-dimethoxy Defined as protecting group for pyrazole nitrogen such as benzyl group, trialkylsilyl group, eg tert-butyldimethylsilyl group. The group G ⁴ in the compounds of the formulas XI, XXXIII and XXXIV is hydrogen or, for example, a trialkylsilyl group, such as a tert-butyldimethylsilyl group, a 2-tetrahydropyranyl group, a benzyl group, 4-methoxybenzyl or 2, Defined as a protecting group for a phenolic hydroxyl group such as a 5-dimethoxybenzyl group. The group G ⁵ in the compound of formula XI is a boronic acid or boronic ester or a cyclic boronic ester. The alkyne linkage of the compound of formula XXX is carried out under a typical Sonogashira reaction condition in a catalytic palladium compound such as palladium in an inert solvent such as ether such as THF, dioxane or amide such as N, N-dimethylformamide or a mixture of solvents. In the presence of a complex such as tetrakis (triphenylphosphine) palladium (0) and conveniently in the presence of a base such as a tertiary amine such as triethylamine and conveniently a copper (I) halide such as iodine. Heating the compound of formula V together with the ω-alkyne derivative of formula XXIX at a temperature of about 20 ° C. to about 200 ° C., for example, at a temperature of about 20 ° C. to about 110 ° C. in the presence of copper (I) chloride. Can be introduced. The reaction time is generally from 30 minutes to 24 hours, preferably from 30 minutes to 16 hours, depending on the composition of the mixture and the selected temperature range. Subsequent removal of the G ¹ protecting group, preferably under basic conditions (eg aqueous sodium hydroxide), yields a compound of formula XXXI which is converted to an amide of formula XXXII by coupling with an amine of formula IX. Then, using the conditions described above for converting the compound of formula X to the compound of formula XII in the first method of the invention (see Scheme 1), a typical Suzuki using a compound of formula XI -Type reaction gives compound of formula XXXIII. The compound of formula XXXIII is converted to the compound of formula XXXIV by reduction, for example, catalytic hydrogenation in the presence of a palladium compound. Compounds of formula XXXIV can be converted to compounds of formula I in one step or in several steps depending on the meaning of the groups G ² , G ⁴ , R ^4a and R ^5a . When the groups R ^4a and / or R ^5a contain protecting groups which can be cleaved by hydrogenation, for example benzyl or 4-methoxybenzyl groups, or the groups G ² and / or G ⁴ consist of these protecting groups, One step in the conversion of a compound of formula Ia to a compound of formula I can be catalytic hydrogenation or transfer hydrogenation. Protecting groups in which the radicals R ^4a and / or R ^5a can be cleaved by treatment with acids, such as 2-tetrahydropyranyl, trimethylsilylethoxymethyl, trialkylsilyl, such as tert-butyldimethylsilyl, 4 When containing a -methoxybenzyl group, a 2,4-dimethoxybenzyl group or a tert-butoxycarbonyl group, or when the groups G ² and / or G ⁴ consist of their protecting groups, from compounds of the formula XII to compounds of the formula I One step in the conversion can be acid deprotection. The radicals R ^4a and / or R ^5a can be cleaved by treatment with a suitable fluoride source, for example tetrabutylammonium fluoride, for example a 2-trimethylsilylethoxymethyl group, a trialkylsilyl group, for example a tert-butyldimethylsilyl group. One step in the conversion of a compound of formula XII to a compound of formula I, when containing possible protecting groups or when the groups G ² and / or G ⁴ consist of those protecting groups, is a desorption with a suitable fluoride source. Can be protective. All deprotection reactions used during the above conversion from compounds of formula XXXIV to compounds of formula I wherein groups R ^4a and / or R ^5a contain protecting groups or groups G ² and / or G ⁴ consist of protecting groups are: Well known to those skilled in the art, and in the literature, e.g. PJ Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 or TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley, New York, It can be carried out according to the method described in 1999 or similarly under standard conditions.

  As another part of the invention, the compounds of formula I, II, III, IV, XXVII and XXVIII may exist in other tautomeric forms as 2H-pyrazolo [3,4-b] pyridine derivatives, In this case, the mobile hydrogen atom bonded to the ring nitrogen atom at the 1-position of the pyrazolo [3,4-b] pyridine ring system in formulas I, II, III, IV, XXVII and XXVIII is pyrazolo [3,4 -B] bonded to the ring nitrogen atom at the 2-position of the pyridine ring system. It is to be understood that all compounds occurring in the preparation of compounds of formula I can exist in any tautomeric form other than those represented in those formulas, as applicable. Applies to compounds. The fact that all acidic or basic compounds occurring in the preparation of the compounds of formula I can be present in the form of their salts applies to all those compounds, unless applicable and unless otherwise specified.

  All reactions used in the above synthesis of compounds of formula I are well known per se to those skilled in the art and are described in the literature, for example in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag. , Stuttgart, or Organic Reactions, John Wiley & Sons, New York, or similarly under standard conditions. If necessary, all intermediate compounds as well as the compounds of formula I obtained can be purified by customary purification methods, for example by recrystallization or chromatography. As already mentioned, all starting compounds and intermediates used in the above synthesis, including acidic or basic groups, can also be used in the form of salts, and all intermediates and final targets The compound can also be obtained in the form of a salt. As above, depending on the circumstances of the particular case, functional groups can be temporarily blocked by introducing protective groups to avoid undesired courses of reactions or side reactions during the synthesis of the compound, It may generally be necessary or beneficial to introduce a functional group in the form of a precursor group that is deprotected at the synthetic stage or later converted to the desired functional group. Examples of protecting groups include amino protecting groups, which can be removed by treatment with acyl groups or alkyloxycarbonyl groups such as trifluoroacetic acid (= TFA), tert-butyloxycarbonyl group (= Boc), Benzyloxycarbonyl groups that can be removed by catalytic hydrogenation, or fluoren-9-ylmethoxycarbonyl groups that can be removed by treatment with piperidine, and protecting groups for carboxylic acid groups that can be protected as ester groups, such as It can be a tert-butyl ester that can be deprotected by treatment with trifluoroacetic acid, or a benzyl ester that can be deprotected by catalytic hydrogenation. Examples of precursors can include the group of nitro groups, which can be converted to amino groups by reduction, for example by catalytic hydrogenation. Such synthetic strategies and suitable protecting and precursor groups for specific cases are known to those skilled in the art.

Another subject of the present invention is the formula II, IIa, III, IV, V, VI, VII, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII in all of their stereoisomeric forms , XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXXI, XXXII, XXXIII and XXXIV (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ R ^4a , R ^5a , G ¹ , G ² , G ³ , G ⁴ , G ⁵ and G ⁶ are as defined above) or mixtures of stereoisomeric forms in all proportions thereof, and New starting compounds and intermediates that occur in the synthesis of compounds of formula I, including salts, and all solvates thereof, and their use as intermediates. The present invention also includes all tautomeric forms of the intermediates and starting compounds. All the above explanations and the embodiments specified above for the compounds of formula I apply correspondingly to said intermediates and starting compounds. Another subject of the invention is in particular the new specific starting compounds and intermediates described herein. Regardless of whether they are described as free compounds and / or as specific salts, the forms of the free compounds and their salt forms, and where specific salts are described, are further described in this specific salt form. Both, and in all their solvate forms, are the subject of the present invention.

〔Example〕
The following examples illustrate the invention. Example compounds containing basic groups were purified by preparative high pressure liquid chromatography (HPLC) on reverse phase (RP) column material and, as usual, water and acetonitrile containing trifluoroacetic acid (TFA) as eluent They were obtained in the form of their acid addition salts with trifluoroacetic acid in part depending on processing details such as evaporation or lyophilization conditions. The names of the example compounds and the trifluoroacetic acid thus contained in their structural formula are not specified at all. When the example compounds containing basicity are obtained after the acid deprotection step, they are partly hydrochloric acid and their acid addition salts depending on the details of the treatment, such as washing step with base or lyophilization conditions. Obtained in the form of The names of the example compounds and the hydrochloric acid thus contained in their structural formulas may be specified or may not be specified at all. The prepared compounds are generally characterized by spectroscopic and chromatographic data, in particular mass spectra (MS) and HPLC retention times (Rt; minutes), which are combined analytical HPLC / MS characterization (LC / MS ) And / or nuclear magnetic resonance (NMR) spectra. For NMR characterization, peak chemical shift δ (ppm), number of hydrogen atoms and multiplicity (s = single line, d = double line, dd = double double line, t = triple line, dt = 2 Double triplet, q = quadruple, m = multiple line; br = broad). In MS characterization, a molecular ion M formed according to a commonly used ionization method, eg M ⁺ , or a related ion, eg ion M + 1, eg [M + 1] ⁺ , ie a protonated molecular ion [M + H] ⁺ The peak mass number (m / z) was obtained. In general, the ionization method was electrospray ionization (ESI). The LC / MS conditions used were as follows:

Method LC1:
Column: Waters Xbridge C18 4.6 mm × 50 mm, 2.5 μM; flow rate: 1.7 ml / min; solvent A: water + 0.05% trifluoroacetic acid; solvent B: acetonitrile + 0.05% trifluoroacetic acid; 95% A + 5% B for 2 minutes, and 95% A + 5% B to 5% A + 95% B in 2.2 minutes and 1.1 minutes 5% A + 95% B; MS ionization method: ESI ⁺
Method LC2:
Column Waters Xbridge C18 4.6 mm × 50 mm, 2.5 μM; flow rate: 1.3 ml / min; solvent A: water + 0.1% formic acid; solvent B: acetonitrile + 0.1% formic acid; gradient within 3.5 minutes 97% A + 3% B to 40% A + 60% B, and 2% A + 98% B in 0.5 minutes; and 1.0% 2% A + 98% B; and 0.2% in 97% A + 3 To% B and 1.3 min 97% A + 3% B; MS ionization method: ESI ⁺
Method LC3:
Column: BEH C18 2.1 × 50 mm; 1.7 μm; flow rate: 0.9 ml; solvent A: water + 0.1% formic acid; solvent B: acetonitrile + 0.08% formic acid; gradient 95% within 1.1 minutes A + 5% B to 5% A + 95% B; and 0.6 min 5% A + 95% B; MS ionization method: ESI ⁺
Method LC8:
Instrument: Waters Acquity UPLC / SQD; Column: BEH C18 (2.1 ^* 50 mm, 1.7 μm); 50 ° C .; 0.8 mL / min; Solvent: A: H ₂ O + 0.1% HCO ₂ H; Solvent B: ACN + 0.1% HCO ₂ H: Gradient: t = 0: 5% B; t = 0.05 min: 6% B; t = 2.5 min: 100% B; MS ionization method: ESI + or ESI−
Method LC9:
UPLC / TOF-column Acquity BEH C18 (50 × 2.1 mm; 1.7 μm); 40 ° C .; Gradient 3 min ;; 1.0 ml / min; Solvent A: H ₂ O + 0.05% TFA; Solvent B: ACN + 0. 035% TFA; Gradient: T0: 98% A-T1.6 to T2.1 min: 100% B-T2.5 to T3 min: 98% A; MS ionization method: ESI + or ESI-
Method LC10:
Instrument: HPLC / ZQ; Column Kromasil C18 (50 ^{* 2, 1} mm; 3.5 μm); 40 ° C .; 0.8 mL / min; Solvent A: CH ₃ COONH ₄ 5 mM + 3% ACN; Solvent B: ACN; Gradient: T0: 100% A − T5, 5 to T7 min: 100% B − T7, 1 to T10 min: 100% A; MS ionization method: ESI + or ESI−
Method LC11
Instrument: HPLC / ZMD; Column XBridge 4.6 × 30 mm, 3 μm, 1 ml / min; Gradient 10 minutes; 1.0 ml / min; Gradient A (0.1% HCO ₂ H / H ₂ O) / B (0. 1% HCO ₂ H to ACN): t = 0: 5% B; t = 5.5 minutes: 100% B; t = 7 minutes: 100% B; MS ionization method: ESI + or ESI−

List of Abbreviations BEP 2-Bromo-1-ethylpyridinium tetrafluoroborate BOC tert. Butoxycarbonyl CDI N, N′-carbonyldiimidazole DCC 1,3-dicyclohexylcarbodiimide DCM dichloromethane DEA diethylamine DMF N, N-dimethylformamide EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EtOAc ethyl acetate EtOH ethanol
exp. No. Example number h Time HOAt 1-hydroxy-aza-benzotriazole HOBt 1-hydroxy-benzotriazole HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′- Tetramethyluronium hexafluorophosphate HPLC High pressure liquid chromatography LC Liquid chromatography MeOH Methanol Min Minute MS Mass spectrometry Rt Retention time r. t. Room temperature sep. Isolated TBTU [(benzotriazol-1-yloxy) -dimethylaminomethylene] -dimethylammonium tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TOTU O- (cyano (ethoxycarbonyl) methyleneamino) -N, N, N ′, N'-tetramethyluronium tetrafluoroborate

Example 1:
[3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone

水（１Ｌ）中の３−アミノピラゾール（２２４ｇ，２．７ｍｏｌ）の溶液に水（１．３Ｌ）中のオキサル酢酸ジエチルナトリウム塩（５６７ｇ，２．７ｍｏｌ）の溶液、次いで酢酸を４つに分けて（０．８Ｌ）加えた。反応混合物を８５℃で１５時間加熱してから室温に冷却し、そして濾過した。沈殿を水で洗浄し、次いで乾燥して表題化合物を橙色固形物（１５９ｇ，２８％）として得た。
1H NMR (250 MHz, DMSO): δ 1.35 (t, 3H), 4.36 (q, 2H,), 6.69 (s, 1H), 8.16 (s, 1H) 1.1: 6-hydroxy-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

Divide the solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) into diethyl oxalate acetate sodium salt (567 g, 2.7 mol) in water (1.3 L), then acetic acid in 4 portions. (0.8 L) was added. The reaction mixture was heated at 85 ° C. for 15 hours, then cooled to room temperature and filtered. The precipitate was washed with water and then dried to give the title compound as an orange solid (159 g, 28%).
1H NMR (250 MHz, DMSO): δ 1.35 (t, 3H), 4.36 (q, 2H,), 6.69 (s, 1H), 8.16 (s, 1H)

６−ヒドロキシ−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（１１６．４ｇ，０．５６２ｍｏｌ）及びオキシ塩化リン（５００ｍＬ）の混合物を１１０℃で６時間加熱し、次いで室温に冷却した後、減圧下で蒸発させた。残留物をＥｔＯＡｃ中に溶解し、そして沈殿を濾過した。トリエチルアミン（５００ｍＬ）を用いて濾液を中和し、そして生成した塩を濾過した。濾液を真空下で濃縮し、そしてトルエン／ＥｔＯＡｃの９／１混合物を用いてシリカゲルカラムクロマトグラフィーに残留物をかけて表題化合物を黄色固形物（２６．３ｇ，２１％）として得た。
1H NMR (200 MHz, DMSO): δ 1.4 (t, 3H), 4.43 (q, 2H,), 7.60 (s, 1H), 8.37 (s, 1H) 1.2: 6-chloro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

A mixture of 6-hydroxy-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (116.4 g, 0.562 mol) and phosphorus oxychloride (500 mL) was heated at 110 ° C. for 6 hours, then After cooling to room temperature, it was evaporated under reduced pressure. The residue was dissolved in EtOAc and the precipitate was filtered. The filtrate was neutralized with triethylamine (500 mL) and the resulting salt was filtered. The filtrate was concentrated in vacuo and the residue was subjected to silica gel column chromatography using a 9/1 mixture of toluene / EtOAc to give the title compound as a yellow solid (26.3 g, 21%).
1H NMR (200 MHz, DMSO): δ 1.4 (t, 3H), 4.43 (q, 2H,), 7.60 (s, 1H), 8.37 (s, 1H)

１Ｌの一つ口フラスコ中に６−クロロ−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（１０ｇ，４４．３ｍｍｏｌ）及びジオキサン（４００ｍｌ）を入れた。この生成した懸濁液に炭酸水素ナトリウム（０．５Ｍ，２６０ｍｌ）及びヨウ素（１１．２ｇ，４４．３ｍｍｏｌ）の飽和溶液を加えた。反応混合物を室温で２４時間撹拌し、次いでヨウ素（２５ｇ，９７．５ｍｍｏｌ）を加え、そして撹拌を４８時間続けた。次に脱色（decolouration）が完了するまでチオ硫酸ナトリウム水溶液（０．９Ｍ）を加え、そしてｐＨ＝２で氷及びＨＣｌの溶液中に注いだ。混合物を濾過して表題化合物を黄色固形物（１４．７ｇ，９５％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．５３分；ｍ／ｚ＝３５１［Ｍ＋Ｈ］⁺ 1.3: 6-Chloro-3-iodo-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

In a 1 L one-necked flask, 6-chloro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (10 g, 44.3 mmol) and dioxane (400 ml) were placed. To this resulting suspension was added a saturated solution of sodium bicarbonate (0.5 M, 260 ml) and iodine (11.2 g, 44.3 mmol). The reaction mixture was stirred at room temperature for 24 hours, then iodine (25 g, 97.5 mmol) was added and stirring was continued for 48 hours. Then an aqueous sodium thiosulfate solution (0.9 M) was added until decolouration was complete and poured into a solution of ice and HCl at pH = 2. The mixture was filtered to give the title compound as a yellow solid (14.7 g, 95%).
LC / MS (Method LC8): Rt = 1.53 min; m / z = 351 [M + H] ⁺

０℃の無水クロロホルム（２００ｍｌ）中の６−クロロ−３−ヨード−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（１４ｇ，３９．８ｍｍｏｌ）及びｐ−トルエンスルホン酸一水和物（０．７５ｇ，３．９ｍｍｏｌ）の溶液に３,４−ジヒドロ−２Ｈ−ピラン（５．４５ｍｌ，５９．７ｍｍｏｌ）を滴加した。反応混合物を室温に温まるのにまかせ、一夜撹拌し、そして減圧下で濃縮した。シクロヘキサン中の酢酸エチル（０−２０％）の段階的勾配を用いて残留物をシリカゲルカラムクロマトグラフィーにかけて表題化合物を黄色固形物（９．４ｇ，５４％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．０８分；ｍ／ｚ＝３５１［Ｍ＋Ｈ−ＴＨＰ］⁺ 1.4: 6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

6-chloro-3-iodo-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (14 g, 39.8 mmol) and mono-p-toluenesulfonic acid in anhydrous chloroform (200 ml) at 0 ° C. 3,4-Dihydro-2H-pyran (5.45 ml, 59.7 mmol) was added dropwise to a solution of hydrate (0.75 g, 3.9 mmol). The reaction mixture was allowed to warm to room temperature, stirred overnight and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using a step gradient of ethyl acetate (0-20%) in cyclohexane to give the title compound as a yellow solid (9.4 g, 54%).
LC / MS (Method LC8): Rt = 2.08 min; m / z = 351 [M + H-THP] ⁺

ジオキサン（５１ｍｌ）中の６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（２ｇ，４．５９ｍｍｏｌ）の溶液にトランス−２−（４−クロロフェニル）ビニルボロン酸（０．８３ｇ，４．５９ｍｍｏｌ）、及び炭酸セシウムの水溶液（０．３Ｍ，８．２６ｍｍｏｌ）を加えた。生成した溶液を、アルゴンを用いて脱気し、次いでテトラキス（トリフェニルホスフィン）パラジウム（０．２６ｇ，０．２３ｍｍｏｌ）を加え、そして反応混合物を一夜還流させた。ジオキサンを真空下で除去し、塩化メチレン及び水を加え、そして混合物をｐＨ＝２に酸性化した。有機層を水で洗浄し、そして塩化メチレンを用いて水相を抽出した。生成した有機層を合わせ、無水硫酸ナトリウムで乾燥し、濾過し、そして減圧下で濃縮して黄色の泡状物（foam）として表題化合物（２ｇ）を得、それをさらになんら精製することなく使用した。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．１０分；ｍ／ｚ＝３３４［Ｍ＋Ｈ−ＴＨＰ］⁺ 1.5: 6-chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxylic acid

6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (2 g, 4.59 mmol) in dioxane (51 ml) ) Was added trans-2- (4-chlorophenyl) vinylboronic acid (0.83 g, 4.59 mmol) and an aqueous solution of cesium carbonate (0.3 M, 8.26 mmol). The resulting solution was degassed with argon, then tetrakis (triphenylphosphine) palladium (0.26 g, 0.23 mmol) was added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, methylene chloride and water were added and the mixture was acidified to pH = 2. The organic layer was washed with water and the aqueous phase was extracted with methylene chloride. The resulting organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2 g) as a yellow foam that was used without further purification. did.
LC / MS (Method LC8): Rt = 2.10 min; m / z = 334 [M + H-THP] ⁺

無水テトラヒドロフラン（４２ｍｌ）及びＮ,Ｎ−ジメチルアセトアミド（１０ｍｌ）の混合物中の６−クロロ−３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸（２ｇ，４．７９ｍｍｏｌ）の溶液に１−ｂｏｃ−ピペラジン（０．９８ｇ，５．２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（０．０６ｇ，０．４８ｍｍｏｌ）、及びＮ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（０．９１ｇ，４．７９ｍｍｏｌ）を加えた。反応混合物を室温で４時間撹拌し、テトラヒドロフランを減圧下で蒸発させ、次いで水及びジクロロメタンを加えた。有機相を分離し、無水硫酸ナトリウムで乾燥し、濾過し、そして真空で濃縮した。シクロヘキサン中の酢酸エチル（０−４５％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を黄色の泡状物（１．５１ｇ，５４％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．３４分；ｍ／ｚ＝５８６［Ｍ＋Ｈ］⁺ 1.6: 4- [6-Chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4] -B] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

6-chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran- in a mixture of anhydrous tetrahydrofuran (42 ml) and N, N-dimethylacetamide (10 ml) To a solution of 2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (2 g, 4.79 mmol), 1-boc-piperazine (0.98 g, 5.27 mmol), 1-hydroxybenzo Triazole (0.06 g, 0.48 mmol) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.91 g, 4.79 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, tetrahydrofuran was evaporated under reduced pressure, then water and dichloromethane were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified on silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to give the title compound as a yellow foam (1.51 g, 54%).
LC / MS (Method LC8): Rt = 2.34 min; m / z = 586 [M + H] ⁺

ジオキサン（３８ｍｌ）中の４−［６−クロロ−３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１．５ｇ，２．５６ｍｍｏｌ）の溶液に４−ヒドロキシフェニルボロン酸（０．３９ｇ，２．８１ｍｍｏｌ）及び炭酸セシウム（０．３Ｍ，４．６ｍｍｏｌ）の水溶液を加えた。生成した溶液を、アルゴンを用いて脱気し、次いでテトラキス（トリフェニルホスフィン）パラジウム（０．１４ｇ，０．１３ｍｍｏｌ）を加え、そして反応混合物を３時間還流させた。溶媒を真空下で除去した。生成した粗混合物を、シクロヘキサン中の酢酸エチル（０−４５％）の勾配を用いてシリカゲルカラムクロマトグラフィーにかけて白色固形物として表題化合物（１．３２ｇ，８０％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．２５分；ｍ／ｚ＝６４４［Ｍ＋Ｈ］⁺ 1.7: 4- [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H -Pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6-Chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3] in dioxane (38 ml). , 4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 2.56 mmol) in a solution of 4-hydroxyphenylboronic acid (0.39 g, 2.81 mmol) and An aqueous solution of cesium carbonate (0.3M, 4.6 mmol) was added. The resulting solution was degassed with argon, then tetrakis (triphenylphosphine) palladium (0.14 g, 0.13 mmol) was added and the reaction mixture was refluxed for 3 hours. The solvent was removed under vacuum. The resulting crude mixture was subjected to silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to give the title compound (1.32 g, 80%) as a white solid.
LC / MS (Method LC8): Rt = 2.25 min; m / z = 644 [M + H] ⁺

乾燥メタノール（２０ｍｌ）中の４−［３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１．３２ｇ，２．０５ｍｍｏｌ）の溶液にジオキサン中の４Ｎ ＨＣｌ（５．１ｍｌ，２０ｍｍｏｌ）を加えた。反応混合物を３０分間還流に加熱してから室温に冷却し、そして濾過した。沈殿を単離し、そして乾燥して表題化合物の塩酸塩を橙色固形物（０．９ｇ，９０％）として得た。
ＬＣ／ＭＳ（方法ＬＣ１０）：Ｒｔ＝３．４７分；ｍ／ｚ＝４５８［Ｍ−Ｈ］⁺ 1.8: [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone

4- [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) in dry methanol (20 ml) ) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (1.32 g, 2.05 mmol) in 4N HCl in dioxane (5.1 ml) , 20 mmol). The reaction mixture was heated to reflux for 30 minutes, then cooled to room temperature and filtered. The precipitate was isolated and dried to give the hydrochloride salt of the title compound as an orange solid (0.9 g, 90%).
LC / MS (Method LC10): Rt = 3.47 min; m / z = 458 [M−H] ⁺

The following examples are described in [3-[(E) -2- (4-chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4] described immediately above. -B] Pyridin-4-yl] -piperazin-1-yl-methanone was prepared in a similar manner to the synthesis. In the fifth step, 6-chloro-3-((E) -styryl) -1- (tetrahydro-pyran-2) was obtained using trans-styrylboronic acid instead of trans-2- (4-chlorophenyl) vinylboronic acid. -Yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid was obtained (LC / MS (Method LC8): Rt = 1.88 min; m / z = 300.1 [M + H-THP] ] ⁺ ). This was reacted with each piperazine in the sixth step and with each phenylboronic acid in the seventh step and deprotected in the eighth step:

Example 14: [3-[(E) -2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-4 -Yl] -piperazin-1-yl-methanone

１,４−ジオキサン（２００ｍＬ）中の６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（２５ｇ，５７ｍｍｏｌ）の溶液に水酸化ナトリウム水溶液（１Ｍ，１８０ｍＬ）を加えた。反応混合物を室温で７時間攪拌し、次いでＨＣｌ水溶液（１Ｍ，２００ｍＬ）を注意深く加えた。水（１４０ｍＬ）を加え、そして５分撹拌した後、沈殿を濾過し、水、シクロヘキサンで洗浄し、次いで乾燥して表題化合物を黄色固形物（１７．１ｇ，７３％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．４８分；ｍ／ｚ＝３２４［Ｍ＋Ｈ−ＴＨＰ］⁺ 14.1: 6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (25 g) in 1,4-dioxane (200 mL) , 57 mmol) was added aqueous sodium hydroxide (1M, 180 mL). The reaction mixture was stirred at room temperature for 7 hours, then aqueous HCl (1M, 200 mL) was carefully added. After adding water (140 mL) and stirring for 5 min, the precipitate was filtered, washed with water, cyclohexane and then dried to give the title compound as a yellow solid (17.1 g, 73%).
LC / MS (Method LC8): Rt = 1.48 min; m / z = 324 [M + H-THP] ⁺

テトラヒドロフラン（２５０ｍＬ）及びＮ，Ｎ−ジメチルアセトアミド（４０ｍＬ）の混合物中の６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸（１７ｇ，４２ｍｍｏｌ）の溶液に１−ｂｏｃ−ピペラジン（８．６ｇ，４６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（０．５６ｇ，４．２ｍｍｏｌ）及びＮ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（８．０３ｇ，４２ｍｍｏｌ）を加えた。反応混合物を室温で２０時間攪拌し、次いでＴＨＦを真空下で蒸発させた。次いで炭酸水素塩（２００ｍＬ）の水溶液を加え、そして混合物を１時間撹拌した。沈殿を濾過し、水で洗浄し、次いで乾燥して表題化合物を黄色固形物（２４ｇ，１００％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．７５分；ｍ／ｚ＝４３６［Ｍ＋Ｈ−ＴＨＰ−ｔＢｕ］⁺ 14.2: 4- [6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

6-chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine in a mixture of tetrahydrofuran (250 mL) and N, N-dimethylacetamide (40 mL) To a solution of 4-carboxylic acid (17 g, 42 mmol), 1-boc-piperazine (8.6 g, 46 mmol), 1-hydroxybenzotriazole (0.56 g, 4.2 mmol) and N- (3-dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride (8.03 g, 42 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours and then the THF was evaporated under vacuum. An aqueous solution of bicarbonate (200 mL) was then added and the mixture was stirred for 1 hour. The precipitate was filtered, washed with water and then dried to give the title compound as a yellow solid (24 g, 100%).
LC / MS (Method LC8): Rt = 1.75 min; m / z = 436 [M + H-THP-tBu] ⁺

１Ｌの一つ口フラスコ中に４−［６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（２１．３ｇ，３７ｍｍｏｌ）、無水テトラヒドロフラン（３７０ｍｌ）及びトリブチル（ビニル）スタナン（１１．９ｍｌ，４０．７ｍｍｏｌ）を入れた。アルゴンを用いて混合物を１５分間脱気し、次いでジクロロビス（トリフェニルホスフィン）パラジウム（１．３ｇ，１．８ｍｍｏｌ）を加えた。生成した溶液をアルゴン下８０℃で一夜加熱し、次いで減圧下で蒸発させた。酢酸エチル及び５％フッ化カリウム水溶液を残留物に加え、生成した沈殿を濾過した。濾液を回収し、そして二層を分離し、有機相を水で洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、そして真空下で濃縮した。シクロヘキサン中の酢酸エチル（０−４０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗生成物を精製して表題化合物を茶色の泡状物（１２．３ｇ，７０％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．７４分；ｍ／ｚ＝４７５［Ｍ＋Ｈ］⁺ 14.3: 4- [6-Chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine in a 1 L one-necked flask 1-carboxylic acid tert-butyl ester (21.3 g, 37 mmol), anhydrous tetrahydrofuran (370 ml) and tributyl (vinyl) stannane (11.9 ml, 40.7 mmol) were added. The mixture was degassed with argon for 15 minutes and then dichlorobis (triphenylphosphine) palladium (1.3 g, 1.8 mmol) was added. The resulting solution was heated overnight at 80 ° C. under argon and then evaporated under reduced pressure. Ethyl acetate and 5% aqueous potassium fluoride solution were added to the residue, and the resulting precipitate was filtered. The filtrate was collected and the two layers were separated and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel column chromatography using a gradient of ethyl acetate (0-40%) in cyclohexane to give the title compound as a brown foam (12.3 g, 70%).
LC / MS (Method LC8): Rt = 1.74 min; m / z = 475 [M + H] ⁺

無水ジクロロメタン（１３０ｍｌ）中３−ヨード−ベンズアルデヒド（３ｇ，１２．９ｍｍｏｌ）の冷（０℃）溶液に酢酸（１．９ｍｌ）及びＮ,Ｎ−ジメチルアセトアミドを加えた。黄色溶液を０℃で１０分間撹拌し、そしてナトリウムトリアセトキシボロヒドリド（６．８５ｇ，３２．３３ｍｍｏｌ）を少しずつ加えた。生成した混合物を室温で９０分間撹拌し、そして減圧下で蒸発乾固した。酢酸エチル及び飽和炭酸水素水溶液を残留物に加え、そして二層を分離した。有機相を水で洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、そして真空下で濃縮して茶色の油として（３−ヨードベンジル）−ジメチルアミン（３．０５ｇ，９０％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝０．８６分；ｍ／ｚ＝２６２［Ｍ＋Ｈ］⁺ 14.4: (3-Iodobenzyl) -dimethyl-amine

Acetic acid (1.9 ml) and N, N-dimethylacetamide were added to a cold (0 ° C.) solution of 3-iodo-benzaldehyde (3 g, 12.9 mmol) in anhydrous dichloromethane (130 ml). The yellow solution was stirred at 0 ° C. for 10 minutes and sodium triacetoxyborohydride (6.85 g, 32.33 mmol) was added in portions. The resulting mixture was stirred at room temperature for 90 minutes and evaporated to dryness under reduced pressure. Ethyl acetate and saturated aqueous bicarbonate were added to the residue and the two layers were separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (3-iodobenzyl) -dimethylamine (3.05 g, 90%) as a brown oil.
LC / MS (Method LC8): Rt = 0.86 min; m / z = 262 [M + H] ⁺

２５０ｍｌの丸底フラスコに４−［６−クロロ−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１．２ｇ，２．５２ｍｍｏｌ）、（３−ヨード−ベンジル）−ジメチル−アミン（１．６４ｇ，６．３ｍｍｏｌ）、テトラブチルアンモニウムブロミド（０．３２ｇ，１ｍｍｏｌ）、炭酸水素ナトリウム（０．５３ｇ，６．３ｍｍｏｌ）及び無水ジメチルホルムアミド（４２ｍｌ）を入れた。アルゴンを用いて混合物を１０分間脱気し、次いで酢酸パラジウム（０．０５ｇ，０．２５ｍｍｏｌ）を加えた。生成した溶液をアルゴン下１００℃で一夜加熱した。ジメチルホルムアミドを真空下で除去し、ジクロロメタン及び水を残留物に加え、有機層を抽出した後、無水硫酸ナトリウムで乾燥し、濾過し、そして減圧下で濃縮して粗生成物を得た。ジクロロメタン中のメタノール（０−５％）の勾配を用いてシリカゲルカラムクロマトグラフィー上でさらに精製して表題化合物を茶色の固形物（０．４４ｇ，２９％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．１７分；ｍ／ｚ＝６０９［Ｍ＋Ｈ］⁺ 14.5: 4- [6-Chloro-3-[(E) -2- (3-dimethylaminomethyl-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3 , 4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

In a 250 ml round bottom flask was added 4- [6-chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1- Carboxylic acid tert-butyl ester (1.2 g, 2.52 mmol), (3-iodo-benzyl) -dimethyl-amine (1.64 g, 6.3 mmol), tetrabutylammonium bromide (0.32 g, 1 mmol), carbonic acid Sodium hydride (0.53 g, 6.3 mmol) and anhydrous dimethylformamide (42 ml) were added. The mixture was degassed with argon for 10 minutes and then palladium acetate (0.05 g, 0.25 mmol) was added. The resulting solution was heated at 100 ° C. overnight under argon. Dimethylformamide was removed under vacuum, dichloromethane and water were added to the residue, the organic layer was extracted, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Further purification on silica gel column chromatography using a gradient of methanol in dichloromethane (0-5%) gave the title compound as a brown solid (0.44 g, 29%).
LC / MS (Method LC8): Rt = 1.17 min; m / z = 609 [M + H] ⁺

４−［６−クロロ−３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを４−［６−クロロ−３−［（Ｅ）−２−（３−ジメチルアミノメチル−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルで置き換えることを除いて実施例１．７に記載された方法を用いて、４−［３−［（Ｅ）−２−（３−ジメチルアミノメチル−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを黄色固形物（０．２５ｇ，５２％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．２２分；ｍ／ｚ＝６６７［Ｍ＋Ｈ］⁺ 14.6: 4- [3-[(E) -2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydropyran-2-yl)- 1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6-Chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine -4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester was converted to 4- [6-chloro-3-[(E) -2- (3-dimethylaminomethyl-phenyl) -vinyl] -1- (tetrahydro -Pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid described in Example 1.7 except replacing with tert-butyl ester Using the method, 4- [3-[(E) -2- (3-dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl ) -1H- Razoro [3,4-b] pyridine-4-carbonyl] - piperazine-1-carboxylic acid tert- butyl ester as a yellow solid (0.25g, 52%).
LC / MS (Method LC8): Rt = 1.22 min; m / z = 667 [M + H] ⁺

乾燥メタノール（５ｍｌ）中の４−［３−［（Ｅ）−２−（３−ジメチルアミノメチル−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．２５ｇ，０．３７ｍｍｏｌ）の冷溶液（０℃）に６Ｎ ＨＣｌ（０．７ｍｌ，３．８ｍｍｏｌ）水溶液を滴加した。反応混合物を室温に温まるのにまかせ、そして撹拌を２時間続けた後、減圧下で濃縮した。水性６Ｎ ＨＣｌ（０．７ｍｌ，３．８ｍｍｏｌ）を粗混合物に加え、そしてさらに１時間撹拌を続けた。溶媒を真空下で蒸発させ、メタノール及びジエチルエーテルを加え、生成した沈殿を濾過し、そして乾燥して表題化合物の塩酸塩を橙色固形物（０．２１ｇ；９５％）として得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．６８分；ｍ／ｚ＝４８３［Ｍ＋Ｈ］⁺ 14.7: [3-[(E) -2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-4 -Yl] -piperazin-1-yl-methanone

4- [3-[(E) -2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2) in dry methanol (5 ml) -Yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.25 g, 0.37 mmol) in a cold solution (0 ° C.) with 6N HCl An aqueous solution (0.7 ml, 3.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 hours before concentrating under reduced pressure. Aqueous 6N HCl (0.7 ml, 3.8 mmol) was added to the crude mixture and stirring was continued for an additional hour. The solvent was evaporated under vacuum, methanol and diethyl ether were added, the resulting precipitate was filtered and dried to give the hydrochloride salt of the title compound as an orange solid (0.21 g; 95%).
LC / MS (Method LC9): Rt = 0.68 min; m / z = 483 [M + H] ⁺

（３−ヨード−ベンジル）−ジメチル−アミンを１−ヨード−３−［（メチルスルホニル）メチル］−ベンゼン（ＷＯ００１５６０９に記載のとおり製造）で置き換えることを除いて実施例１４の記載と同じ合成順序を用いて、｛６−（４−ヒドロキシ−フェニル）−３−［（Ｅ）−２−（３−メタンスルホニルメチル−フェニル）−ビニル］−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル｝−ピペラジン−１−イル−メタノンを塩酸塩として得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．８分；ｍ／ｚ＝５１８［Ｍ＋Ｈ］⁺ Example 15: {6- (4-hydroxy-phenyl) -3-[(E) -2- (3-methanesulfonylmethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridine-4 -Yl} -piperazin-1-yl-methanone

The same synthetic sequence as described in Example 14 except that (3-iodo-benzyl) -dimethyl-amine is replaced with 1-iodo-3-[(methylsulfonyl) methyl] -benzene (prepared as described in WO0015609). {6- (4-hydroxy-phenyl) -3-[(E) -2- (3-methanesulfonylmethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridine-4 -Il} -piperazin-1-yl-methanone was obtained as the hydrochloride salt.
LC / MS (Method LC9): Rt = 0.8 min; m / z = 518 [M + H] ⁺

Example 16
((R) -2-Hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine- 4-yl] -methanone

無水テトラヒドロフラン（１１５ｍｌ）中の６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（５．００ｇ，１１．４８ｍｍｏｌ）の溶液にトリブチル（ビニル）スタナン（３．５２ｍｌ，１２．０５ｍｍｏｌ）を加えた。アルゴンを用いて混合物を１５分間脱気し、次いでジクロロビス（トリフェニルホスフィン）パラジウム（０．４０ｇ，０．５７ｍｍｏｌ）を加えた。生成した溶液をアルゴン下８０℃で一夜加熱し、そして減圧下で蒸発させた。酢酸エチル及び５％フッ化カリウム水溶液を残留物に加え、生成した沈殿を濾過した。濾液を回収し、そして二層を分離し、有機相をブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、そして真空下で濃縮した。シクロヘキサン中の酢酸エチル（０−１０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗生成物を精製して表題化合物を黄色固形物（３．２４ｇ，８４％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．９７分；ｍ／ｚ＝２５１［Ｍ＋Ｈ−ＴＨＰ］⁺ 16.1: 6-Chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

6-Chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (5.00 g, in anhydrous tetrahydrofuran (115 ml) Tributyl (vinyl) stannane (3.52 ml, 12.05 mmol) was added to a solution of 11.48 mmol). The mixture was degassed with argon for 15 minutes and then dichlorobis (triphenylphosphine) palladium (0.40 g, 0.57 mmol) was added. The resulting solution was heated overnight at 80 ° C. under argon and evaporated under reduced pressure. Ethyl acetate and 5% aqueous potassium fluoride solution were added to the residue, and the resulting precipitate was filtered. The filtrate was collected and the two layers were separated and the organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified on silica gel column chromatography using a gradient of ethyl acetate (0-10%) in cyclohexane to give the title compound as a yellow solid (3.24 g, 84%).
LC / MS (Method LC8): Rt = 1.97 min; m / z = 251 [M + H-THP] ⁺

４−［６−クロロ−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを６−クロロ−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステルで、そして（３−ヨードベンジル）−ジメチルアミンをヨードベンゼンで置き換えることを除いて実施例１４．５に記載された方法を用いて、６−クロロ−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステルを黄色固形物（２．８ｇ，６５％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．２２分；ｍ／ｚ＝４１２［Ｍ＋Ｈ］⁺ 16.2: 6-Chloro-3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

4- [6-Chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester 6-chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester and (3-iodobenzyl) -dimethyl Using the method described in Example 14.5 except replacing the amine with iodobenzene, 6-chloro-3-((E) -styryl) -1- (tetrahydro-pyran-2-yl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester was obtained as a yellow solid (2.8 g, 65%).
LC / MS (Method LC8): Rt = 2.22 min; m / z = 412 [M + H] ⁺

ジオキサン（６０ｍｌ）中の６−クロロ−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（２．８ｇ，６．８０ｍｍｏｌ）の溶液に４−ヒドロキシフェニルボロン酸（１．０３ｇ，７．４８ｍｍｏｌ）及び炭酸セシウムの水溶液（０．４Ｍ，３０ｍＬ）を加えた。生成した溶液を、アルゴンを用いて脱気し、次いでテトラキス（トリフェニルホスフィン）パラジウム（０．７１ｇ，０．６１ｍｍｏｌ）を加え、そして反応混合物を一夜還流させた。ジオキサンを真空下で除去し、塩化メチレン及び水を加え、そして混合物をｐＨ＝２に酸性化した。有機層を水で洗浄し、そして塩化メチレンを用いて水相を抽出した。生成した有機層を合わせ、無水硫酸ナトリウムで乾燥し、濾過し、そして減圧下で濃縮して黄色固形物として表題化合物（２．３７ｇ，７９％）を得、それをさらになんら精製することなく使用した。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．９２分；ｍ／ｚ＝４４２［Ｍ＋Ｈ］⁺ 16.3: 6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4- carboxylic acid

6-Chloro-3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester in dioxane (60 ml) To a solution of (2.8 g, 6.80 mmol) was added 4-hydroxyphenylboronic acid (1.03 g, 7.48 mmol) and an aqueous solution of cesium carbonate (0.4 M, 30 mL). The resulting solution was degassed with argon, then tetrakis (triphenylphosphine) palladium (0.71 g, 0.61 mmol) was added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, methylene chloride and water were added and the mixture was acidified to pH = 2. The organic layer was washed with water and the aqueous phase was extracted with methylene chloride. The resulting organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.37 g, 79%) as a yellow solid that was used without any further purification. did.
LC / MS (Method LC8): Rt = 1.92 min; m / z = 442 [M + H] ⁺

６−クロロ−３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸を６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸で、そして１−ｂｏｃ−ピペラジンを（Ｒ）−３−ヒドロキシメチル−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルで置き換えることを除いて実施例１．６に記載された方法を用いて（Ｒ）−３−ヒドロキシメチル−４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．１６ｇ，２８％）を黄色固形物として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．８６分；ｍ／ｚ＝６４０［Ｍ＋Ｈ］⁺ 16.4: (R) -3-hydroxymethyl-4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H- Pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

6-chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4- Carboxylic acid is converted to 6- (4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid Using the method described in Example 1.6 except that 1-boc-piperazine is replaced with (R) -3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (R ) -3-Hydroxymethyl-4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4 b] Pyridine-4-carbo Le] - piperazine-1-carboxylic acid tert- butyl ester (0.16g, 28%) as a yellow solid.
LC / MS (Method LC8): Rt = 1.86 min; m / z = 640 [M + H] ⁺

４−［３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを（Ｒ）−３−ヒドロキシメチル−４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルで置き換えることを除いて実施例１．８に記載された方法を用いて、（（Ｒ）−２−ヒドロキシメチル−ピペラジン−１−イル）−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル］−メタノンの塩酸塩を赤色固形物（０．１２ｇ，９１％）として得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．８分；ｍ／ｚ＝４５６［Ｍ＋Ｈ］⁺ 16.5: ((R) -2-hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4- b] pyridin-4-yl] -methanone

4- [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3 , 4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester as (R) -3-hydroxymethyl-4- [6- (4-hydroxy-phenyl) -3-((E ) -Styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid, except for replacement with tert-butyl ester Using the method described in Example 1.8, ((R) -2-hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) ) -1H Pyrazolo [3,4-b] pyridin-4-yl] - methanone hydrochloride salt of a red solid (0.12g, 91%) was obtained as a.
LC / MS (Method LC9): Rt = 0.8 min; m / z = 456 [M + H] ⁺

Example 17:
[6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone

トランス−２−（４−クロロフェニル）ビニルボロン酸をトランス−２−フェニルビニルボロン酸で置き換えることを除いて第７の工程まで実施例１に記載された方法を用いて、（４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１カルボン酸ｔｅｒｔ−ブチルエステルを黄色固形物として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．９９分；ｍ／ｚ＝６１０［Ｍ＋Ｈ］⁺ 17.1: 4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine -4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

Using the method described in Example 1 up to the seventh step, except replacing trans-2- (4-chlorophenyl) vinylboronic acid with trans-2-phenylvinylboronic acid, (4- [6- ( 4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1carboxylic The acid tert-butyl ester was obtained as a yellow solid.
LC / MS (Method LC8): Rt = 1.99 min; m / z = 610 [M + H] ⁺

乾燥メタノール（４０ｍｌ）中の４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．７４ｇ，１．２２ｍｍｏｌ）の溶液にＰｄ／Ｃ（１５０ｍｇ）を加えた。反応混合物を水素雰囲気下で１時間撹拌し、濾過し、そして減圧下で濃縮した。粗残留物を乾燥メタノール（３０ｍｌ）中に溶解し、そしてＰｄ／Ｃ（１５０ｍｇ）を加えた。混合物を１バールの水素圧にかけ、そして１時間撹拌し、濾過し、そして真空下で濃縮して表題化合物（０．７２ｇ，９６％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．１０分；ｍ／ｚ＝６１２［Ｍ＋Ｈ］⁺ 17.2: 4- [6- (4-Hydroxy-phenyl) -3-phenethyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl]- Piperazine-1-carboxylic acid tert-butyl ester

4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4- in dry methanol (40 ml) b] Pd / C (150 mg) was added to a solution of pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.74 g, 1.22 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 1 hour, filtered and concentrated under reduced pressure. The crude residue was dissolved in dry methanol (30 ml) and Pd / C (150 mg) was added. The mixture was subjected to 1 bar of hydrogen pressure and stirred for 1 hour, filtered and concentrated in vacuo to give the title compound (0.72 g, 96%).
LC / MS (Method LC8): Rt = 2.10 min; m / z = 612 [M + H] ⁺

４−［３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを４−［６−（４−ヒドロキシ−フェニル）−３−フェネチル−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルで置き換えることを除いて実施例１．８に記載された方法を用いて、［６−（４−ヒドロキシ−フェニル）−３−フェネチル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル］−ピペラジン−１−イル−メタノンの塩酸塩を黄色固形物（０．５ｇ，定量的）として得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．７３分；ｍ／ｚ＝４２８［Ｍ＋Ｈ］⁺ 17.3: [6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone

4- [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3 , 4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester to 4- [6- (4-hydroxy-phenyl) -3-phenethyl-1- (tetrahydro-pyran-2-yl ) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid using the method described in Example 1.8 except replacing with tert-butyl ester 6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone hydrochloride was converted to a yellow solid (0.5 g, Was obtained as a quantitative).
LC / MS (Method LC9): Rt = 0.73 min; m / z = 428 [M + H] ⁺

Example 18: (±)-[6- (4-Hydroxy-phenyl) -3trans- (2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone

乾燥ジオキサン（６０ｍＬ）中の水素化ナトリウム（油中６０％，２．０３ｇ，５０．７８ｍｍｏｌ）の懸濁液にアセトニトリル（２．６５ｍＬ，５０．７８ｍｍｏｌ）を滴加した。３０分後、乾燥ジオキサン（３０ｍｌ）中の（±）−エチルトランス−２−フェニルシクロプロパンカルボキシレート（８．０５ｇ，４２．３１ｍｍｏｌ）の溶液を反応混合物に滴加した。懸濁液を１００℃で３時間加熱し、０℃に冷却した後、水及びジクロロメタンを加えた。１Ｍ ＨＣｌ水溶液を加えて混合物をｐＨ＝５に酸性化した。有機層を分離し、そして水層をジクロロメタンで抽出した。合わせた有機抽出物を乾燥し（ＭｇＳＯ₄）、濾過し、真空下で濃縮した。シクロヘキサン中のＥｔＯＡｃ（０−３０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して無色の油として表題化合物（３．１７ｇ，４０％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．２８分；ｍ／ｚ＝１８６［Ｍ＋Ｈ］⁺ 18.1: (±) -3-oxo-3trans- (2-phenyl-cyclopropyl) -propionitrile

Acetonitrile (2.65 mL, 50.78 mmol) was added dropwise to a suspension of sodium hydride (60% in oil, 2.03 g, 50.78 mmol) in dry dioxane (60 mL). After 30 minutes, a solution of (±) -ethyltrans-2-phenylcyclopropanecarboxylate (8.05 g, 42.31 mmol) in dry dioxane (30 ml) was added dropwise to the reaction mixture. The suspension was heated at 100 ° C. for 3 hours, cooled to 0 ° C., and water and dichloromethane were added. 1M aqueous HCl was added to acidify the mixture to pH = 5. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under vacuum. The crude residue was purified on silica gel column chromatography using a gradient of EtOAc in cyclohexane (0-30%) to give the title compound (3.17 g, 40%) as a colorless oil.
LC / MS (Method LC8): Rt = 1.28 min; m / z = 186 [M + H] ⁺

エタノール（７０ｍＬ）中の（±）−３−オキソ−３−トランス−（２−フェニル−シクロプロピル）−プロピオニトリル（３．１５ｇ，１７ｍｍｏｌ）の溶液にヒドラジン一水和物（０．８２ｍＬ，１７ｍｍｏｌ）を加えた。反応混合物を８５℃で２．５時間加熱し、次いで真空下で濃縮した。残留物をＥｔＯＡｃ中に溶解し、次いで有機層をブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮して黄色の油として表題化合物（３．２５ｇ，９６％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝０．７１分；ｍ／ｚ＝２００［Ｍ＋Ｈ］⁺ 18.2: (±) -5-trans- (2-phenyl-cyclopropyl) -2H-pyrazol-3-ylamine

To a solution of (±) -3-oxo-3-trans- (2-phenyl-cyclopropyl) -propionitrile (3.15 g, 17 mmol) in ethanol (70 mL) was added hydrazine monohydrate (0.82 mL, 17 mmol) was added. The reaction mixture was heated at 85 ° C. for 2.5 hours and then concentrated under vacuum. The residue was dissolved in EtOAc, then the organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (3.25 g, 96%) as a yellow oil. Got.
LC / MS (Method LC8): Rt = 0.71 min; m / z = 200 [M + H] ⁺

（±）−５−トランス−（２−フェニル−シクロプロピル）−２Ｈ−ピラゾール−３−イルアミン（３．２４ｇ，１６．２６ｍｍｏｌ）、４−ヒドロキシベンズアルデヒド（１．９８ｇ，１６．２６ｍｍｏｌ）、ピルビン酸（１．１３ｍｌ，１６．２６ｍｍｏｌ）及び氷酢酸（２５ｍｌ）を窒素下で還流に１．５時間加熱し、次いで減圧下で蒸発させた。残留物をジエチルエーテル中に溶解し、沈殿を濾過し、そしてジエチルエーテルで洗浄して茶色の固形物として粗表題化合物（４ｇ，６７％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．５３分；ｍ／ｚ＝３７２［Ｍ＋Ｈ］⁺ 18.3: (±) -6- (4-Hydroxy-phenyl) -3- (trans-2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

(±) -5-trans- (2-phenyl-cyclopropyl) -2H-pyrazol-3-ylamine (3.24 g, 16.26 mmol), 4-hydroxybenzaldehyde (1.98 g, 16.26 mmol), pyruvic acid (1.13 ml, 16.26 mmol) and glacial acetic acid (25 ml) were heated to reflux under nitrogen for 1.5 hours and then evaporated under reduced pressure. The residue was dissolved in diethyl ether, the precipitate was filtered and washed with diethyl ether to give the crude title compound (4 g, 67%) as a brown solid.
LC / MS (Method LC8): Rt = 1.53 min; m / z = 372 [M + H] ⁺

テトラヒドロフラン（２９ｍＬ）及びＮ,Ｎ−ジメチルアセトアミド（３ｍＬ）の混合物中の（±）−６−（４−ヒドロキシ−フェニル）−３−（トランス−２−フェニル−シクロプロピル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸（１．２ｇ，３．２３ｍｍｏｌ）の溶液に１−ｂｏｃ−ピペラジン（０．７２ｇ，３．８８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（５２ｍｇ，０．３９ｍｍｏｌ）、及びＮ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（０．７４ｇ，３．８８ｍｍｏｌ）を加えた。反応混合物を室温で１８時間撹拌し、ＥｔＯＡｃ及びクエン酸の水溶液を加えた。有機層を分離し、そして水層をＥｔＯＡｃで抽出した。合わせた有機抽出物をブラインで洗浄し、乾燥し（ＭｇＳＯ₄）、濾過し、真空下で濃縮した。シクロヘキサン中のＥｔＯＡｃ（２０−６０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を黄色のロウ（０．０９ｇ，９％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．６８分；ｍ／ｚ＝５４０［Ｍ＋Ｈ］⁺ 18.4: (±) -4- [6- (4-Hydroxy-phenyl) -3-trans- (2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -Piperazine-1-carboxylic acid tert-butyl ester

(±) -6- (4-Hydroxy-phenyl) -3- (trans-2-phenyl-cyclopropyl) -1H-pyrazolo [3] in a mixture of tetrahydrofuran (29 mL) and N, N-dimethylacetamide (3 mL). , 4-b] pyridine-4-carboxylic acid (1.2 g, 3.23 mmol) in a solution of 1-boc-piperazine (0.72 g, 3.88 mmol), 1-hydroxybenzotriazole (52 mg, 0.39 mmol) , And N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.74 g, 3.88 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours and EtOAc and an aqueous solution of citric acid were added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under vacuum. The crude residue was purified on silica gel column chromatography using a gradient of EtOAc in cyclohexane (20-60%) to give the title compound as a yellow wax (0.09 g, 9%).
LC / MS (Method LC8): Rt = 1.68 min; m / z = 540 [M + H] ⁺

メタノール（３．３ｍｌ）中の（±）−４−［６−（４−ヒドロキシ−フェニル）−３−トランス−（２−フェニル−シクロプロピル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．１２ｇ，０．２３ｍｍｏｌ）の溶液にジオキサン（０．３ｍｌ）中の４Ｎ ＨＣｌを加えた。反応混合物を室温で１８時間撹拌し、次いでジエチルエーテルを加え、生成した沈殿を濾過し、そしてジエチルエーテルで１回洗浄して橙色固形物として表題化合物の塩酸塩（０．０９ｇ，８０％）を得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．８２分；ｍ／ｚ＝４４０［Ｍ＋Ｈ］⁺ 18.5: (±)-[6- (4-Hydroxy-phenyl) -3-trans- (2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone (SAR240501A)

(±) -4- [6- (4-Hydroxy-phenyl) -3-trans- (2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridine in methanol (3.3 ml) To a solution of 4-yl] -piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) was added 4N HCl in dioxane (0.3 ml). The reaction mixture was stirred at room temperature for 18 hours, then diethyl ether was added and the resulting precipitate was filtered and washed once with diethyl ether to give the hydrochloride salt of the title compound (0.09 g, 80%) as an orange solid. Obtained.
LC / MS (Method LC9): Rt = 0.82 min; m / z = 440 [M + H] ⁺

Example 19: (6- (4-Hydroxy-phenyl) -3-{(E) -2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1H-pyrazolo [3,4-b ] Pyridin-4-yl) -piperazin-1-yl-methanone

ジクロロメタン（２５ｍＬ）中の４−ヨードベンゾイルクロリド（２．００ｇ，７．５１ｍｍｏｌ）の懸濁液にピペリジン（１．８５ｍＬ，１８．７６ｍｍｏｌ）を加えた。反応混合物を還流で１．５時間加熱し、次いで室温に冷却した。有機層を水性１Ｍ ＨＣｌ溶液、ブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮して白色固形物として表題化合物（２．３７ｇ，１００％）を得た。
1H NMR (400 MHz, CDCl₃): δ 1.40-1.65 (m, 6H), 3.18-3.68 (m, 4H), 7.06-7.10 (m, 2H), 7.66-7.70 (m, 2H) 19.1: (4-Iodophenyl) -piperidin-1-yl-methanone

To a suspension of 4-iodobenzoyl chloride (2.00 g, 7.51 mmol) in dichloromethane (25 mL) was added piperidine (1.85 mL, 18.76 mmol). The reaction mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The organic layer was washed with aqueous 1M HCl solution, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (2.37 g, 100%) as a white solid.
1H NMR (400 MHz, CDCl ₃ ): δ 1.40-1.65 (m, 6H), 3.18-3.68 (m, 4H), 7.06-7.10 (m, 2H), 7.66-7.70 (m, 2H)

ジオキサン（５４ｍＬ）中の実施例１６．１に記載された６−クロロ−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（２．００ｇ，５．９６ｍｍｏｌ）の溶液に４−ヒドロキシフェニルボロン酸（０．９０ｇ，６．５５ｍｍｏｌ）及び炭酸セシウム（０．４Ｍ，２７ｍＬ，１０．８ｍｍｏｌ）の水溶液を加えた。生成した溶液を、アルゴンを用いて脱気し、次いでテトラキス（トリフェニルホスフィン）パラジウム（０．６２ｇ，０．５４ｍｍｏｌ）を加え、そして反応混合物を一夜還流させた。ジオキサンを真空下で除去し、水を加え、次いで混合物をｐＨ＝２に酸性化した。水相をテトラヒドロフラン及びＥｔＯＡｃの混合物で抽出した。合わせた有機抽出物をブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮して茶色の泡状物として表題化合物（３．１３ｇ）を得、これをさらに精製することなく用いた。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．５７分；ｍ／ｚ＝３６６［Ｍ＋Ｈ］⁺ 19.2: 6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

6-Chloro-1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid described in Example 16.1 in dioxane (54 mL) To a solution of acid ethyl ester (2.00 g, 5.96 mmol) was added an aqueous solution of 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and cesium carbonate (0.4 M, 27 mL, 10.8 mmol). The resulting solution was degassed with argon, then tetrakis (triphenylphosphine) palladium (0.62 g, 0.54 mmol) was added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, water was added and the mixture was then acidified to pH = 2. The aqueous phase was extracted with a mixture of tetrahydrofuran and EtOAc. The combined organic extracts are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum to give the title compound (3.13 g) as a brown foam, which is further purified. Used without.
LC / MS (Method LC8): Rt = 1.57 min; m / z = 366 [M + H] ⁺

テトラヒドロフラン（４４ｍＬ）中の６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸（３．１２ｇ，６．６２ｍｍｏｌ）の溶液に１−ｂｏｃ−ピペラジン（１．３５ｇ，７．２８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（０．０９ｇ，０．６６ｍｍｏｌ）、及びＮ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（１．２７ｇ，６．６２ｍｍｏｌ）を加えた。２時間後、Ｎ,Ｎ−ジメチルアセトアミド（３ｍｌ）、１−ｂｏｃ−ピペラジン（０．２４ｇ，１．３２ｍｍｏｌ）及びＮ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（０．２５ｇ，１．３２ｍｍｏｌ）を反応混合物に加えた。１時間後、テトラヒドロフランを減圧下で蒸発させ、次いで水及びジクロロメタンを加えた。有機層を１Ｍ ＨＣｌ水溶液、水、ブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮した。ジクロロメタン中のメタノール（０−５％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を黄色の泡状物（３．１７ｇ，９０％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．７７分；ｍ／ｚ＝５３４［Ｍ＋Ｈ］⁺ 19.3: 4- [6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl]- Piperazine-1-carboxylic acid tert-butyl ester

6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (3) in tetrahydrofuran (44 mL) .12 g, 6.62 mmol) in a solution of 1-boc-piperazine (1.35 g, 7.28 mmol), 1-hydroxybenzotriazole (0.09 g, 0.66 mmol), and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1.27 g, 6.62 mmol) was added. After 2 hours, N, N-dimethylacetamide (3 ml), 1-boc-piperazine (0.24 g, 1.32 mmol) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.25 g , 1.32 mmol) was added to the reaction mixture. After 1 hour, the tetrahydrofuran was evaporated under reduced pressure and then water and dichloromethane were added. The organic layer was washed with 1M aqueous HCl, water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residue was purified on silica gel column chromatography using a gradient of methanol (0-5%) in dichloromethane to give the title compound as a yellow foam (3.17 g, 90%).
LC / MS (Method LC8): Rt = 1.77 min; m / z = 534 [M + H] ⁺

ジクロロメタン（２２ｍｌ）中の４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（３．１５ｇ，５．９０ｍｍｏｌ）の溶液にイミダゾール（０．９６ｇ，１４．１７ｍｍｏｌ）及びｔｅｒｔ−ブチル（クロロ）ジメチルシラン（１．０７ｇ，７．０８ｍｍｏｌ）を加えた。反応混合物を室温で５時間撹拌し、次いで水及びジクロロメタンを加えた。水層を分離し、そして有機層を水、ブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮した。シクロヘキサン中のＥｔＯＡｃ（０−３０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を黄色の泡状物（２．０５ｇ，５３％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．４１分；ｍ／ｚ＝６４８［Ｍ＋Ｈ］⁺ 19.4: 4- [6- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b ] Pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl in dichloromethane (22 ml) ] -Piperazine-1-carboxylic acid tert-butyl ester (3.15 g, 5.90 mmol) in a solution of imidazole (0.96 g, 14.17 mmol) and tert-butyl (chloro) dimethylsilane (1.07 g, 7. 08 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours and then water and dichloromethane were added. The aqueous layer was separated and the organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residue was purified on silica gel column chromatography using a gradient of EtOAc in cyclohexane (0-30%) to give the title compound as a yellow foam (2.05 g, 53%).
LC / MS (Method LC8): Rt = 2.41 min; m / z = 648 [M + H] ⁺

ＤＭＦ（２．１ｍＬ）中の４−［６−［４−（ｔｅｒｔ−ブチルジメチル−シラニルオキシ）−フェニル］−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．３ｇ，０．４６ｍｍｏｌ）の溶液に（４−ヨード−フェニル）−ピペリジン−１−イル−メタノン（０．１７５ｇ，０．５６ｍｍｏｌ）、トリ（ｏ−トリル）ホスフィン（２８ｍｇ．０．０９ｍｍｏｌ）及びトリエチルアミン（２．１ｍＬ）を加えた。生成した溶液を、アルゴンを用いて脱気し、次いで酢酸パラジウム（５ｍｇ，０．０２ｍｍｏｌ）を加え、そして反応混合物を１２５℃で一夜加熱した。反応混合物を真空下で濃縮し、そして残留物を水中に溶解し、次いでｐＨ＝１に酸性化した。沈殿を濾過し、水で洗浄し、次いで真空下で乾燥した。ジクロロメタン中のメタノール（０−３％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を薄茶色の固形物（０．２５ｇ，６５％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．９２分；ｍ／ｚ＝７２１［Ｍ＋Ｈ］⁺ 19.5: 4- [6- (4-Hydroxy-phenyl) -3-{(E) -2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1- (tetrahydro-pyran- 2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6- [4- (tert-Butyldimethyl-silanyloxy) -phenyl] -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3, in DMF (2.1 mL) 4-b] Pyridin-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.46 mmol) in a solution of (4-iodo-phenyl) -piperidin-1-yl-methanone (0 .175 g, 0.56 mmol), tri (o-tolyl) phosphine (28 mg.0.09 mmol) and triethylamine (2.1 mL) were added. The resulting solution was degassed with argon, then palladium acetate (5 mg, 0.02 mmol) was added and the reaction mixture was heated at 125 ° C. overnight. The reaction mixture was concentrated under vacuum and the residue was dissolved in water and then acidified to pH = 1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified on silica gel column chromatography using a gradient of methanol (0-3%) in dichloromethane to give the title compound as a light brown solid (0.25 g, 65%).
LC / MS (Method LC8): Rt = 1.92 min; m / z = 721 [M + H] ⁺

メタノール（５ｍｌ）中の４−［４−［６−（４−ヒドロキシ−フェニル）−３−｛（Ｅ）−２−［４−（ピペリジン−１−カルボニル）−フェニル］−ビニル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１カルボン酸ｔｅｒｔ−ブチルエステル（０．２５ｇ，０．３５ｍｍｏｌ）の溶液にジオキサン（０．９ｍｌ）中の４Ｎ ＨＣｌを加えた。反応混合物を室温で１８時間撹拌し、次いでジエチルエーテルを加え、生成した沈殿を濾過し、そしてジエチルエーテルで１回洗浄して橙色固形物として表題化合物の塩酸塩（０．１７５ｇ，８２％）を得た。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．８９分；ｍ／ｚ＝５３７［Ｍ＋Ｈ］⁺ 19.6: (6- (4-hydroxy-phenyl) -3-{(E) -2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1H-pyrazolo [3,4-b ] Pyridin-4-yl) -piperazin-1-yl-methanone

4- [4- [6- (4-Hydroxy-phenyl) -3-{(E) -2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1- in methanol (5 ml) To a solution of (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 carboxylic acid tert-butyl ester (0.25 g, 0.35 mmol) was added dioxane ( 0.9 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, then diethyl ether was added and the resulting precipitate was filtered and washed once with diethyl ether to give the hydrochloride salt of the title compound (0.175 g, 82%) as an orange solid. Obtained.
LC / MS (Method LC9): Rt = 0.89 min; m / z = 537 [M + H] ⁺

Example 20: 1- (3-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridine-3 -Yl] -vinyl} -phenyl) -pyrrolidin-2-one

０℃のジクロロメタン（２８ｍＬ）中の３−ヨードアニリン（１．５ｇ，６．８５ｍｍｏｌ）及びトリエチルアミン（１．３４ｍＬ，９．５９ｍｍｏｌ）の溶液に４−ブロモブチリルクロリド（０．９９ｍＬ，８．５６ｍｍｏｌ）を滴加した。次いで、反応混合物を室温で一夜撹拌した。有機抽出物を１Ｍ ＨＣｌ水溶液、１Ｍ ＮａＯＨ水溶液及びブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮してシクロヘキサン中のＥｔＯＡｃ（０−１５％）の勾配を用いてシリカゲルカラムクロマトグラフィーによって粗残留物を精製して粘着性の固形物を得た。シクロヘキサン及びエーテルの混合物中で摩砕し、次いで濾過して表題化合物を固形物（１．６１ｇ，６４％）として得た。
1H NMR (400 MHz, CDCl₃): δ 2.17-2.33 (m, 2H), 2.58 (t, 2H), 3.54 (t, 1H), 3.68 (t, 1H), 7.03-7.08 (m, 1H), 7.32-7.51 (m, 3H), 7.96 (s, 1H). 20.1: 4-Bromo-N- (3-iodo-phenyl) -butyramide

To a solution of 3-iodoaniline (1.5 g, 6.85 mmol) and triethylamine (1.34 mL, 9.59 mmol) in dichloromethane (28 mL) at 0 ° C. was 4-bromobutyryl chloride (0.99 mL, 8.56 mmol). ) Was added dropwise. The reaction mixture was then stirred overnight at room temperature. The organic extract is washed with 1M aqueous HCl, 1M aqueous NaOH and brine, dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and using a gradient of EtOAc in cyclohexane (0-15%). The crude residue was purified by silica gel column chromatography to give a sticky solid. Trituration in a mixture of cyclohexane and ether, followed by filtration gave the title compound as a solid (1.61 g, 64%).
1H NMR (400 MHz, CDCl ₃ ): δ 2.17-2.33 (m, 2H), 2.58 (t, 2H), 3.54 (t, 1H), 3.68 (t, 1H), 7.03-7.08 (m, 1H), 7.32-7.51 (m, 3H), 7.96 (s, 1H).

０℃の乾燥ＤＭＦ（２０ｍＬ）中の４−ブロモ−Ｎ−（３−ヨード−フェニル）−ブチルアミド（１．６０ｇ，４．３６ｍｍｏｌ）の溶液に水素化ナトリウム（油中６０％，０．２０ｇ，５．０１ｍｍｏｌ）を少しずつ加えた。次いで０℃で１５分後、反応混合物を室温で一夜撹拌した。反応が不完全であるとＴＬＣによって判断されたため、水素化ナトリウム（油中６０％，４５ｍｇ，１．０９ｍｍｏｌ）を加えた。２時間後、水（４０ｍＬ）及び飽和塩化アンモニウム水溶液（４０ｍＬ）を反応混合物に加えた。水相をＥｔＯＡｃで抽出し、次いで有機抽出物をブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮した。シクロヘキサン中のＥｔＯＡｃ（０−３０％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で粗残留物を精製して表題化合物を黄色固形物（０．９４ｇ，７５％）として得た。
1H NMR (400 MHz, CDCl₃): δ 2.14-2.23 (m, 2H), 2.63 (t, 2H), 3.85 (t, 2H), 7.1 (t, 1H), 7.48-7.51 (m, 1H), 7.66-7.70 (m, 1H), 7.96 (t, 1H) 20.2: 1- (3-Iodo-phenyl) -pyrrolidin-2-one

To a solution of 4-bromo-N- (3-iodo-phenyl) -butyramide (1.60 g, 4.36 mmol) in dry DMF (20 mL) at 0 ° C. was added sodium hydride (60% in oil, 0.20 g, 5.01 mmol) was added in small portions. Then after 15 minutes at 0 ° C., the reaction mixture was stirred overnight at room temperature. Since the reaction was judged incomplete by TLC, sodium hydride (60% in oil, 45 mg, 1.09 mmol) was added. After 2 hours, water (40 mL) and saturated aqueous ammonium chloride (40 mL) were added to the reaction mixture. The aqueous phase was extracted with EtOAc, then the organic extract was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residue was purified on silica gel column chromatography using a gradient of EtOAc in cyclohexane (0-30%) to give the title compound as a yellow solid (0.94 g, 75%).
1H NMR (400 MHz, CDCl ₃ ): δ 2.14-2.23 (m, 2H), 2.63 (t, 2H), 3.85 (t, 2H), 7.1 (t, 1H), 7.48-7.51 (m, 1H), 7.66-7.70 (m, 1H), 7.96 (t, 1H)

ＤＭＦ（２．５５ｍＬ）中の４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．３０ｇ，０．５６ｍｍｏｌ）の溶液に１−（３−ヨード−フェニル）−ピロリジン−２−オン（０．１９ｇ，０．６７ｍｍｏｌ）、トリ（ｏ−トリル）ホスフィン（３４ｍｇ，０．１１ｍｍｏｌ）及びトリエチルアミン（２．５５ｍＬ）を加えた。生成した溶液を、アルゴンを用いて脱気し、次いで酢酸パラジウム（６ｍｇ，０．０３ｍｍｏｌ）を加え、そして反応混合物を１２５℃で一夜加熱した。反応混合物を真空下で濃縮し、そして残留物を水中に溶解し、次いでｐＨ＝１に酸性化した。沈殿を濾過し、水で洗浄し、次いで真空下で乾燥した。シクロヘキサン中のＥｔＯＡｃ（０−１００％）の勾配を用いてシリカゲルカラムクロマトグラフィーによって粗残留物を精製して表題化合物を淡褐色の固形物（０．２６ｇ，６６％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．８９分；ｍ／ｚ＝６９３［Ｍ＋Ｈ］⁺ 20.3: 4- [6- (4-Hydroxy-phenyl) -3-{(E) -2- [3- (2-oxo-pyrrolidin-1-yl) -phenyl] -vinyl} -1- ( Tetrahydropyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4 in DMF (2.55 mL) 1- (3-Iodo-phenyl) -pyrrolidin-2-one (0.19 g, 0.67 mmol) in a solution of -carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) , Tri (o-tolyl) phosphine (34 mg, 0.11 mmol) and triethylamine (2.55 mL) were added. The resulting solution was degassed with argon, then palladium acetate (6 mg, 0.03 mmol) was added and the reaction mixture was heated at 125 ° C. overnight. The reaction mixture was concentrated under vacuum and the residue was dissolved in water and then acidified to pH = 1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc in cyclohexane (0-100%) to give the title compound as a light brown solid (0.26 g, 66%).
LC / MS (Method LC8): Rt = 1.89 min; m / z = 693 [M + H] ⁺

メタノール（５ｍｌ）中の４−［６−（４−ヒドロキシ−フェニル）−３−｛（Ｅ）−２−［３−（２−オキソ−ピロリジン−１−イル）−フェニル］−ビニル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．２４６ｇ，０．３６ｍｍｏｌ）の溶液にジオキサン（０．９ｍｌ）中の４Ｎ ＨＣｌを加えた。反応混合物を室温で１８時間撹拌し、次いでジエチルエーテルを加え、生成した沈殿を濾過し、そしてジエチルエーテルで１回洗浄して橙色固形物として表題化合物の塩酸塩（０．１９ｇ，９３％）を得た。
ＬＣ／ＭＳ（方法ＬＣ１０）：Ｒｔ＝２．９８分；ｍ／ｚ＝５０９［Ｍ＋Ｈ］⁺ 20.4: 1- (3-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridine-3 -Yl] -vinyl} -phenyl) -pyrrolidin-2-one

4- [6- (4-Hydroxy-phenyl) -3-{(E) -2- [3- (2-oxo-pyrrolidin-1-yl) -phenyl] -vinyl} -1 in methanol (5 ml) To a solution of-(tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.246 g, 0.36 mmol) 4N HCl in dioxane (0.9 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, then diethyl ether was added and the resulting precipitate was filtered and washed once with diethyl ether to give the hydrochloride salt of the title compound (0.19 g, 93%) as an orange solid. Obtained.
LC / MS (Method LC10): Rt = 2.98 min; m / z = 509 [M + H] ⁺

  The following examples are based on 1- (3-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3] described immediately above. , 4-b] pyridin-3-yl] -vinyl} -phenyl) -pyrrolidin-2-one. In the third step, 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl ] -Piperazine-1-carboxylic acid tert-butyl ester was reacted with the respective aryl halide and deprotected in the fourth step:

Example 34:
3-{(E) -2- [4- (2,2-Dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-3- Yl] -vinyl} -N, N-dimethyl-benzamide

ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルの代わりに３,３−ジメチル−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを用いて４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルと同様のやり方で４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−３,３−ジメチル−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．８６分；ｍ／ｚ＝５６２．３［Ｍ＋Ｈ］⁺ 34.1: 4- [6- (4-Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl]- 3,3-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester

Using 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester, 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro- 4- [6- (4) pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester in a similar manner. -Hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -3,3-dimethyl-piperazine-1-carvone The acid tert-butyl ester was obtained.
LC / MS (Method LC8): Rt = 1.86 min; m / z = 562.3 [M + H] ⁺

１−（３−｛（Ｅ）−２−［６−（４−ヒドロキシ−フェニル）−４−（ピペラジン−１−カルボニル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−３−イル］−ビニル｝−フェニル）−ピロリジン−２−オンの合成と同様のやり方で３−｛（Ｅ）−２−［４−（２,２−ジメチル−ピペラジン−１−カルボニル）−６−（４−ヒドロキシ−フェニル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−３−イル］−ビニル｝−Ｎ,Ｎ−ジメチル−ベンズアミドを製造した。第３の工程では、４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルの代わりに４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−３,３−ジメチル−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを３−ヨード−Ｎ,Ｎ−ジメチル−ベンズアミドと反応させ、そして第４の工程で脱保護した。
ＬＣ／ＭＳ（方法ＬＣ９）：Ｒｔ＝０．７８分；ｍ／ｚ＝５２５［Ｍ＋Ｈ］⁺ 34.2: 3-{(E) -2- [4- (2,2-dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] Pyridin-3-yl] -vinyl} -N, N-dimethyl-benzamide

1- (3-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl]- 3-{(E) -2- [4- (2,2-dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy) in a manner similar to the synthesis of vinyl} -phenyl) -pyrrolidin-2-one. -Phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -N, N-dimethyl-benzamide was prepared. In the third step, 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl ] Instead of 4-piperazine-1-carboxylic acid tert-butyl ester 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3, 4-b] pyridine-4-carbonyl] -3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester is reacted with 3-iodo-N, N-dimethyl-benzamide and removed in a fourth step. Protected.
LC / MS (Method LC9): Rt = 0.78 min; m / z = 525 [M + H] ⁺

Example 35:
6-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- 2-Methyl-2,3-dihydro-isoindol-1-one

ＴＨＦ（６．５ｍＬ）中の５−ブロモ−２−ブロモメチル−安息香酸メチルエステル（１．００ｇ，３．２５ｍｍｏｌ）の溶液にＴＨＦ中のメチルアミンの溶液（２Ｍ，８．１２ｍＬ，１６．２４ｍｍｏｌ）を加えた。反応混合物を５０℃で４時間加熱し、次いで真空下で濃縮した。残留物をＥｔＯＡｃ中に溶解し、次いで有機層を１Ｍ ＨＣｌ水溶液、ブラインで洗浄し、乾燥し（Ｎａ₂ＳＯ₄）、濾過し、真空下で濃縮して黄色固形物として表題化合物（０．７３ｇ，１００％）を得た。
1H NMR (400 MHz, CDCl₃): δ 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H) 35.1: 6-Bromo-2-methylisoindoline-1-one

A solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol) in a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL). Was added. The reaction mixture was heated at 50 ° C. for 4 hours and then concentrated under vacuum. The residue was dissolved in EtOAc, then the organic layer was washed with 1M aqueous HCl, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (0.73 g) as a yellow solid. , 100%).
1H NMR (400 MHz, CDCl ₃ ): δ 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H)

１−（３−ヨード−フェニル）−ピロリジン−２−オンを６−ブロモ−２−メチルイソインドリン−１−オンで置き換えることを除いて実施例２０．３に記載された方法を用いて黄色固形物として表題化合物を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．６２分；ｍ／ｚ＝６７９［Ｍ＋Ｈ］⁺ 35.2: 4- [6- (4-hydroxy-phenyl) -3-[(E) -2- (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl) -Vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

A yellow solid using the method described in Example 20.3 except that 1- (3-iodo-phenyl) -pyrrolidin-2-one was replaced with 6-bromo-2-methylisoindoline-1-one. The title compound was obtained as a product.
LC / MS (Method LC8): Rt = 2.62 min; m / z = 679 [M + H] ⁺

メタノール（４ｍｌ）中の４−［６−（４−ヒドロキシ−フェニル）−３−［（Ｅ）−２−（２−メチル−３−オキソ−２,３−ジヒドロ−１Ｈ−イソインドール−５−イル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．１９ｇ，０．２８ｍｍｏｌ）の溶液にジオキサン（０．７ｍｌ）中の４Ｎ ＨＣｌを加えた。反応混合物を室温で３日間撹拌し、次いでジエチルエーテルを加え、生成した沈殿を濾過し、そしてジエチルエーテルで１回洗浄して橙色固形物として表題化合物の塩酸塩（０．１５ｇ，９６％）を得た。
ＬＣ／ＭＳ（方法ＬＣ１０）：Ｒｔ＝２．８２分；ｍ／ｚ＝４９５［Ｍ＋Ｈ］⁺ 35.3: 6-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -Vinyl} -2-methyl-2,3-dihydro-isoindol-1-one

4- [6- (4-Hydroxy-phenyl) -3-[(E) -2- (2-methyl-3-oxo-2,3-dihydro-1H-isoindole-5] in methanol (4 ml) Yl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.19 g, To a solution of 0.28 mmol) was added 4N HCl in dioxane (0.7 ml). The reaction mixture is stirred at room temperature for 3 days, then diethyl ether is added, the precipitate formed is filtered and washed once with diethyl ether to give the hydrochloride salt of the title compound (0.15 g, 96%) as an orange solid. Obtained.
LC / MS (Method LC10): Rt = 2.82 min; m / z = 495 [M + H] ⁺

Example 36: [3- (2-Cyclocyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone

ＴＨＦ（７．６５ｍＬ）中の６−クロロ−３−ヨード−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステル（１．０ｇ，２．３０ｍｍｏｌ）及びトリエチルアミン（１．９２ｍＬ，１３．７７ｍｍｏｌ）の溶液を、アルゴンを用いて３分間脱気した。次いで、シクロヘキシルアセチレン（０．４５ｍＬ，３．４４ｍｍｏｌ）、ヨウ化銅（Ｉ）（０．０８ｇ，０．４６ｍｍｏｌ）及びテトラキス（トリフェニルホスフィン）パラジウム（０．１３ｇ，０．１１ｍｍｏｌ）を加え、そして反応混合物を室温で一夜撹拌した。反応混合物を真空下で濃縮し、そしてシクロヘキサン中の酢酸エチル（０−５％）の勾配を用いてシリカゲルカラムクロマトグラフィー上で残留物を精製して表題化合物を淡褐色の固形物（０．９３ｇ，９７％）として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．２７分；ｍ／ｚ＝４１６［Ｍ＋Ｈ］⁺ 36.1: 6-Chloro-3-cyclohexylethynyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester

6-chloro-3-iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester (1.0 g) in THF (7.65 mL) , 2.30 mmol) and triethylamine (1.92 mL, 13.77 mmol) were degassed with argon for 3 min. Then cyclohexylacetylene (0.45 mL, 3.44 mmol), copper (I) iodide (0.08 g, 0.46 mmol) and tetrakis (triphenylphosphine) palladium (0.13 g, 0.11 mmol) were added, and The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel column chromatography using a gradient of ethyl acetate (0-5%) in cyclohexane to give the title compound as a pale brown solid (0.93 g 97%).
LC / MS (Method LC8): Rt = 2.27 min; m / z = 416 [M + H] ⁺

６−クロロ−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステルを６−クロロ−３−シクロヘキシルエチニル−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸エチルエステルで置き換えることを除いて実施例１６．３に記載された方法を用いて３−シクロヘキシルエチニル−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸（０．９３ｇ，９７％）を淡褐色の固形物として得た。ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝１．９１分；ｍ／ｚ＝４４６［Ｍ＋Ｈ］⁺ 36.2: 3-cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

6-chloro-3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester is converted to 6-chloro-3 -The method described in Example 16.3 except replacing with cyclohexylethynyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid ethyl ester 3-cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (0.93 g 97%) as a light brown solid. LC / MS (Method LC8): Rt = 1.91 min; m / z = 446 [M + H] ⁺

６−クロロ−３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸を３−シクロヘキシルエチニル−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸で置き換えることを除いて実施例１．６に記載された方法を用いて４−［３−シクロヘキシルエチニル−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．７２ｇ，９６％）を黄色固形物として得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．０６分；ｍ／ｚ＝６１４［Ｍ＋Ｈ］⁺ 36.3: 4- [3-cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -Piperazine-1-carboxylic acid tert-butyl ester

6-chloro-3-[(E) -2- (4-chloro-phenyl) -vinyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4- Replacing the carboxylic acid with 3-cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid. Except as described in Example 1.6, 4- [3-cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3 , 4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.72 g, 96%) was obtained as a yellow solid.
LC / MS (Method LC8): Rt = 2.06 min; m / z = 614 [M + H] ⁺

メタノール（１５ｍｌ）中の４−［３−シクロヘキシルエチニル−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（０．３４ｇ，０．５６ｍｍｏｌ）の溶液にＰｄ／Ｃ（１０％，１２ｍｇ，０．０１ｍｍｏｌ）を加えた。反応混合物を４バールで１８時間水素化し、Ｐｄ／Ｃ（１０％，１２ｍｇ，０．０１ｍｍｏｌ）を加え、そしてさらに８時間水素化した。次いで、反応混合物を濾過し、そして減圧下で濃縮して灰色の固形物として表題化合物（０．３３ｇ，９５％）を得た。
ＬＣ／ＭＳ（方法ＬＣ８）：Ｒｔ＝２．１７分；ｍ／ｚ＝６１８［Ｍ＋Ｈ］⁺ 36.4: 4- [3- (2-Cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine -4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester

4- [3-Cyclohexylethynyl-6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-l in methanol (15 ml) To a solution of carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (0.34 g, 0.56 mmol) was added Pd / C (10%, 12 mg, 0.01 mmol). The reaction mixture was hydrogenated at 4 bar for 18 hours, Pd / C (10%, 12 mg, 0.01 mmol) was added and hydrogenated for an additional 8 hours. The reaction mixture was then filtered and concentrated under reduced pressure to give the title compound (0.33 g, 95%) as a gray solid.
LC / MS (Method LC8): Rt = 2.17 min; m / z = 618 [M + H] ⁺

４−［３−［（Ｅ）−２−（４−クロロ−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−
ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを４−［３−（２−シクロヘキシル−エチル）−６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステルで置き換えることを除いて実施例１．８に記載された方法を用いて［３−（２−シクロヘキシル−エチル）−６−（４−ヒドロキシ−フェニル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル］−ピペラジン−１−イル−メタノンの塩酸塩を黄色固形物（０．１５ｇ，５８％）として得た。
ＬＣ／ＭＳ（方法ＬＣ１０）：Ｒｔ＝３．４７分；ｍ／ｚ＝４３４［Ｍ＋Ｈ］⁺ 36.5: [3- (2-cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone

4- [3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3 , 4-
b] Pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester was converted to 4- [3- (2-cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran- 2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester was used except that the method described in Example 1.8 was used. [3- (2-cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone hydrochloride Obtained as a yellow solid (0.15 g, 58%).
LC / MS (Method LC10): Rt = 3.47 min; m / z = 434 [M + H] ⁺

１−フルオロ−４ヨード−ベンゼン０．２５ｍｍｏｌを反応管に計り込んだ。炭酸水素ナトリウム２．５ｍｍｏｌを固形物として、続いてＤＭＦ０．５ｍｌ中のテトラブチルアンモニウムフルオリド０．２５ｍｍｏｌ及びＤＭＦ１ｍｌ中の４−［６−（４−ヒドロキシ−フェニル）−１−（テトラヒドロ−ピラン−２−イル）−３−ビニル−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル０．１ｍｍｏｌを加えた。管をアルゴンでパージした。ＤＭＦ０．２５ｍｍｏｌ中の酢酸パラジウム（ＩＩ）０．０１ｍｍｏｌを加え、管をスクリューキャップで閉じ、そして８０℃で８時間撹拌した。新たな酢酸パラジウム（ＩＩ）（０．０１ｍｍｏｌ）を加え、そして１００℃で１時間加熱を続けた。反応混合物を酢酸エチル２０ｍｌで希釈し、そして水２０ｍｌで洗浄し、乾燥し、そして蒸発させた。残留物をＴＨＦ５ｍｌ及びメタノール１ｍｌ中に溶解し、そしてシリカ結合したプロパンチオールスカベンジャー１００ｍｇと共に室温で４時間振盪した。混合物を濾過し、フィルターをＴＨＦで洗浄し、濾液を蒸発させ、そして残留物をＳＦＣ精製にかけた。精製した生成物をジオキサン中のメタノール３ｍｌ及び４Ｎ ＨＣｌ０．５ｍｌ中に溶解した。混合物を６５℃で３０分間撹拌した。冷却した溶液をジエチルエーテル１０ｍｌでゆっくり希釈して生成物を沈殿させ、それを濾過し、ジエチルエーテル１ｍｌで洗浄し、そして真空で乾燥して［３−［（Ｅ）−２−（４−フルオロ−フェニル）−ビニル］−６−（４−ヒドロキシ−フェニル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−イル］−ピペラジン−１−イル−メタノン（１８ｍｇ，３７％）を得た。
ＬＣ／ＭＳ（方法ＬＣ１）：Ｒｔ＝１，７４分；ｍ／ｚ＝４４４．１７［Ｍ＋Ｈ］^+
1H-NMR (500MHz, d6-DMSO): 2,72-3,27 (bm, 4H), 3,4-3,5 (bm, 3H), 4,22-4,44 (bm, 1H) 6,92 (d, 2H), 7,11 (d, 1H), 7,23 (m, 2H), 7,32 (d, 1H), 7,61 (m, 2H), 7.79 (s, 1H), 8.09 (d, 2H), 9.2 (bs, 1H), 9.5 (bs, 1H) Example 37:
[3-[(E) -2- (4-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone

0.25 mmol of 1-fluoro-4iodo-benzene was measured into the reaction tube. 2.5 mmol of sodium hydrogen carbonate as a solid, followed by 0.25 mmol of tetrabutylammonium fluoride in 0.5 ml of DMF and 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran- 2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester 0.1 mmol was added. The tube was purged with argon. 0.01 mmol of palladium (II) acetate in 0.25 mmol of DMF was added, the tube was closed with a screw cap and stirred at 80 ° C. for 8 hours. Fresh palladium (II) acetate (0.01 mmol) was added and heating was continued at 100 ° C. for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with 20 ml of water, dried and evaporated. The residue was dissolved in 5 ml THF and 1 ml methanol and shaken with 100 mg silica bonded propane thiol scavenger for 4 hours at room temperature. The mixture was filtered, the filter was washed with THF, the filtrate was evaporated, and the residue was subjected to SFC purification. The purified product was dissolved in 3 ml methanol in dioxane and 0.5 ml 4N HCl. The mixture was stirred at 65 ° C. for 30 minutes. The cooled solution is slowly diluted with 10 ml of diethyl ether to precipitate the product, which is filtered, washed with 1 ml of diethyl ether and dried in vacuo [3-[(E) -2- (4-fluoro -Phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone (18 mg, 37%) was obtained. .
LC / MS (Method LC1): Rt = 1, 74 min; m / z = 444.17 [M + H] ^+
1 H-NMR (500MHz, d6-DMSO): 2,72-3,27 (bm, 4H), 3,4-3,5 (bm, 3H), 4,22-4,44 (bm, 1H) 6,92 (d, 2H), 7,11 (d, 1H), 7,23 (m, 2H), 7,32 (d, 1H), 7,61 (m, 2H), 7.79 (s, 1H ), 8.09 (d, 2H), 9.2 (bs, 1H), 9.5 (bs, 1H)

  The following example shows 4- [6- (4-hydroxy-phenyl) -1- (tetrahydro-pyran-2-yl) -3-vinyl-1H-pyrazolo [3,4-b] pyridine-4-carbonyl ] [3-[(E) -2- (4-Fluoro-phenyl) -vinyl] -6 described immediately above using piperazine-1-carboxylic acid tert-butyl ester and the respective aryl iodide or bromide. Prepared in a manner similar to the synthesis of-(4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone:

ピペラジン−１−カルボン酸ジメチルアミド０．２４ｍｍｏｌを反応管に計り込み、そしてＴＨＦ１ｍｌ中に溶解／懸濁した。６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボン酸０．２４ｍｍｏｌを含むＤＭＦ保存溶液１ｍｌ、Ｎ−メチルモルホリン１ｍｍｏｌ、４−ジメチルアミノピリジン０．０１ｍｍｏｌ及び１−ヒドロキシベンゾトリアゾール０．３ｍｍｏｌ、続いてＥＤＣ０．３ｍｍｏｌを加えた。管を閉じ、そして５０℃で一夜振盪した。ＴＨＦを蒸発させたままにし、ＴＦＡ０．１ｍｌを加え、ＤＭＦを用いて体積を２ｍｌに調節した。溶液を濾過し、そして分取ＲＰ ＨＰＬＣ精製にかけて４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ジメチルアミドを得た。トリフルオロ酢酸塩を塩酸塩に変換するため、そして他の例については、酸不安定な保護基を切断するため、上で得た生成物をメタノール３ｍｌ及びジオキサン中４Ｍ ＨＣｌ０．５ｍｌと共に６５℃で３０分間振盪した。次いで、ジエチルエーテル１０ｍｌを冷却した溶液にゆっくり加え、そして形成された沈殿を濾過し、ジエチルエーテル１ｍｌで洗浄し、そして真空で乾燥して４−［６−（４−ヒドロキシ−フェニル）−３−（（Ｅ）−スチリル）−１Ｈ−ピラゾロ［３,４−ｂ］ピリジン−４−カルボニル］−ピペラジン−１−カルボン酸ジメチルアミド０．０８５ｍｍｏｌ（３５％）を得た。
ＬＣ／ＭＳ（方法ＬＣ２）：Ｒｔ＝３，８２分；ｍ／ｚ＝４９７．２６［Ｍ＋Ｈ］^+
1H-NMR (400MHz, d6-DMSO): 2,70 (s, 6H), 2,14-2,34 (m, 1H), 2,90-3,40 (bm, 4H), 3,30-4,0 (bm, 4H), 6,91 (d, 2H), 7,20 (d, 1H), 7,29-7,42 (m, 4H), 7,56 (d, 2H), 7,70 (s, 1H), 8.09 (d, 2H), 10 (bs, 1H) Example 74
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide

Piperazine-1-carboxylic acid dimethylamide 0.24 mmol was weighed into a reaction tube and dissolved / suspended in 1 ml THF. 6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid 1 ml of DMF stock solution containing 24 mmol, 1 mmol of N-methylmorpholine, 0.01 mmol of 4-dimethylaminopyridine and 0.3 mmol of 1-hydroxybenzotriazole, followed by 0.3 mmol of EDC. The tube was closed and shaken overnight at 50 ° C. The THF was allowed to evaporate, 0.1 ml of TFA was added and the volume was adjusted to 2 ml with DMF. The solution was filtered and subjected to preparative RP HPLC purification to 4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo. [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide was obtained. In order to convert the trifluoroacetate salt to the hydrochloride salt and for other examples to cleave the acid labile protecting group, the product obtained above was combined with 3 ml methanol and 0.5 ml 4M HCl in dioxane at 65 ° C Shake for 30 minutes. Then 10 ml of diethyl ether are slowly added to the cooled solution and the precipitate formed is filtered, washed with 1 ml of diethyl ether and dried in vacuo to give 4- [6- (4-hydroxy-phenyl) -3- 0.085 mmol (35%) of ((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide was obtained.
LC / MS (Method LC2): Rt = 3, 82 min; m / z = 497.26 [M + H] ^+
1 H-NMR (400MHz, d6-DMSO): 2,70 (s, 6H), 2,14-2,34 (m, 1H), 2,90-3,40 (bm, 4H), 3,30 -4,0 (bm, 4H), 6,91 (d, 2H), 7,20 (d, 1H), 7,29-7,42 (m, 4H), 7,56 (d, 2H), 7,70 (s, 1H), 8.09 (d, 2H), 10 (bs, 1H)

  The following example shows the following: 6- (4-hydroxy-phenyl) -3-((E) -styryl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-b] pyridine- 4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] described immediately above using 4-carboxylic acid and the respective amine. Prepared in a manner similar to the synthesis of pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide:

Measurement of PKC βII inhibition PKC βII inhibition was measured according to the following protocol:
Active human full length recombinant PKC βII and peptide substrate, fluorescein-RFARKGSLRQKNV, were purchased from Invitrogen GmbH, Darmstadt, Germany. Adenosine-5′-triphosphate (ATP), bovine serum albumin (BSA), dimethyl sulfoxide (DMSO), 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes), Triton X-100, 1 , 2-Dioleyl-sn-glycerol (DAG), L-α-phosphatidyl-L-serine (PS), calcium chloride (CaCl ₂ ), and Pluronic F-68 are available from Sigma-Aldrich, Munich, Germany. , Munich, Germany). Magnesium chloride, 1M sodium hydroxide solution, 1M hydrochloric acid solution and EDTA were obtained from Merck Biosciences, Darmstadt, Germany. Test compounds were diluted to 3 times the test concentration in buffer 1 (30 mM Hepes-NaOH, pH 7.4, 0.01% Pluronic F-68 and 3% (v / v) DMSO). PKC βII enzyme in buffer 2 (30 mM Hepes-NaOH, pH 7.4, 15 mM MgCl2, 150 μM CaCl ₂ , 150 μg / ml PS, 60 μg / ml DAG, and 0.045% (w / v) Triton X-100) To a concentration of 30 ng / ml. Peptide substrate and ATP were diluted in buffer 2 to concentrations of 3 μM and 120 μM, respectively. 2 μl of compound solution is mixed with 2 μl of diluted enzyme in a 384 well small volume microtiter plate (Greiner, Bio-One, Frickenhausen, Germany) and peptide substrate and The kinase reaction was initiated by adding 2 μl of a solution containing ATP. After incubation at 32 ° C. for 60 minutes, 130 mM Hepes-NaOH, pH 7.4, 0.0195% (v / v) Brij-35, 6.5 mM EDTA, 0.13% chip coating reagent 3 (Caliper Life Science, The reaction was stopped by adding 20 μl of a solution containing Hopperton, MA (Caliper Lifescience Inc, Hopkinton, Mass.) And 6.5% (v / v) DMSO. Substrate peptide phosphorylation was then detected in a Caliper 3000 instrument essentially as described by Pommereau et al. (J. Biomol. Screening 2004, 9 (5), 409-416). The separation conditions were as follows: pressure -0.8 psi, upstream potential -3000V, downstream potential -800V. A positive control (buffer 1 instead of compound) and a negative control (buffer 1 instead of compound and buffer 2 instead of kinase solution) were run in parallel on each plate. The fractional turnover (R) was measured as the peak height of the phosphorylated peptide product divided by the sum of the non-phosphorylated substrate and phosphorylated product peak heights. The percent-inhibition value for the test compound is
Formula% inhibition = 100 ^* (1- (R _compound- R _{negative control} ) / (R _{positive control-} R _{negative control} )
It measured using.

  The following table lists the% inhibition values observed with the example compounds at a final concentration of 1.14 μM (± 0.15 μM):

Claims (11)

Formula I of any stereoisomeric form, or a mixture of stereoisomeric forms in any ratio

[Where,
R ¹ is
a) Formula Ia

[Where:
R ⁶ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted Is or is substituted by 1 to 5 F;
R ⁷ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. Or substituted by 1 to 5 F, or CN, (C ₀ -C ₂ ) -alkylene-SO ₂ (C ₁ -C ₃ ) -alkyl, (C ₀ -C ₂ ) -alkylene-N ((C ₁ -C ₄ ) -alkyl) ₂ , CO-N ((C ₁ -C ₄ ) -alkyl) ₂ , 1-pyrrolidinyl, 1-piperidinyl, 1-pyrrolidinyl-2-one, 1-piperidinyl-2 -One or 4-morpholinyl;
R ⁸ is H, F, Cl, (C ₁ -C ₅ ) -alkyl or O- (C ₁ -C ₅ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. is substituted or or by 1-5 F, or CN, OH, _{O-phenyl, SO 2 (C 1 -C 3} ) - _{alkyl, CO- (C 1 -C 4)} - alkyl, CO-N ((C ₁ -C ₄ ) -alkyl) ₂ , CO-1-piperidinyl, CO-1-pyrrolidinyl, or CO-4-morpholinyl;
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁶ and R ⁷ together with the two carbon atoms to which they are attached form a 5-6 membered heterocycloalkyl ring, which is selected from nitrogen and oxygen In which the heterocycloalkyl is unsubstituted or monosubstituted by (C ₁ -C ₄ ) -alkyl or oxo (═O) Or R ⁷ and R ⁸ together with the two carbon atoms to which they are attached form a 5-6 membered heterocycloalkyl ring, which is 1 or 2 identical selected from nitrogen and oxygen Or containing different heteroatoms, wherein the heterocycloalkyl is unsubstituted or monosubstituted by (C ₁ -C ₄ ) -alkyl or oxo (═O)]
Residues of;
b) ethylene - phenyl, phenyl or unsubstituted wherein _{F, Cl, CH 3, O} -CH 3, CF 3, O-CF 3, CN, SO 2 CH 3, CO-CH 3, and CO Substituted by 1 or 2 identical or different substituents selected from —N ((CH ₃ ) ₂ ;
c) 2-phenyl-cyclopropyl, phenyl or unsubstituted wherein _{F, Cl, CH 3, O} -CH 3, CF 3, O-CF 3, CN, SO 2 CH 3, CO-CH 3, And CO—N ((CH ₃ ) ₂ ) substituted with one or two identical or different substituents;
d) ethylene - (C ₅ -C ₇₎ cycloalkyl;
Is;
R ² is H, F, Cl, or CH ₃ ;
R ³ is H, F, or O—CH ₃ ;
R ⁴ is piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, which are unsubstituted or (C ₁ -C ₃ ) -alkyl (which is unsubstituted or 1 Monosubstituted by ˜5 F);
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them a) Formula Ib

[Where:
R ¹¹ is H, (C ₃ -C ₅ ) -cycloalkyl, (C ₁ -C ₄ ) -alkylene-OH or (C ₁ -C ₄ ) -alkyl, which is unsubstituted or Substituted by 5 F;
R ¹² is H or (C ₁ -C ₄ ) -alkyl;
R ¹³ is H, (C ₁ -C ₄ ) -alkyl, or (C ₃ -C ₅ ) -cycloalkyl;
R ¹⁴ is H or (C ₁ -C ₄ ) -alkyl; or R ¹³ and R ¹⁴ together with the carbon atom carrying them are 1′-spiro-cyclo- (C ₃ -C ₆ ) -alkyl; and R ¹⁵ is H, CH ₂ —CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , CO— (C ₁ -C ₆ ) -alkyl, CO— (C ₁ -C ₄₎ - _{alkylene--OH, CO- (C 1 -C 4} ) - _{alkylene--O-CH 3, CO-CH} 2 -4- _{morpholinyl, CO-O- (C 1 -C} 4) - Alkyl, CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , (C ₃ -C ₆ ) -cycloalkyl, or pyridyl;
R ¹⁶ is H or (C ₁ -C ₄ ) -alkyl;
R ¹⁷ is H or CH ₃ ;
R ¹⁸ is H or CH ₃ ;
R ¹⁹ is H]
Residues of;
b) a 9-11 membered spiro-heterocycloalkyl containing two nitrogen atoms linked via a nitrogen atom;
Represents)
Or a physiologically acceptable salt thereof, or all physiologically acceptable solvates thereof. R ¹ is a) Formula Ia

[Where:
R ⁶ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. Or is substituted by 1 to 5 F;
R ⁷ is H, F, Cl, (C ₁ -C ₃ ) -alkyl or O- (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. It is substituted or or by 1-5 F, or _{CN, SO 2 (C 1 -C} 3) - _{alkyl, N ((C 1 -C 4} ) - alkyl) _2, 1-piperidinyl, or 4- Morpholinyl;
R ⁸ is H, F, Cl, (C ₁ -C ₅ ) -alkyl or O- (C ₁ -C ₅ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl is unsubstituted. to or is substituted by 1-5 F, or OH, _{O-phenyl, SO 2 (C 1 -C 3} ) - _{alkyl, CO- (C 1 -C 4)} - alkyl, CO-N (( C ₁ -C ₄₎ - alkyl) _2;
R ⁹ is H, F, CH ₃ , O—CH ₃ ;
R ¹⁰ is H; or R ⁷ and R ⁸ are taken together

Is]
Residues of;
b) Ethylene-phenyl, where phenyl is unsubstituted or F, Cl, CH ₃ , O—CH ₃ , CF ₃ , O—CF ₃ , CN, SO ₂ CH ₃ , CO—CH ₃ , and Substituted with 1 to 2 identical or different substituents selected from CO—N ((CH ₃ ) ₂ ;
R ² is H, F, CH ₃ ;
R ³ is H, O—CH ₃ ;
R ⁴ is piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, which are unsubstituted or (C ₁ -C ₃ ) -alkyl (which is unsubstituted or Substituted with 5 F); preferably 4-methyl-piperidin-4-yl and R ⁵ is H; or R ⁴ and R ⁵ carry them A) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , (C ₃ -C ₄ ) -alkyl, or (C ₃ -C ₄ ) -cycloalkyl;
R ¹² is H;
R ¹³ is H, (C ₁ -C ₄ ) -alkyl, or (C ₃ -C ₄ ) -cycloalkyl;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ together with the carbon atom carrying them 1′-spiro-cyclo- (C ₃ -C ₆ ) -alkyl; Preferably 1′-spiro-cyclopentyl; and R ¹⁵ is H, CH ₂ —CO—N ((C ₁ -C ₄ ) -alkyl) ₂ , CO— (C ₁ -C ₆ ) -alkyl, CO - (C ₁ -C ₄₎ - _{alkylene--OH, CO- (C 1 -C 4} ) - _{alkylene--O-CH 3, CO-CH} 2 -4- _{morpholinyl, CO-O- (C 1 -C} 4) - alkyl, CO-N (- (C 1 -C 4) - _{alkyl) 2, - (C 3 -C} 6) - cycloalkyl, or pyridyl;
R ¹⁶ is H or (C ₁ -C ₄ ) -alkyl;
R ¹⁷ is H;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) a 9-11 membered spiro-heterocycloalkyl containing two nitrogen atoms linked via a nitrogen atom;
Represents
A compound of formula I according to claim 1. R ¹ is
a) Formula Ia

[Wherein R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CH ₂ —SO ₂ —CH ₃ , CF ₃ , CN, CH ₂ —N (CH ₃ ) ₂ , CO—N (CH ₃ ) ₂ , O—CH _3. , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, or 1-pyrrolidinyl-2-one;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , CN, OH, O—CH ₃ , O—C ₂ H _{5. , O-CHF 2, O-} CF 3, O- _{phenyl, SO 2 CH 3, CO-} CH 3, CO-N (CH 3) 2, or CO-1-be-piperidinyl;
R ⁹ is H, Cl, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁶ and R ⁷ are taken together

Or R ⁷ and R ⁸ are taken together

Is]
Residues of;
b) phenethyl;
c) 2-phenylcyclopropyl;
d) 2-cyclohexylethyl;
And
R ² is H, F, Cl, or CH ₃ ;
R ³ is H, F, or O—CH ₃ ;
R ⁴ is 4-methyl-piperidin-4-yl;
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them a) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , C ₂ H ₅ , (CH ₂ ) ₃ —CH ₃ , or CH ₂ —OH;
R ¹² is H or CH ₃ ;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ together with the carbon atom carrying them is 1′-spiro-cyclopentyl; and R ¹⁵ is H, CH _{2 -CO-N (CH 3)} 2, CO-CH (C 2 H 5) 2, CO-C (CH 3) 2 -OH, CO-C (CH 3) 2 -CH 2 -OH, CO- ( _{CH 2) 2 -O-CH 3} , CO-CH 2 -4- _{morpholinyl, CO-OCH 3, CO-} N (CH 3) 2, cyclopropyl, or CO-3- pyridyl;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) (2,7-diaza-spiro [4.4] non-2-yl)
Represents
3. A compound of formula I according to claim 1 or 2. R ¹ is
a) Formula Ia

[Where:
R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CF ₃ , CN, O—CH ₃ , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-piperidinyl, or 4-morpholinyl;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , OH, O—CH ₃ , O—C ₂ H ₅ , O _{-CHF 2, O-CF 3,} O- _{phenyl, SO 2 CH 3, CO-} CH 3, or CO-N (CH _{3) 2;}
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H; or R ⁷ and R ⁸ are taken together

Is]
Residues of;
b) phenethyl;
Is;
R ² is H or CH ₃ ;
R ³ is H or O—CH ₃ ;
R ⁴ is 4-methyl-piperidin-4-yl;
R ⁵ is H; or R ⁴ and R ⁵ together with the nitrogen carrying them a) Formula Ib

[Where:
R ¹¹ is H, CH ₃ , or (CH ₂ ) ₃ —CH ₃ ;
R ¹² is H;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ are 1′-spiro-cyclopentyl together with the carbon atom carrying them; and R ¹⁵ is H, CH ₂ —CO—. _{N (CH 3) 2, CO} -CH (C 2 H 5) 2, CO-C (CH 3) 2 -OH, CO-C (CH 3) 2 -CH 2 -OH, CO- (CH 2) 2 _{-O-CH 3, CO-CH} 2 -4- _{morpholinyl, CO-OCH 3, CO-} N (CH 3) 2, cyclopropyl, or 3-pyridyl;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹¹ and R ¹² together with the carbon atom carrying them are 1′-spiro-cyclopentyl;
R ¹⁸ is H;
R ¹⁹ is H]
Residues of;
b) (2,7-diaza-spiro [4.4] non-2-yl)
Represents
4. A compound of formula I according to any one of claims 1-3. R ¹ is of formula Ia

[Where:
R ⁶ is H, F, Cl, CH ₃ , CF ₃ , or O—CH ₃ ;
R ⁷ is H, F, Cl, CH ₃ , CF ₃ , CN, O—CH ₃ , SO ₂ CH ₃ , N (CH ₃ ) ₂ , 1-piperidinyl, or 4-morpholinyl;
R ⁸ is H, F, Cl, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , CF ₃ , OH, O—CH ₃ , O—C ₂ H ₅ , O _{-CHF 2, O-CF 3,} O- _{phenyl, SO 2 CH 3, CO-} CH 3, or CO-N (CH _{3) 2;}
R ⁹ is H, F, CH ₃ , or O—CH ₃ ;
R ¹⁰ is H]
Residues of;
R ² is H;
R ³ is H;
R ⁴ and R ⁵ together with the nitrogen carrying them have the formula Ib

[Where:
R ¹¹ is H, CH ₃ , or (CH ₂ ) ₃ —CH ₃ ;
R ¹² is H;
R ¹³ is H, CH ₃ , or CH ₂ —CH (CH ₃ ) ₂ ;
R ¹⁴ is H or CH ₃ ; or R ¹³ and R ¹⁴ together with the carbon atom carrying them are 1′-spiro-cyclopentyl; and R ¹⁵ is H ;
R ¹⁶ is H or CH ₃ ;
R ¹⁷ is H;
R ¹¹ and R ¹² together with the carbon atom carrying them are 1′-spiro-cyclopentyl;
R ¹⁸ is H;
R ¹⁹ is H]
Represents a residue of
5. A compound of formula I according to any one of claims 1-4. 1
[3-[(E) -2- (4-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 2
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 3
(2,2-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -methanone 4
(3,3-Dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Methanone 5
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -3-isobutyl-piperazine-1 -Yl) -methanone 6
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl-piperazine-1 -Yl) -methanone 7
[6- (4-Hydroxy-2-methyl-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 8
((2S, 5R) -2,5-dimethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 9
[6- (4-Hydroxy-3-methoxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 10
((S) -2-Ethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -methanone 11
[6- (2-Fluoro-4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-((S) -2-methyl -Piperazin-1-yl) -methanone 12
[6- (3-Fluoro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 13
[6- (2-Chloro-4-hydroxy-phenyl) -3- (styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 14
[3- [2- (3-Dimethylaminomethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- Il-methanone 15
{6- (4-Hydroxy-phenyl) -3- [2- (3-methanesulfonylmethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine-1- Il-methanone 16
((R) -2-hydroxymethyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine- 4-yl] -methanone 17
[6- (4-Hydroxy-phenyl) -3-phenethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 18
[6- (4-Hydroxy-phenyl) -3-((1R, 2R) -2-phenyl-cyclopropyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl -Methanone 19
(6- (4-Hydroxy-phenyl) -3- {2- [4- (piperidine-1-carbonyl) -phenyl] -vinyl} -1H-pyrazolo [3,4-b] pyridin-4-yl)- Piperazin-1-yl-methanone 20
1- (3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -phenyl ) -Pyrrolidin-2-one 21
[6- (4-Hydroxy-phenyl) -3-((E) -2-p-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 22
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 23
[3-[(E) -2- (3-Dimethylamino-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone 24
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methanesulfonyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine -1-yl-methanone 25
3-{(E) -2- [6- (4-Hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- Benzonitrile 26
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-piperidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 27
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-morpholin-4-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 28
{6- (4-Hydroxy-phenyl) -3- [2- (3-pyrrolidin-1-yl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 29
4- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- Benzonitrile 30
[3- [2- (3-Chloro-5-piperidin-1-yl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 31
3- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -N, N- Dimethyl-benzamide 32
5- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 33
[3- [2- (2,3-Dihydro-1H-indol-7-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 34
3- {2- [4- (2,2-Dimethyl-piperazine-1-carbonyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl } -N, N-dimethyl-benzamide 35
6- {2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl} -2-methyl- 2,3-dihydro-isoindol-1-one 36
[3- (2-Cyclohexyl-ethyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl-methanone 37
[3-[(E) -2- (4-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 38
[6- (4-Hydroxy-phenyl) -3-((E) -2-m-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 39
[3-[(E) -2- (2,4-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 40
[3-[(E) -2- (3,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 41
[3-[(E) -2- (4-Difluoromethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine -1-yl-methanone 42
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 43
[3-[(E) -2- (2,4-Dimethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 44
{6- (4-hydroxy-phenyl) -3-[(E) -2- (4-phenoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 45
[3-[(E) -2- (3,4-dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 46
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 47
[3-[(E) -2- (4-Hydroxy-3-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 48
[3-[(E) -2- (3-Chloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 49
[3-[(E) -2- (2,4-Dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 50
[3-[(E) -2- (2,5-dimethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 51
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-isopropyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1
-Ile-methanone 52
[3-[(E) -2- (2-Chloro-4-fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 53
[3-[(E) -2- (4-Ethyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 54
[3-[(E) -2- (4-tert-butyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 55
[3-[(E) -2- (3-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 56
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 57
1- (4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl]- Vinyl} -phenyl) -ethanone 58
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 59
[3-[(E) -2- (3,4-Difluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl]- Piperazin-1-yl-methanone 60
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (2-methoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl} -piperazine- 1-yl-methanone 61
[3-[(E) -2- (4-Fluoro-2-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 62
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (3,4,5-trimethoxy-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 63
[3-[(E) -2- (2-Fluoro-4-methyl-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 64
[3-[(E) -2- (2,3-Dihydro-benzofuran-5-yl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridine-4 -Yl] -piperazin-1-yl-methanone 65
[3-((E) -2-Benzo [1,3] dioxol-5-yl-vinyl) -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl ] -Piperazin-1-yl-methanone 66
4-{(E) -2- [6- (4-hydroxy-phenyl) -4- (piperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -vinyl}- N, N-dimethyl-benzamide 67
[3-[(E) -2- (4-Ethoxy-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 68
{6- (4-hydroxy-phenyl) -3-[(E) -2- (2-trifluoromethyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl}- Piperazin-1-yl-methanone 69
[6- (4-Hydroxy-phenyl) -3-((E) -2-o-tolyl-vinyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazin-1-yl- Methanon 70
[3- [2- (3,5-Dichloro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine-1- Il-methanone 71
[3-[(E) -2- (3-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 72
[3-[(E) -2- (2-Fluoro-phenyl) -vinyl] -6- (4-hydroxy-phenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -piperazine- 1-yl-methanone 73
{6- (4-Hydroxy-phenyl) -3-[(E) -2- (4-methoxy-3-methyl-phenyl) -vinyl] -1H-pyrazolo [3,4-b] pyridin-4-yl } -Piperazin-1-yl-methanone 74
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid dimethylamide 75
6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (4-methyl-piperidin-4-yl) -amide 76
((S) -2-Butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -Methanone 77
((R) -2-butyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4 -Il] -methanone 78
(2,7-diaza-spiro [4.4] non-2-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 79
(6,9-diaza-spiro [4.5] dec-9-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b ] Pyridin-4-yl] -methanone 80
2-ethyl-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Il} -butan-1-one 81
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- 2-morpholin-4-ylethanone 82
4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1-carboxylic acid methyl ester 83
[6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl]-[4- (pyridine-3-carbonyl) -piperazine -1-yl] -methanone 84
2- {4- [6- (4-Hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- N, N-dimethyl-acetamide 85
(4-Cyclopropyl-piperazin-1-yl)-[6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridin-4-yl] -Methanone 86
2-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2-methyl-propan-1-one 87
3-hydroxy-1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazine-1 -Yl} -2,2-dimethyl-propan-1-one 88
1- {4- [6- (4-hydroxy-phenyl) -3-((E) -styryl) -1H-pyrazolo [3,4-b] pyridine-4-carbonyl] -piperazin-1-yl}- 2. A compound according to claim 1 selected from the group consisting of 3-methoxy-propan-1-one.   7. At least one compound of formula I according to any one of claims 1-6, or a physiologically acceptable salt thereof, or all physiologically acceptable solvates thereof, and pharmaceutically A pharmaceutical composition comprising an acceptable carrier.   7. A compound of formula I according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, or all physiologically acceptable solvates thereof for use as a medicament.   7. A compound of formula I according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, or a method thereof for the manufacture of a medicament for treating diseases associated with diabetes and diabetic complications Use of all physiologically acceptable solvates.   Any one of claims 1 to 6 for producing a drug for preventing and treating nephropathy, neuropathy, retinopathy, ischemia, inflammation, central nervous system disorder, cardiovascular disease, skin disease, autoimmune disease and cancer Use of a compound of formula I as defined in claim 1, or a physiologically acceptable salt thereof, or all physiologically acceptable solvates thereof.   7. A compound of formula I according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, or all physiology thereof for the manufacture of a medicament for treating diseases associated with PKC receptors. Use of pharmaceutically acceptable solvates.