HK1141734B

HK1141734B - Pyrazolo pyridine derivatives as nadph oxidase inhibitors

Info

Publication number: HK1141734B
Application number: HK10108322.0A
Authority: HK
Inventors: P‧帕日; M‧奥查德; L‧菲奥拉索-卡迪埃尔; B‧莫迪洛尼
Original assignee: Calliditas Therapeutics Suisse Sa
Priority date: 2007-03-22
Filing date: 2008-03-20
Publication date: 2016-02-19

Description

Pyrazolopyridine derivatives as NADPH oxidase inhibitors

Technical Field

The present invention relates to pyrazolo pyridine derivatives of formula (I), pharmaceutical compositions thereof and their use for the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases, respiratory diseases, disorders affecting metabolism, skin and/or bone diseases, neurodegenerative diseases, kidney diseases, reproductive disorders, inflammatory disorders and cancer. The invention relates in particular to pyrazolopyridine derivatives for producing pharmaceutical preparations which modulate, in particular inhibit, the activity or function of coenzyme II oxidases (NADPH oxidases).

Background

NADPH Oxidase (NOX) is a protein that transfers electrons across biological membranes. Generally, the electron acceptor is oxygen and the electron transfer reaction product is superoxide. The biological function of the NOX enzyme is thus the generation of Reactive Oxygen Species (ROS) from oxygen. Reactive Oxygen Species (ROS) are oxygen derived from small molecules, including oxygen radicals (superoxide anion [ sic ], [ solution of ] or^·O₂ ^-]Hydroxy radical [ HO ]^·]Hydrogen peroxide [ ROO ]^·]Alkoxy [ RO)^·]And hydroperoxy [ HOO ]^·]) And some are oxidizing agents and/or non-free radicals that are readily converted to free radicals. Nitrogen-containing oxidizing agents, such as nitric oxide, are also known as Reactive Nitrogen Species (RNS). The generation of ROS is generally a cascade of reactions starting from superoxide production. Superoxide dissociates spontaneously, particularly at low pH, or is catalyzed by superoxide dismutase to hydrogen peroxide. Other elements in the ROS generation cascade include the reaction of superoxide with nitric oxide to produce peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide and the iron-catalyzed fenton reaction to generate hydroxyl radicals.

ROS interact strongly with a large number of molecules, including other small inorganic molecules as well as DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction can generate a second free radical, thereby multiplying the potential damage. ROS are involved not only in cell damage and killing of pathogens, but also in a number of reversible regulatory processes in virtually all cells and tissues. However, although ROS are important in regulating fundamental physiological processes, ROS production can also irreversibly disrupt or alter the function of the target molecule. Therefore, ROS are increasingly identified as major contributors to damage to biological organisms, so-called "oxidative stress".

NADPH oxidase is one of the most important sources of ROS production in vascular cells under inflammatory conditions during inflammation (Tha but et al, 2002, J.biol.chem., 277: 22814-22821).

In the lung, tissues are constantly exposed to oxidants that are produced endogenously by metabolic reactions (e.g., by mitochondrial respiration or activation of recruited inflammatory cells) or exogenously in the air (e.g., cigarette smoke or air pollutants). Moreover, lungs, which are constantly subjected to high oxygen tension compared to other tissues, have considerable surface area and blood supply, and are particularly susceptible to ROS-mediated damage (Brigham, 1986, Chest, 89 (6): 859-863). NADPH oxidase-dependent ROS generation in lung endothelial cells and smooth muscle cells has been described. NADPH oxidase activation is thought to be involved in respiratory diseases as a response to stimuli, such as the development of pulmonary arterial hypertension and enhancement of pulmonary vasoconstriction (Djordjevic et al, 2005, Arterioscler.Thromb.Vasc.biol., 25, 519-525; Liua et al, 2004, am.J.Physiol.Lung, cell.mol.Physiol., 287: L111-118). In addition, pulmonary fibrosis is characterized by pulmonary inflammation and excessive ROS generation.

Osteoclasts, which are macrophage-like cells, play a key role in bone turnover (e.g., bone resorption) and generate ROS through an NADPH oxidase-dependent mechanism (Yang et al, 2002, j.cell. chem.84, 645-.

Diabetes is known to increase oxidative stress (e.g., increased production of ROS by autooxidation of glucose) in humans and animals, and it is believed that increased oxidative stress plays an important role in the development of diabetic complications. It has been demonstrated that the increase in localised peroxide and endothelial dysfunction in the central retina of diabetic rats is the same as the NADPH oxidase active region in retinal endothelial cells (Ellis et al, 2000, Free Rad.biol.Med., 28: 91-101). Furthermore, it is suggested that oxidative stress (ROS) in mitochondria and/or inflammation may be a beneficial means of treating diabetes (Pillarisetti et al, 2004, Expert opin. the. targets, 8 (5): 401 4008).

ROS are also strongly implicated in the pathogenesis of atherosclerosis, cell proliferation, hypertension and reperfusion injury cardiovascular diseases in general (Cai et al, 2003, Trends Pharmacol. Sci., 24: 471-478). ROS not only induce superoxide production, e.g. in the arterial wall, which increases all risk factors for atherosclerosis, but ROS induce a number of "atherogenic" in vitro cellular responses. An important consequence of ROS formation in vascular cells is the consumption of Nitric Oxide (NO). NO inhibits the development of vascular disease and NO depletion is of considerable importance in the pathogenesis of cardiovascular disease. Increased activity of NADPH oxidase on the vessel wall following foam injury has been reported (Shi et al, 2001, from. Vasc. biol., 2001, 21, 739-.

Oxidative stress or free radical damage is also believed to be a major causative factor in neurodegenerative diseases. Such damage may include mitochondrial abnormalities, neuronal demyelination, apoptosis, neuronal death and decreased cognitive performance, which may lead to the development of progressive neurodegenerative disorders (Nunomura et al, 2001, J.Neurophothol.Exp.Neurol.60: 759-767; Girouard, 2006, J.Appl.Physiol.100: 328-335).

Furthermore, the production of ROS in seminal fluid has been demonstrated in a number of species and suggests that this is due to NADPH oxidase in the sperm (Vernet et al, biol. reprod., 2001, 65: 1102-. Excessive ROS production is implicated in seminal pathologies, including male infertility, and also in certain penile disorders and prostate cancer.

NADPH oxidase is a multi-subunit enzyme composed of the membrane-bound cytochrome b558 domain and three cytosolic protein subunits, p47phox, p67phox and small GTPase Rac. 7 subtypes of NOX enzymes have been identified, including NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2(Leto et al, 2006, Artificial Redox Signal, 8 (9-10): 1549-61; Cheng et al, 2001, Gene, 16; 269 (1-2): 131-40).

Thus, NADPH-derived ROS contribute to the pathogenesis of a number of diseases, in particular cardiovascular diseases or conditions, respiratory diseases or diseases, diseases or conditions affecting metabolism, bone diseases, neurodegenerative diseases, inflammatory diseases, reproductive conditions or diseases, pain, cancer and diseases or conditions of the gastrointestinal system. Therefore, it is highly desirable to develop new active agents focusing on the ROS signaling cascade, especially on NADPH Oxidase (NOX).

Disclosure of Invention

The present invention relates to novel molecules for the treatment and/or prophylaxis of conditions associated with coenzyme II oxidase (NADPH oxidase), such as cardiovascular diseases, respiratory diseases, conditions affecting metabolism, skin and/or bone diseases, neurodegenerative diseases, kidney diseases, reproductive disorders, inflammatory disorders, cancer, allergic conditions, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases of the gastrointestinal system, or conditions and conditions associated with coenzyme II oxidase (NADPH oxidase). The invention particularly relates to novel molecules for inhibiting or reducing the production of ROS in a cell.

In a first aspect the invention provides a pyrazolo pyridine derivative of formula (I) wherein G is a pharmaceutically acceptable salt thereof and pharmaceutically active derivatives thereof for use as a medicament₁，G₂，G₃，G₄And G₅As defined below.

A second aspect of the invention relates to a pharmaceutical composition comprising at least one pyrazolo pyridine derivative according to the invention as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof as well as pharmaceutically acceptable carriers, diluents or excipients thereof.

A third aspect of the invention relates to the use of the pyrazolo pyridine derivatives of the invention as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof for the preparation of a pharmaceutical composition for the treatment or prevention of a disease or condition selected from: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproductive disorders, disorders affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system and/or other diseases and/or disorders associated with coenzyme II oxidase (NADPH oxidase).

A fourth aspect of the invention relates to a method of treating a patient suffering from a disease or condition selected from: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproductive disorders, disorders affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system and/or other diseases and/or disorders associated with coenzyme II oxidase (NADPH oxidase). The method comprises administering to a patient in need thereof a pyrazolopyridine derivative of formula (I) wherein G is₁，G₂，G₃，G₄And G₅As defined below.

A fifth aspect of the invention relates to pyrazolo pyridine derivatives of formula (I) wherein G is a pharmaceutically acceptable salt or pharmaceutically active derivative thereof for use in the treatment of a disease or condition₁，G₂，G₃，G₄And G₅As defined below, the disease or condition is selected from: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproductive disorders, disorders affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system and/or other diseases and/or disorders associated with coenzyme II oxidase (NADPH oxidase).

Other features and advantages of the present invention will be apparent from the detailed description that follows.

Detailed Description

Definitions of the various chemical moieties that make up the compounds of the present invention are provided in the following paragraphs and it is intended that they be applied consistently throughout this specification and claims, unless a broader definition is provided by specifically set forth in the definition.

The term "alkyl" used alone or in combination with other terms includes straight or branched chain C₁-C₂₀Alkyl, which means a monovalent alkyl group having 1 to 20 carbon atoms. The term may cite the following groups: such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl and n-eicosyl, and the like. Preferably comprises C₁-C₉Alkyl, more preferably C₁-C₆Alkyl, particularly preferably C₁-C₄Alkyl, which similarly means monovalent alkyl groups having 1 to 9 carbon atoms, monovalent alkyl groups having 1 to 6 carbon atoms and monovalent alkyl groups having 1 to 4 carbon atoms, respectively.

The term "alkenyl", alone or in combination with other terms, includes straight or branched chain C₂-C₂₀An alkenyl group. It may carry any available number of double bonds at any available position, and the configuration of the double bond may be in either the (E) or (Z) configuration. The term may cite the following groups: such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenylAlkenyl, 1-eicosenyl, and 3, 7, 11, 15-tetramethyl-1-hexadecenyl, and the like. Preferably comprises C₂-C₈Alkenyl, more preferably C₂-C₆An alkenyl group. Among them, vinyl (vinyl) or vinyl (-CH ═ CH) is particularly preferable₂) N-2-propenyl (allyl, -CH)₂CH＝CH₂) Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl and the like.

The term "alkynyl" used alone or in combination with other terms includes straight or branched chain C₂-C₂₀Alkynyl. It may carry any available number of triple bonds at any available location. The term may cite the following groups: such as an alkynyl group which may have 2 to 20 carbon atoms and optionally a double bond, such as an ethynyl group (-C.ident.CH), 1-propynyl group, 2-propynyl group (propargyl group: -CH)₂C.ident.CH), 2-butynyl, 2-penten-4-ynyl and the like. Preferably comprises C₂-C₈Alkynyl, more preferably C₂-C₆Alkynyl and the like.

The term "heteroalkyl" means C₁-C₁₂Alkyl, preferably C₁-C₆-alkyl wherein at least one carbon is replaced by a heteroatom selected from O, N or S, including 2-methoxyethyl and the like.

The term "aryl" means an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms with a single ring (e.g., phenyl) or multiple condensed rings (e.g., indenyl, naphthyl). Aryl groups include phenyl, naphthyl, anthryl, phenanthryl and the like.

The term "alkylaryl" refers to an aryl group with alkyl substituents and includes methylphenyl, ethylphenyl, and the like.

The term "arylalkyl" refers to an alkyl group with an aryl substituent and includes 3-phenylpropyl, benzyl, and the like.

The term "heteroaryl" refers to a monocyclic heteroaromatic or a bicyclic or tricyclic fused heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3, 4-b ] pyridyl, pyrido [3, 2-b ] pyridyl, pyrido [4, 3-b ] pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6, 7, 8-tetrahydroquinolinyl, 5,6, 7, 8-tetrahydroisoquinolinyl, purinyl, pteridinyl, carbazolyl, xanthenyl, or benzoquinolinyl.

The term "alkylheteroaryl" refers to heteroaryl groups bearing alkyl substituents, including methylfuryl and the like.

The term "heteroarylalkyl" refers to an alkyl group bearing a heteroaryl substituent, including furanylmethyl and the like.

The term "alkenylaryl" refers to aryl groups bearing an alkenyl substituent, including vinylphenyl and the like.

The term "arylalkenyl" refers to an alkenyl group bearing an aryl substituent, including phenylvinyl and the like.

The term "alkenylheteroaryl" refers to heteroaryl groups bearing an alkenyl substituent, including vinylpyridinyl and the like.

The term "heteroarylalkenyl" means an alkenyl group bearing a heteroaryl substituent, including pyridylvinyl and the like.

The term "C₃-C₈By-cycloalkyl "is meant a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). C₃-C₈-the cycloalkyl group comprises a cyclopentyl group,cyclohexyl, norbornyl, and the like.

The term "heterocycloalkyl" means a C as defined above in which up to 3 carbon atoms are replaced by a heteroatom selected from O, S, NR₃-C₈Cycloalkyl, wherein R is defined as hydrogen or methyl. Heterocycloalkyl includes pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.

The term "alkyl C₃-C₈-cycloalkyl "means C with an alkyl substituent₃-C₈Cycloalkyl groups, including methylcyclopentyl and the like.

The term "C₃-C₈-cycloalkylalkyl "means having C₃-C₈Alkyl groups as cycloalkyl substituents, including 3-cyclopentylpropyl and the like.

The term "alkylheterocycloalkyl" refers to heterocycloalkyl groups bearing alkyl substituents, including 4-methylpiperidinyl and the like.

The term "heterocycloalkylalkyl" refers to an alkyl group bearing a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl) methyl and the like.

The term "carboxy" means the group-C (O) OH.

The term "carboxyalkyl" refers to alkyl groups bearing a carboxy substituent, including 2-carboxyethyl and the like.

The term "acyl" means the group-C (O) R, wherein R includes H, "alkyl", preferably "alkyl", "aryl", "heteroaryl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," arylalkyl "," heteroarylalkyl "," C₃-C₈Cycloalkylalkyl "or" heterocycloalkylalkyl "including acetyl and the like.

The term "acylalkyl" refers to an alkyl group bearing an acyl substituent, including 2-acetylethyl and the like.

The term "acylaryl" refers to an aryl group with an acyl substituent, including 2-acetylphenyl and the like.

The term "acyloxy" means the group-OC (O) R, where R includes H, "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," C₃-C₈Cycloalkylalkyl "or" heterocycloalkylalkyl "including acetoxy and the like.

The term "acyloxyalkyl" refers to an alkyl group with an acyloxy substituent, including 2- (ethylcarbonyloxy) ethyl and the like.

The term "alkoxy" refers to the group-O-R, where R includes "alkyl", "aryl", "heteroaryl", "arylalkyl" or "heteroarylalkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group bearing an alkoxy substituent, including methoxyethyl, and the like.

The term "alkoxycarbonyl" refers to the group-C (O) OR, where R includes "alkyl", "aryl", "heteroaryl", "arylalkyl", "heteroarylalkyl", OR "heteroalkyl".

The term "alkoxycarbonylalkyl" refers to alkyl groups bearing an alkoxycarbonyl substituent, including 2- (benzyloxycarbonyl) ethyl and the like.

The term "aminocarbonyl" means the group-C (O) NRR ', where R and R' are independently H, alkyl, aryl, heteroaryl, "arylalkyl" or "heteroarylalkyl," including N-phenylcarbonyl, and the like.

The term "aminocarbonylalkyl" refers to alkyl groups bearing an aminocarbonyl substituent and includes 2- (dimethylaminocarbonyl) ethyl, N-ethylacetamido, N, N-diethyl-acetamido, and the like.

The term "acylamino" meansOr a group-NRC (O) R ', wherein R and R' are independently H, "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," cycloalkylalkyl "or" heterocycloalkylalkyl ", including acetylamino and the like.

The term "acylaminoalkyl" refers to alkyl groups bearing an acylamino substituent, including 2- (propionylamino) ethyl and the like.

The term "ureido" means the group-NRC (O) NR ' R ' where R, R and R ' are independently H, "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," cycloalkylalkyl "or" heterocycloalkylalkyl ", wherein R' and R", together with the nitrogen atom to which they are attached, may optionally form a 3-8-membered heterocycloalkyl ring.

The term "ureidoalkyl" refers to alkyl groups having a ureido substituent and includes 2- (N' -methylureido) ethyl and the like.

The term "carbamate" means the group-NRC (O) OR ', where R and R' are independently "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," alkylaryl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," cycloalkylalkyl "or" heterocycloalkylalkyl ", optionally R may also be hydrogen.

The term "amino" means the group-NRR ', wherein R and R ' are independently H, "alkyl", "aryl", "heteroaryl", "alkylaryl", "alkylheteroaryl", "cycloalkyl" or "heterocycloalkyl", wherein R and R ' and the nitrogen atom to which they are attached may optionally form a 3-8-membered heterocycloalkyl ring.

The term "aminoalkyl" refers to alkyl groups bearing an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

The term "ammonium" means a positively charged group-N⁺RR ' R ', wherein R, R ', and R ' are independently "alkyl", "alkylaryl", "alkylheteroaryl", "cycloalkyl", or "heterocycloalkyl", wherein R and R ', together with the nitrogen atom to which they are attached, may optionally form a 3-8-membered heterocycloalkyl ring.

The term "aminoalkyl" refers to an alkyl group bearing an ammonium substituent, including 1-ethylpyrrolidinium and the like.

The term "halogen" means fluorine, chlorine, bromine and iodine atoms.

The term "sulfonyloxy" means the group-OSO₂-R, wherein R is selected from "alkyl", alkyl substituted by halogen, such as-OSO₂-CF₃The group "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," cycloalkylalkyl "or" heterocycloalkylalkyl ".

The term "sulfonyloxyalkyl" refers to an alkyl group with a sulfonyloxy substituent, including 2- (methylsulfonyloxy) ethyl and the like.

The term "sulfonyl" means the group "-SO₂-R ", wherein R is selected from" aryl "," heteroaryl "," alkyl ", alkyl substituted by halogen, for example-SO₂-CF₃The group "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl ","heteroarylalkynyl", "cycloalkylalkyl" or "heterocycloalkylalkyl".

The term "sulfonylalkyl" refers to alkyl groups bearing a sulfonyl substituent, including 2- (methylsulfonyl) ethyl and the like.

The term "sulfinyl" means the group "-S (O) -R", wherein R is selected from "alkyl", alkyl substituted by halogen, e.g. -SO-CF₃The group "alkenyl", "alkynyl" or "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," C₃-C₈-cycloalkylalkyl "or" heterocycloalkylalkyl ".

The term "sulfinylalkyl" refers to an alkyl group bearing a sulfinyl substituent, including 2- (methylsulfinyl) ethyl and the like.

The term "thioalkyl" means the group-S-R, where R includes H, "alkyl", alkyl substituted with halo, e.g., -S-CF₃The group "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," alkynylheteroaryl "," cycloalkylalkyl "or" heterocycloalkylalkyl ". Preferred sulfanyl groups include methylthioalkyl, ethylsulfanyl and the like.

The term "thioalkyl" refers to a C having a thioalkyl substituent₁-C₅Alkyl groups including 2- (ethylsulfanyl) ethyl and the like.

The term "sulfonylamino" means the group-NRSO₂-R ', wherein R and R' are independently "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylkylAlkenylene, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, C₃-C₈-cycloalkylalkyl "or" heterocycloalkylalkyl ".

The term "sulfonylaminoalkyl" refers to an alkyl group bearing a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl, and the like.

The term "aminosulfonyl" means the group-SO₂-NRR ', wherein R and R' are independently H, "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl "," heteroarylalkyl "," arylalkenyl "," heteroarylalkenyl "," arylalkynyl "," heteroarylalkynyl "," C₃-C₈-cycloalkylalkyl "or" heterocycloalkylalkyl ", wherein R and R' and the nitrogen atom to which they are attached may optionally form a 3-8-membered heterocycloalkyl ring. Aminosulfonyl includes cyclohexylaminosulfonyl, piperidinosulfonyl and the like.

The term "aminosulfonylalkyl" refers to alkyl groups bearing an aminosulfonyl substituent, including 2- (cyclohexylaminosulfonyl) ethyl and the like.

Unless the definition of each substituent is otherwise limited, the term "substituted" means a group substituted with 1 to 5 substituents selected from the group consisting of "alkyl", "alkenyl", "alkynyl", "C₃-C₈-cycloalkyl "," heterocycloalkyl "," alkylaryl "," alkylheteroaryl "," alkylcycloalkyl "," alkylheterocycloalkyl "," amino "," aminosulfonyl "," ammonium "," acylamino "," aminocarbonyl "," aryl "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," alkoxycarbonyl "," carbamate "," sulfanyl "," halogen ", trihalomethyl, cyano, hydroxy, mercapto, nitro and the like.

The term "pharmaceutically acceptable salt or complex" refers to the specific salt or complex of a compound of formula (I) as follows. Examples of such salts include, but are not limited to, base addition salts formed by reacting a compound of formula (I) with an organic or inorganic base such as a hydroxide, carbonate or bicarbonate of a metal cation, such as those selected from alkali metals (sodium, potassium or lithium), alkaline earth metals (e.g. calcium or magnesium) or with an organic primary, secondary or tertiary alkyl amine. Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N' -bis (phenylmethyl) -1, 2-ethylenediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are within the scope of the present invention.

Also included are salts formed as follows: acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) and salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.

By "pharmaceutically active derivative" is meant any compound that, when administered to a recipient, is capable of providing, directly or indirectly, the activity disclosed herein. The term "indirect" also includes prodrugs that can be converted to the active form of the drug by endogenous enzymes or metabolism. Prodrugs are derivatives of the compounds of the present invention which bear chemically or metabolically cleavable groups and provide NADPH oxidase inhibitory activity and are compounds which can be converted in vivo by solvolysis under physiological conditions to pharmaceutically active compounds. The invention also includes any tautomers of the compounds of the invention.

The term "cardiovascular disorder or disease" includes atherosclerosis, particularly diseases or disorders associated with endothelial dysfunction, including, but not limited to, hypertension, cardiovascular complications of type I or type II diabetes, intimal hyperplasia, coronary heart disease, cerebral, coronary or arterial vasospasm, endothelial dysfunction, heart failure (including congestive heart failure), peripheral arterial disease, restenosis, stent-induced trauma, stroke, ischemic attacks, vascular complications such as following organ transplantation or following viral or bacterial infection, myocardial infarction, hypertension, atherosclerotic plaque formation, platelet aggregation, angina, aneurysm, aortic dissection, ischemic heart disease, cardiac hypertrophy, pulmonary embolism, thrombosis (including deep vein thrombosis), damage following ischemia due to blood flow restoration or oxygen transport in organ transplantation, open heart surgery, angioplasty, hemorrhagic shock, angioplasty of ischemic organs (including heart, brain, liver, kidney, retina and intestine).

The term "respiratory disease or disorder" includes bronchial asthma, bronchitis, allergic rhinitis, adult respiratory distress syndrome, cystic fibrosis, lung viral infection (influenza), pulmonary hypertension and Chronic Obstructive Pulmonary Disease (COPD).

The term "allergic conditions" includes hay fever and asthma.

The term "trauma" includes multiple injuries.

The term "diseases or disorders affecting metabolism" includes obesity, metabolic syndrome and type II diabetes.

The term "skin disease" or disorder "includes psoriasis, eczema, dermatitis, wound healing and scarring.

The term "bone disease" includes osteoporosis, osteoporosis (osteoporotis), bone sclerosis, periodontitis and hyperparathyroidism.

The term "neurodegenerative disease or disorder" includes diseases or conditions characterized by degeneration or alteration of the Central Nervous System (CNS), especially at the neuronal level, such as alzheimer's disease, parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis, epilepsy and muscular dystrophy. It also includes neuroinflammation and demyelinating states or diseases such as leukoencephalopathy and leukodystrophy.

The term "demyelination" is intended to include CNS states or diseases in which myelin is degraded around axons. In the context of the present invention, the term demyelinating disease is intended to include conditions comprising a process of demyelinating cells, such as multiple sclerosis, Progressive Multifocal Leukoencephalopathy (PML), myelopathy, any neuroinflammatory condition involving autoreactive leukocytes within the CNS, inborn errors of metabolism, neuropathy with abnormal myelination, drug-induced demyelination, radiation-induced demyelination, genetic demyelinating conditions, prion-induced demyelinating conditions, encephalitis-induced demyelination or spinal cord injury. Preferably the disorder is multiple sclerosis.

The term "renal disease or disorder" includes diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity caused by aminoglycosides and platinum compounds, and overactive bladder.

The term "reproductive disorder or disease" includes erectile dysfunction, reproductive disorders, prostatic hypertrophy and benign prostatic hypertrophy.

The term "disease or condition that affects the eye and/or lens" includes cataracts (including diabetic cataracts), re-opacification of the lens after cataract surgery, diabetes mellitus due to retinopathy and other forms.

The term "conditions affecting the inner ear" includes presbycusis, tinnitus, meniere's disease and other balance problems, utriculolithiasis (utriculolithiasis), vestibular migraine and noise-induced deafness and drug-induced hearing loss (ototoxicity).

The term "inflammatory disorder or disease" means inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatoid arthritis, arteriosclerosis, cerebral hemorrhage, cerebral infarction, heart failure, myocardial infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, myelitis, ankylosing spondylitis, Reuter syndrome, psoriatic arthritis, spondyloarthritis, juvenile arthritis or juvenile ankylosing spondylitis, reactive arthritis, infectious arthritis or post-infectious arthritis, gonococcal arthritis, tubercular arthritis, viral arthritis, bacterially-induced arthritis, syphilitic arthritis, lyme disease, "vasculitis syndrome" -induced arthritis, polyarteritis nodosa, allergic vasculitis, Luegenec granulomatosis, rheumatoid polymyalgia, articular cellular rheumatism, calcium crystalloid arthritis, pseudogout, non-arthritic rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), carpal tunnel syndrome, conditions resulting from repeated use (typing), mixed arthritis, neuropathic joint disease, hemorrhagic arthritis, vascular purpura, hypertrophic osteoarthropathy, polycythemia, special disease-induced arthritis, hemochromatosis, sickle cell disease and other hemoglobinopathies, hyperlipoproteinemia, aberoproteinemia, hyperparathyroidism, acromegaly-like disease, familial mediterranean fever, Behcet's disease, systemic lupus erythematosus autoimmune disease, multiple sclerosis and crohn's disease or diseases such as relapsing polychondritis, chronic Inflammatory Bowel Disease (IBD) or related diseases that require the administration to a mammal of a therapeutically effective dose of a compound represented by formula (I) in a dose sufficient to inhibit NADPH oxidase.

The term liver disease or disorder includes liver fibrosis, alcohol-induced fibrosis, sebaceous gland disease and non-alcoholic steatohepatitis.

The term "arthritis" means acute rheumatoid arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, chylotic arthritis, enteropathy-based arthritis, filarial arthritis, gonococcal arthritis, gouty arthritis, hemophilia arthritis, proliferative arthritis, juvenile chronic arthritis, lyme arthritis, neonatal arthritis (neonatal arthritis), nodular arthritis, pheochromogenous arthritis, psoriatic arthritis or suppurative arthritis, or related diseases requiring the administration to a mammal of a therapeutically effective dose of a compound represented by formula (I) in a dose sufficient to inhibit NADPH oxidase.

The term "pain" includes hyperalgesia associated with inflammatory pain.

The term "cancer" means a carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, periostioma, mesothelioma, ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer or epithelial cancer) or a related disease requiring administration to a mammal of a therapeutically effective dose of a compound represented by formula (I) in a dose sufficient to inhibit NADPH oxidase.

The term "diseases or disorders of the gastrointestinal system" includes gastric mucosal disorders, ischemic bowel disease control, enteritis/colitis, cancer chemotherapy or neutropenia.

As used herein, "treatment" and "treating" and the like are generally intended to obtain a desired pharmacological and physiological effect. The effect may be prophylactic in preventing or partially preventing a disease, symptom or condition thereof and/or therapeutic in partially or completely curing the disease, condition, symptom or adverse reaction to the disease. The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, including: (a) preventing a susceptible disease from occurring in a subject who has not yet been diagnosed as having it; (b) inhibiting the disease, i.e. arresting its development; or relieving the disease, i.e., causing regression of the disease and/or its symptoms or conditions.

The term "subject" as used herein means a mammal. For example, mammals of the invention include humans, primates, domestic animals such as cattle, sheep, pigs, horses, and the like.

The term "inhibitor" as used in the context of the present invention is defined as a molecule that completely or partially inhibits the activity of NADPH oxidase and/or inhibits or reduces the generation of Reactive Oxygen Species (ROS).

Composition comprising a metal oxide and a metal oxide

The invention provides a medicament or therapeutic agent as a composition and a method of treating a patient, preferably a mammalian patient and most preferably a human patient, suffering from a medical condition, in particular a condition mediated by NADPH oxidase, such as a cardiovascular condition or disease, a respiratory condition or disease, a disease or condition affecting metabolism, a skin disease, a bone disease, a neuroinflammatory condition, a neurodegenerative condition, a kidney disease, a reproductive condition, a disease or condition affecting the eye and/or the lens, a condition affecting the inner ear, an inflammatory condition or disease, a liver disease, pain, cancer and/or a disease or condition of the gastrointestinal system.

The pharmaceutical compositions of the present invention may comprise one or more pyrazolopyridine derivatives in any form described herein. The compositions of the present invention may further comprise one or more pharmaceutically acceptable additional components, such as alum, stabilizers, antimicrobials, buffers, colorants, flavorants, adjuvants and the like.

The compounds of the present invention may be incorporated in pharmaceutical compositions and unit dosage forms thereof with conventional adjuvants, carriers, diluents or excipients and, in such forms, may be employed as solids such as tablets or filled capsules or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled with them, all for oral use or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may contain the ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage to be employed. The composition of the invention is preferably injectable.

The compositions of the present invention may also be liquid preparations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. Liquid dosage forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles including buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle immediately prior to use. Such liquid formulations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Non-aqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oil esters, propylene glycol and ethyl alcohol. Preservatives include, but are not limited to, methylparaben or propylparaben and sorbic acid. Additional materials and processing techniques, etc., can be cited Remington's Pharmaceutical Sciences, 20^thEdition, 2000, Merck Publishing Company, Easton, Pennsylvania section 5, which is incorporated herein by reference.

The solid compositions of the present invention may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binders, fillers, lubricants, disintegrants, and wetting agents. Binders include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, starch slurry and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.

Injectable compositions are generally based on injectable sterile saline or phosphate buffered saline or other injectable carriers well known in the art.

The compositions of the present invention may also be formulated as suppositories, which may contain a suppository base (including, but not limited to, cocoa butter or glycerides). The compositions of the present invention may also be formulated as an inhaler, which may be in the form of a solution, suspension or emulsion that may be administered as a dry powder, or an aerosol using a propellant, such as dichlorodifluoromethane or trichlorofluoromethane. The compositions of the present invention may also be formulated as transdermal formulations containing aqueous or non-aqueous vehicles, including but not limited to creams, ointments, lotions, pastes, medicated plasters (salves), patches or films.

The compositions of the present invention may also be formulated for parenteral administration, including but not limited to by injection or continuous infusion. Injectable preparations may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents including, but not limited to, suspending, stabilizing and dispersing agents. The compositions may also be prepared in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water.

The compositions of the present invention may also be formulated as a long acting formulation, which may be administered by implantation or by intramuscular injection. The compositions may be formulated using suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), ion exchange resins, or sparingly soluble derivatives (e.g., as a sparingly soluble salt).

The compositions of the invention may also be formulated as liposomal formulations. The liposome preparation may comprise liposomes that penetrate the cell or stratum corneum of interest and fuse with the cell membrane, thereby delivering the contents of the liposomes into the cell. Other suitable formulations may use niosomes. Niosomes are lipid vesicles similar to liposomes, with membranes composed primarily of non-ionic lipids, some of which are effective in transporting compounds across the stratum corneum.

The compounds of the present invention may also be administered in sustained release dosage forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the mixed materials in Remington's pharmaceutical sciences.

Mode of administration

The compositions of the present invention may be administered in any manner, including but not limited to orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, by inhalation, by buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarticular. The compositions of the present invention may also be administered in the form of an implant that enables slow release and slow controlled intravenous infusion of the composition. In a preferred embodiment, the pyrazolopyridine derivative of the invention is administered intravenously or subcutaneously.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

The dose administered to an individual as a single dose or as multiple doses will vary depending on various factors including pharmacokinetic properties, condition and characteristics (sex, age, body weight, health, size) of the patient, extent of symptoms, concurrent treatment, frequency of treatment and desired effect.

Patient's health

In one embodiment, the patient of the invention is a patient suffering from a cardiovascular condition or disease.

In another embodiment, the patient of the invention is a patient suffering from a respiratory disease or disorder.

In another embodiment, the patient of the invention is a patient suffering from a disease or disorder that affects metabolism.

In another embodiment, the patient of the invention is a patient suffering from a skin disease.

In another embodiment, the patient of the invention is a patient suffering from a bone disease.

In another embodiment, the patient of the invention is a patient suffering from a neuroinflammatory and/or neurodegenerative disorder.

In another embodiment, the patient of the invention is a patient suffering from kidney disease.

In another embodiment, the patient of the invention is a patient suffering from a reproductive disorder.

In another embodiment, the patient of the invention is a patient suffering from a disease or disorder that affects the eye and/or lens and/or a condition that affects the inner ear.

In another embodiment, the patient of the invention is a patient suffering from an inflammatory condition or disease.

In another embodiment, the patient of the invention is a patient suffering from a liver disease.

In another embodiment, the patient of the invention is a patient suffering from pain, such as inflammatory pain.

In another embodiment, the patient of the invention is a patient suffering from cancer.

In another embodiment, the patient of the invention is a patient suffering from an allergic disorder.

In another embodiment, the patient of the invention is a patient suffering from a trauma disorder.

In another embodiment, the patient of the invention is a patient suffering from septic shock, hemorrhagic shock and anaphylactic shock.

In another embodiment, the patient of the invention is a patient suffering from a disease or disorder of the gastrointestinal system.

Application of the invention

The present invention provides in one embodiment the use of pyrazolopyridine derivatives of formula (I) and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof as medicaments:

wherein G is₁Selected from H, optionally substituted alkyl, such as aminocarbonylalkyl (e.g. phenylacetamido), optionally substituted C₃-C₈Cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, such as optionally substituted phenylalkyl, such as optionally substituted phenylmethyl (e.g. phenylmethyl or 3-methylphenylmethyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-methylbenzyl or 4-bromobenzyl); and optionally substituted heteroarylalkyl, such as optionally substituted pyridylalkyl, e.g., pyridin-2-ylmethyl;

G₂is selected from H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl, such as optionally substituted phenyl (e.g. phenyl or 4-fluorophenyl or 4-methoxyphenyl or 4-nitrophenyl or 2-chlorophenyl or 2-methylphenyl or 4- (trifluoromethyl) phenyl or 4- (trifluoromethoxy) phenyl or 2, 5-difluorophenyl or 2-methoxyphenyl); optionally substituted alkylaryl; optionally substituted arylalkyl; optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (e.g., 1, 3-benzothiazol-2-yl) or optionally substituted pyridyl (e.g., pyridin-2-yl); optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl; optionally substituted alkyl C₃-C₈-RingAn alkyl group; optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl;

G₃is selected from H; optionally substituted alkyl, such as methyl or ethyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl, such as optionally substituted phenyl (e.g., phenyl); optionally substituted alkylaryl; optionally substituted arylalkyl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl; optionally substituted alkyl C₃-C₈-a cycloalkyl group; optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl;

G₄selected from H, optionally substituted alkyl, such as optionally substituted pentyl (e.g. isopentyl) or optionally substituted heteroalkyl, such as optionally substituted methoxy (e.g. 2-methoxyethyl); optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkylaryl; optionally substituted arylalkyl, such as optionally substituted phenylmethyl (e.g., benzoic acid methyl or benzyl) or optionally substituted phenylethyl (e.g., 2-phenylethyl, 4-methoxyphenylethyl); optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl, such as optionally substituted thienylalkyl, such as optionally substituted thienylmethyl (e.g. thien-2-ylmethyl) or optionally substituted imidazolylalkyl, such as optionally substituted imidazolylethyl (e.g. imidazol-4-ylethyl) or optionally substituted indolylalkyl, such as optionally substituted indolylethyl (e.g. indol-3-ylethyl) or optionally substituted furanylalkyl, such as optionally substituted furanylmethyl (e.g. furan-2-ylmethyl) or optionally substituted benzodioxolanyl alkyl, such as optionally substituted benzodioxolylmethyl (e.g. optionally substituted benzodioxolmethyl)Such as 1, 3-benzodioxol-5-ylmethyl) or optionally substituted pyridylalkyl, such as optionally substituted pyridylmethyl (e.g. pyridin-3-ylmethyl or pyridin-2-ylmethyl); optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl, such as optionally substituted morpholinyl (e.g. 5-morpholin-4-yl) or optionally substituted piperazinyl (e.g. 4-methylpiperazinyl) or optionally substituted piperidinyl (e.g. 4-methylbenzylpiperidin-4-yl); optionally substituted alkyl C₃-C₈-a cycloalkyl group; and optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl, such as optionally substituted morpholinylalkyl, such as optionally substituted morpholinylpropyl (e.g. 3- (morpholin-4-yl) propyl), optionally substituted morpholinylethyl (e.g. 2-morpholin-4-ylethyl); or optionally substituted piperazinylalkyl, such as optionally substituted piperazinylethyl (e.g. 2- (4-acetylpiperazin-1-yl) ethyl or 2- (4-hexanoylpiperazin-1-yl) ethyl) or optionally substituted pyrrolidinylalkyl, such as optionally substituted pyrrolidinopropyl (e.g. 3- (2-oxopyrrolidin-1-yl) propyl) or optionally substituted tetrahydrofuranylalkyl, such as optionally substituted tetrahydrofuranylmethyl (e.g. tetrahydrofur-2-ylmethyl);

G₅selected from H, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkylaryl; optionally substituted arylalkyl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl; optionally substituted alkyl C₃-C₈-a cycloalkyl group; optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₁Is H.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₁Selected from optionally substituted arylalkyl and optionally substituted heteroarylalkyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₁Is an optionally substituted alkyl group.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₂Selected from optionally substituted aryl and optionally substituted heteroaryl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₃Is H.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₃Is optionally substituted alkyl, such as optionally substituted methyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₃Is an optionally substituted aryl group.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₄Selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₄Selected from optionally substituted arylalkyl and substituted heteroarylalkyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₄Selected from optionally substituted C₃-C₈Cycloalkylalkyl and optionally substitutedIs a heterocycloalkyl group.

In another embodiment, the invention provides a pyrazolo pyridine derivative of the invention wherein G is₄Is optionally substituted heterocycloalkyl.

In another embodiment, the present invention provides a pyrazolo pyridine derivative of the invention wherein G₅Is H.

In another embodiment the invention provides the use of a pyrazolo pyridine derivative of formula (I) as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof in the preparation of a pharmaceutical composition for the treatment or prevention of a disease or condition selected from the group consisting of:

wherein G is₁Selected from H, optionally substituted alkyl such as aminocarbonylalkyl (e.g. phenylacetamido), optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl such as optionally substituted phenylalkyl, e.g. optionally substituted phenylmethyl (e.g. phenylmethyl or 3-methylphenylmethyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-methylbenzyl or 4-bromobenzyl); and optionally substituted heteroarylalkyl, such as optionally substituted pyridylalkyl, e.g., pyridin-2-ylmethyl;

G₂is selected from H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl, such as optionally substituted phenyl (e.g. phenyl or 4-fluorophenyl or 4-methoxyphenyl or 4-nitrophenyl or 2-chlorophenyl or 2-methylphenyl or 4- (trifluoromethyl) phenyl or 4- (trifluoromethoxy) phenyl or 2, 5-difluorophenyl or 2-methoxyphenyl); optionally substituted alkylaryl; optionally substituted arylalkyl; optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (e.g., 1, 3-benzothiazol-2-yl) or optionally substituted pyridyl (e.g., pyridin-2-yl); optionally substituted alkylheteroaryl; optionally substitutedA heteroarylalkyl group; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl; optionally substituted alkyl C₃-C₈-a cycloalkyl group; optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl;

G₄selected from H, optionally substituted alkyl such as pentyl (e.g. isopentyl) or optionally substituted heteroalkyl such as optionally substituted methoxy (e.g. 2-methoxyethyl); optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkylaryl; optionally substituted arylalkyl, such as optionally substituted phenylmethyl (e.g., benzoic acid methyl or benzyl) or optionally substituted phenylethyl (e.g., 2-phenylethyl, 2- (4-methoxyphenyl) ethyl); optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl, such as optionally substituted thienylalkyl, such as optionally substituted thienylmethyl (e.g. thien-2-ylmethyl) or optionally substituted imidazolylalkyl, such as optionally substituted imidazolylethyl (e.g. imidazol-4-ylethyl) or optionally substituted indolylalkyl,such as optionally substituted indolylethyl (e.g. indol-3-ylethyl) or optionally substituted furanylalkyl, such as optionally substituted furanylmethyl (e.g. furan-2-ylmethyl) or optionally substituted benzodioxolanyl alkyl, such as optionally substituted benzodioxolyl (e.g. 1, 3-benzodioxol-5-ylmethyl) or optionally substituted pyridylalkyl, such as optionally substituted pyridylmethyl (e.g. pyridin-3-ylmethyl or pyridin-2-ylmethyl); optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl, such as optionally substituted morpholinyl (e.g. 5-morpholin-4-yl) or optionally substituted piperazinyl (e.g. 4-methylpiperazinyl) or optionally substituted piperidinyl (e.g. 4-methylbenzyl) piperidin-4-yl); optionally substituted alkyl C₃-C₈-a cycloalkyl group; and optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl, such as optionally substituted morpholinylalkyl, such as optionally substituted morpholinylpropyl (e.g. 3- (morpholin-4-yl) propyl), optionally substituted morpholinylethyl (e.g. 2-morpholin-4-ylethyl); or optionally substituted piperazinylalkyl, such as optionally substituted piperazinylethyl (e.g. 2- (4-acetylpiperazin-1-yl) ethyl or 2- (4-hexanoylpiperazin-1-yl) ethyl) or optionally substituted pyrrolidinylalkyl, such as optionally substituted pyrrolidinopropyl (e.g. 3- (2-oxopyrrolidin-1-yl) propyl) or optionally substituted tetrahydrofuranylalkyl, such as optionally substituted tetrahydrofuranylmethyl (e.g. tetrahydrofur-2-ylmethyl);

G₅selected from H, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkylaryl; optionally substituted arylalkyl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; optionally substituted C₃-C₈-a cycloalkyl group; optionally substituted heterocycloalkyl; optionally substituted alkyl C₃-C₈-a cycloalkyl group; optionally substituted C₃-C₈-a cycloalkylalkyl group; optionally substituted alkylheterocycloalkyl and optionally substituted heterocycloalkylalkyl;

the disease or condition is selected from cardiovascular conditions, respiratory conditions, metabolic conditions, skin conditions, bone conditions, neuroinflammatory and/or neurodegenerative conditions, kidney conditions, reproductive conditions, conditions affecting the eye and/or lens and/or conditions affecting the inner ear, inflammatory conditions, liver conditions, pain, cancer, allergic conditions, trauma conditions, septic, hemorrhagic and anaphylactic shock, conditions of the gastrointestinal system and conditions associated with coenzyme II oxidase (NADPH oxidase).

In another embodiment, the invention provides the use of a pyrazolo pyridine derivative of formula (I) wherein G is as defined in₁，G₂，G₃，G₄And G₅As described herein, in the context of the present disclosure,

the disease or condition is selected from: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproduction disorders, diseases affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, gastrointestinal system disorders and diseases and disorders associated with coenzyme II oxidase (NADPH oxidase).

The compounds of the invention include in particular those selected from:

4-methyl-2-phenyl-5- (thiophen-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -5- [2- (1H-imidazol-4-yl) ethyl ] -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -5- [2- (1H-indol-3-yl) ethyl ] -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5- (furan-2-ylmethyl) -4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4- { [2- (1, 3-benzothiazol-2-yl) -4-methyl-3, 6-dioxo-1, 2,3, 6-tetrahydro-5H-pyrazolo [4,3-c ] pyridin-5-yl ] methyl } benzoic acid;

4-methyl-2-phenyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-methyl-2-phenyl-5- (2-phenylethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5- [2- (4-acetylpiperazin-1-yl) ethyl ] -2- (1, 3-benzothiazol-2-yl) -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (2-methylbutyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -5- [2- (4-methoxyphenyl) ethyl ] -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -5- [2- (4-hexanoylpiperazin-1-yl) ethyl ] -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1-benzyl-5- (furan-2-ylmethyl) -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5- [2- (1H-indol-3-yl) ethyl ] -4-methyl-1- (3-methylbenzyl) -2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

1- (4-fluorobenzyl) -5- [2- (1H-indol-3-yl) ethyl ] -4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

1- (2-chlorobenzyl) -4-methyl-5- [3- (2-oxopyrrolidin-1-yl) propyl ] -2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1-benzyl-4-methyl-5- (tetrahydrofuran-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

1- (4-chlorobenzyl) -5- [2- (1H-imidazol-4-yl) ethyl ] -4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione; and

5- (1, 3-benzodioxol-5-ylmethyl) -4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5-benzyl-4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5-benzyl-2- (4-fluorophenyl) -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5-benzyl-2- (4-methoxyphenyl) -4-methyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-5-morpholin-4-yl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5-benzyl-4-methyl-2- (4-nitrophenyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (3-methylbenzyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1- (4-fluorobenzyl) -4-methyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (4-methylbenzyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1- (2-chlorobenzyl) -4-methyl-5-morpholin-4-yl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1- (4-bromobenzyl) -4-methyl-5- (2-morpholin-4-ylethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- [2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (3-morpholin-4-ylpropyl) -3, 6-dioxo-2, 3,5, 6-tetrahydro-1H-pyrazolo [4,3-c ] pyridin-1-yl ] -N-phenylacetamide;

4-methyl-2-phenyl-5- (tetrahydrofuran-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (2-phenylethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5- [2- (1H-indol-3-yl) ethyl ] -4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-methyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -1- (2-chlorobenzyl) -4-methyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5-benzyl-4-ethyl-2- (4-fluorophenyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-2- (4-fluorophenyl) -5- (2-phenylethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-2- (4-fluorophenyl) -5-morpholin-4-yl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-methyl-5- (2-morpholin-4-ylethyl) -2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (2-chlorophenyl) -4-methyl-5- (pyridin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-methyl-2- (2-methylphenyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (pyridin-2-ylmethyl) -5- (tetrahydrofuran-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (pyridin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (2-methoxyethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- [1- (4-methylbenzyl) piperidin-4-yl ] -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-2- (4-fluorophenyl) -5- (pyridin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-2- (4-fluorophenyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-2- (4-fluorophenyl) -5- (2-methoxyethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

5- (2-morpholin-4-ylethyl) -2-pyridin-2-yl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2, 4-diphenyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (2-chlorophenyl) -4-ethyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-methyl-2- (2-methylphenyl) -5- (pyridin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-5- (3-morpholin-4-ylpropyl) -2- [4- (trifluoromethyl) phenyl ] -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

4-ethyl-5- (3-morpholin-4-ylpropyl) -2- [4- (trifluoromethoxy) phenyl ] -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (2, 5-difluorophenyl) -4-ethyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione; and

4-Ethyl-2- (2-methoxyphenyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione.

In another embodiment, the invention provides a method of treating a patient having a disease or condition selected from the group consisting of: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproduction disorders, diseases affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, gastrointestinal disorders and other diseases and disorders associated with coenzyme II oxidase (NADPH oxidase). The method comprises administering to a patient in need thereof a compound of formula (I).

In another embodiment, the invention provides the use of a pyrazolo pyridine of the invention and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof in the treatment of a disease or condition selected from: cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney disorders, reproduction disorders, diseases affecting the eye and/or the lens and/or disorders affecting the inner ear, inflammatory disorders, liver disorders, pain, cancer allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, gastrointestinal disorders and other diseases and disorders associated with coenzyme II oxidase (NADPH oxidase).

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one pyrazolopyridine derivative of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient thereof.

The compounds of the invention have been named according to the IUPAC standard for the program ACD/Name (product version 10.01).

The compounds of the present invention also include tautomers thereof, geometrical isomers thereof, optically active forms thereof as enantiomers, diastereomers and racemic forms thereof, and pharmaceutically acceptable salts thereof. Typical derivatives of the present invention are prepared from readily available starting materials using the following general procedures and procedures. It is understood that even if typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise stated. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions may be determined by one skilled in the art using routine optimization procedures.

The references cited herein are incorporated by reference in their entirety. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and compositions are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such variations are also within the scope of the invention as claimed.

The invention having been thus described, the following examples are offered by way of illustration only and are not intended to be limiting.

Synthesis of the Compounds of the invention:

the novel derivatives of formula (I) can be prepared from readily available starting materials using the following general procedures and procedures. It is understood that even if typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise stated. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

A general synthetic procedure for obtaining the compounds of formula (I) is shown in scheme 1 below.

Scheme 1

Pyrazolopyridine derivatives of formula (I), wherein substituent G is as outlined in scheme 1 below, may be prepared in three chemical steps from custom-made or commercially-available substituted hydrazine derivatives of formula (IV), acetone dicarboxylate derivatives of formula (V), primary amine derivatives of formula (II) and trialkyl orthoester derivatives of formula (III) according to the synthetic scheme outlined in scheme 1 below₁，G₂，G₃，G₄And G₅As defined above). In a more specific process, a hydrazine derivative of formula (VI) (wherein G₂As defined above) with an acetone dicarboxylate derivative of formula (V) (whereinG₅And R¹As defined above) under neutral and reflux conditions in a suitable solvent such as benzene, toluene or other non-reactive solvent for a time dependent on the intrinsic reactivity of the compound of formula (VI) to give the corresponding 4-substituted 2-hydroxypyrazole derivative of formula (IV). Further reacting the intermediate compound of formula (IV) with a trialkyl orthoester derivative of formula (III) (wherein G₃And R²As defined above) to form an intermediate of formula (VII) in the presence of acetic acid and under reflux conditions. Further with a primary amine derivative of the formula (II) (wherein G₄As defined above) in a solvent such as toluene or benzene under reflux conditions to give an intermediate compound of formula (VIII). After cyclization of the intermediate compound of formula (VIII), the pyrazolo derivative of formula (Ia) (i.e. formula (I)) wherein G is isolated using standard reflux conditions well known to those skilled in the art as shown in scheme 1, preferably in a protic solvent in the presence of a base such as sodium methoxide, sodium isopropoxide, and the like₁Is H).

The reaction may be carried out in a solvent such as methanol, ethanol, isopropanol or other non-reactive solvent at room temperature, for a period of time depending on the intrinsic reactivity of the compound of formula (VIII), but generally requires conventional heating or microwave methods, using standard conditions well known to those skilled in the art as outlined above in scheme 1. In a subsequent step, the pyrazolopyridine derivative of formula (Ia) (wherein G is G-dimethylformamide or tetrahydrofuran) is treated with an alkylating agent such as alkyl chloride, alkyl bromide, alkyl iodide or alkyl methanesulfonate in a suitable solvent with a suitable base such as triethylamine, sodium hydride or potassium carbonate as base, for example N, N-dimethylformamide or tetrahydrofuran, by conventional heating methods or using microwave techniques₁As defined above). After this treatment, the pyrazolopyridine derivative of formula (I) is isolated using standard conditions well known to those skilled in the art as shown in scheme 1.

The following abbreviations are intended to be defined as follows:

(angstroms), Ac₂O (acetic anhydride), eq. (eq.), min (min), h (h), g (g), MHz (megahertz), mL (mL), mM (millimeter), mmol (millimole), mM (millimole), ng (nanogram), nm (nanometer), rt (room temperature), NADPH (nicotinamide adenine dinucleotide phosphate form), BSA (bovine serum albumin), DCF (2, 7-dichlorodihydrofluorescein), DCM (dichloromethane), DIPEA (di-isopropylethylamine), DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), DAPI (4, 6-diamidino-2-phenylindole), DPI (diphenyliodide), cHex (cyclohexane), EDTA (ethylenediaminetetraacetic acid), EGF (epidermal growth factor), EtOAc (ethyl acetate), FC (silica gel flash chromatography), HBSS (Hanks buffered saline solution), HPLC (high Performance liquid chromatography), H₂DCF-DA (2 ', 7' -dichlorodihydrofluorescein diethyl ester), MEM (2-methoxyethoxymethyl), MS (mass spectrometry), NBT (nitroblue tetrazolium), NMR (nuclear magnetic resonance), PBS (phosphate buffered saline), petethere (petroleum ether), TEA (triethylamine), TFA (trifluoroacetic acid), TGF- β (tumor growth factor β), THF (tetrahydrofuran), tBuOK (potassium tert-butoxide), ROS (reactive oxygen), SOD (superoxide dismutase), SPA (scintillation proximity assay), TLC (thin layer chromatography), UV (ultraviolet).

If the general synthetic methods described above are not suitable for obtaining the compounds of formula (I) and/or the necessary intermediates for the synthesis of the compounds of formula (I), suitable preparation methods known to the person skilled in the art should be used. In general, the synthetic route for any of the individual compounds of formula (I) depends on the specific substituents per molecule and the preparative availability of the necessary intermediates, as well as the factors described above as understood by those skilled in the art. For all protection and deprotection methods see Philip j. kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994; and Theodora W.Greene and Peter G.M.Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, 3 rd edition, 1999.

The compound of the invention can be separated from the bound solvent molecules by crystallization from evaporation of the appropriate solvent. Pharmaceutically acceptable acid addition salts of compounds of formula (I) containing a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid (neat or in a suitable solution) and the resulting salt isolated by filtration or by evaporation of the reaction solvent in vacuo. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of the compound of formula (I) with a suitable base. Ion exchange resin techniques can be used to form or interconvert both types of salts.

In the following, the invention will be illustrated by means of some examples, which are not to be construed as limiting the scope of the invention.

The HPLC, NMR and MS data provided in the following examples were obtained as follows: HPLC: column: waters Symmetry C850x4.6mm, conditions: MeCN/H₂O, 5-100% (8min), maximum 230-400 nm; mass spectrum: PE-SCIEX API 150EX (APCI and ESI), LC/MS Spectroscopy: waters ZMD (ES);¹H-NMR：BrukerDPX-300MHz。

use of Presp Nova-HR C186μm40X30mm (up to 100mg) orPrep HPLC purification on HPLCWaters Prep LC 4000 system at Prep MS C8, 10 μm, 50 × 300mm (up to 1 g). Using MeCN/H₂All purifications were performed with an O0.09% TFA gradient, UV detection at 254nm and 220nm, flow rate 20mL/min (up to 50 mg). In Merck Precoated 60F₂₅₄TLC analysis was performed on the plates. In SiO₂The carrier was purified by flash chromatography using cyclohexane/EtOAc or DCM/MeOH mixtures as eluent.

Example 1: 4-methyl-2-phenyl-5- (thien-2-ylmethyl) -1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -diones(1)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7 below, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 1-thiophen-2-ylmethylamine, the title compound (1) was isolated as a white solid in a yield of 70% (98% purity by HPLC). MS (ESI)⁺)：338.6；MS(ESI^-)：336.4。

Example 2: 2- (1, 3-benzothiazol-2-yl) -5- [2- (1H-imidazol-4-yl) ethyl Base of]-4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C2)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (1H-imidazol-5-yl) ethylamine, the title compound (2) was isolated as a yellow-beige solid in 75% yield (98% purity by HPLC). MS (ESI)⁺)：393.5；MS(ESI^-)：391.6。

Example 3: 2- (1, 3-benzothiazol-2-yl) -5- [2- (1H-indol-3-yl) ethyl Base of]-4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C3)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (1H-indol-3-yl) ethylamine, the title compound (3) was isolated as a white solid in 76% yield (98% purity by HPLC). MS (ESI)⁺)：442.6；MS(ESI^-)：440.7。

Example 4: 2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (3-morpholin-4-ylpropan) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C4)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 3-morpholin-4-ylpropan-1-amine, the title compound (4) was isolated as a white solid in a yield of 72% (96% purity by HPLC). MS (ESI)⁺)：426.6；MS(ESI^-)：424.7。

Example 5: 5- (furan-2-ylmethyl) -4-methyl-2-phenyl-1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -diones(5)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7, with phenylhydrazine, dimethyl 3-oxoglutarate1, 1, 1-Triethoxyethane and 1-furan-2-ylmethylamine as starting materials the title compound (5) was isolated as a white solid in 79% yield (96% purity by HPLC). MS (ESI)⁺)：322.5；MS(ESI^-)：320.4。

Example 6: 4- { [2- (1, 3-benzothiazol-2-yl) -4-methyl-3, 6-dioxo -1, 2,3, 6-tetrahydro-5H-pyrazolo [4,3-c]Pyridin-5-yl]Methyl benzoic acid(6)Shape of Become into(Compound Ia, scheme 1)

Following the general method as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 4- (aminomethyl) benzoic acid, the title compound (6) was isolated as a white solid in 78% yield (99% purity by HPLC). MS (ESI)⁺)：433.5；MS(ESI^-)：431.4。

Example 7: 4-methyl-2-phenyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -dione (C7)Formation of(Compound Ia, scheme 1)

a) Methyl (5-hydroxy-1-phenyl-1H-pyrazol-3-yl) acetate (compound of formula (IV), scheme 1).

A mixture of dimethyl 3-oxoglutarate (10mmol, 1.74g) and phenylhydrazine (10mmol, 1.08g) was refluxed in dry benzene (50ml) for 8h, then the solvent was removed in vacuo and the title compound was isolated by recrystallization from i-PrOH (20 ml). Yield: 80 percent.¹HNMR(500MHz，DMSO-d6，ppm)：3.49(2H，s)，3.68(3H，s)，5.43(1H，s)，7.12(1H，t，7.4Hz)，7.35(2H，t，7.6Hz)，7.78(2H，d，7.9Hz)，11.1(1H，bs)

b) Methyl [ (4Z) -4- (1-ethoxyethylene) -5-oxo-1-phenyl-4, 5-dihydro-1H-pyrazol-3-yl ] acetate (compound of formula (VII), scheme 1).

Methyl (5-hydroxy-1-phenyl-1H-pyrazol-3-yl) acetate (compound of formula (IV), 1.85g), acetic anhydride (1.00ml) and MeC (OEt) obtained above₃(2.50ml) the mixture was refluxed for 1h and kept at ambient temperature overnight. The resulting precipitate was collected by filtration and washed with diethyl ether (10ml) to give the crude [ (4Z) -4- (1-ethoxyethylene) -5-oxo-1-phenyl-4, 5-dihydro-1H-pyrazol-3-yl]Methyl acetate (1.20g, 80% purity). Yield: 50 percent.¹HNMR(400MHz，CDCl3，ppm)：1.42(3H，t，7.1Hz)，2.78(3H，s)，3.73(3H，s)，3.76(2H，s)，4.31(2H，q，6.9Hz)，7.16(1H，t，7.2Hz)，7.37(2H，t，7.6Hz)，7.97(2H，d，8.0Hz)。MS(ESI⁺)：303.3；MS(ESI^-)：301.2。

c) [ (4Z) -5-oxo-1-phenyl-4- {1- [ (pyridin-3-ylmethyl) amino ] ethylidene } -4, 5-dihydro-1H-pyrazol-3-yl ] acetic acid methyl ester (compound of formula (VIII), scheme 1).

Subjecting the [ (4Z) -4- (1-ethoxyethylene) -5-oxo-1-phenyl-4, 5-dihydro-1H-pyrazol-3-yl group obtained above to condensation]A mixture of methyl acetate (compound of formula (VII), 1.20g) and 3-aminomethylpyridine (0.45g) was refluxed for 0.5h in toluene (20ml) and kept at ambient temperature overnight. The expected product [ (4Z) -5-oxo-1-phenyl-4- {1- [ (pyridin-3-ylmethyl) amino group was collected by filtration]Ethylene } -4, 5-dihydro-1H-pyrazol-3-yl radical]Methyl acetate (0.87g) and washed with diethyl ether (20 ml). The yield thereof was found to be 60%.¹HNMR(400MHz，CDCl3，ppm)：2.38(3H，s)，3.71(3H，s)，3.82(2H，s)，4.71(2H，d，5.9Hz)，7.18(1H，t ，7.2Hz)，7.38(3H，m)，7.70(1H，d，7.7Hz)，7.97(2H，d，8.0Hz)，8.63(2H，b s)，12.17(1H，b s)。MS(ESI⁺)：365.3；MS(ESI^-)：363.5。

d)4-methyl-2-phenyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c]Pyridine compound -3,6(2H,5H) -dione (C)7) (Compound of formula (Ia), scheme 1)

Using [ (4Z) -5-oxo-1-phenyl-4- {1- [ (pyridin-3-ylmethyl) amino ] group obtained as described above]Ethylene } -4, 5-dihydro-1H-pyrazol-3-yl radical]A solution of NaOi-Pr in isopropanol obtained by dissolving sodium (0.055g) in i-PrOH (50ml) was treated with methyl acetate (compound of formula (VIII), 0.87 g). The reaction mixture was refluxed for 9h, then cooled and neutralized to pH 7 with aqueous HCl (20%). The precipitate formed was filtered off, washed with water (20ml) and air dried. 0.46g of chromatographically pure product are obtained in 58% yield.¹HNMR(400MHz，DMSO-d6，ppm)：2.77(3H，s)，5.38(2H，s)，5.82(1H，s)，7.18(1H，t，7.5Hz)，7.36(1H，m)，7.45(2H，t，7.6Hz)，7.56(1H，d，7.7Hz)，7.73(2H，d，8.0Hz)，8.49(2H，bs)，10.8(1H，bs).MS(ESI⁺)：333.5；MS(ESI^-)：331.5。

Example 8: 4-methyl-2-phenyl-5- (2-phenylethyl) -1H-pyrazolo [4,3-c]Pyridine compound -3,6(2H,5H) -dione (C)8)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2-phenylethylamine, the title compound (8) was isolated as a white solid in 80% yield (98% purity by HPLC). MS (ESI)⁺)：346.7；MS(ESI^-)：344.5。

Example 9: 5- [2- (4-acetylpiperazin-1-yl) ethyl]-2- (1, 3-benzothiazole -2-yl) -4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C9)Formation of(Compound Ia, scheme 1)

The title compound (9) was isolated as a white solid in 73% yield (94% purity by HPLC) according to the same procedure as outlined in example 7 starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (4-acetylpiperazin-1-yl) ethylamine. MS (ESI)⁺)：453.6；MS(ESI^-)：451.7。

Example 10: 2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (2-methylbutan-2-ol) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C10)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2-methylbutan-1-amine, the title compound (10) was isolated as a white solid in 77% yield (99% purity by HPLC). MS (ESI)⁺)：369.7；MS(ESI^-)：367.8。

Example 11: 2- (1, 3-benzothiazol-2-yl) -5- [2- (4-methoxyphenyl) ethyl ester Base of]-4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C11)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (4-methoxyphenyl) ethylamine, the title compound (11) was isolated as a white solid in 79% yield (97% purity by HPLC). MS (ESI)⁺)：433.6；MS(ESI^-)：431.7。

Example 12: 2- (1, 3-benzothiazol-2-yl) -5- [2- (4-hexanoylpiperazin-1-yl) Ethyl radical]-4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C12)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (4-hexanoylpiperazin-1-yl) ethylamine, the title compound (12) was isolated as a pale brown solid in 71% yield (95% purity by HPLC). MS (ESI)⁺)：508.8；MS(ESI^-)：506.6。

Example 13: 2- (1, 3-benzothiazol-2-yl) -1-benzyl-5- (furan-2-ylmethyl) Yl) -4-methyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C13)Formation of(Compound Ib, scheme 1)

Following the general procedure as outlined in example 7, the reaction product was purified by reaction with 2-hydrazino-1, 3-benzothiazole, 3-oxoglutarate bisMethyl ester, 1, 1, 1-triethoxyethane, 1-furan-2-ylmethylamine as starting material, alkylated using (chloromethyl) benzene (1eq.) and the corresponding intermediate compound of formula (Ia) (1eq.) in the presence of triethylamine (1.5eq.) in refluxing THF, and the title compound (13) was isolated as a light brown solid in 61% yield (purity by HPLC 97%). MS (ESI)⁺)：469.6；MS(ESI^-)：467.3。

Example 14: 5- [2- (1H-indol-3-yl) ethyl]-4-methyl-1- (3-methylbenzyl) Yl) -2-phenyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(14)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 2- (1H-indol-3-yl) ethylamine and 1- (chloromethyl) -3-methylbenzene, the title compound (14) was isolated as a white solid in 58% yield (98% purity by HPLC). MS (ESI)⁺)：489.6；MS(ESI^-)：487.5。

Example 15: 1- (4-Fluorobenzyl) -5- [2- (1H-indol-3-yl) ethyl]-4-methyl group -2-phenyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C15)Formation of(Compound Ib, scheme 1)

Following the general procedures outlined in examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 2- (1H-indol-3-yl) ethylamine and 1- (chloromethyl) -4-fluorobenzene, the title compound was isolatedTitle compound (15) was a white solid in 55% yield (95% purity by HPLC). MS (ESI)⁺)：493.6；MS(ESI^-)：491.6。

Example 16: 1- (2-chlorobenzyl) -4-methyl-5- [3- (2-oxopyrrolidin-1-yl) propane Base of]-2-phenyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C16)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 1- (3-aminopropyl) pyrrolidin-2-one and 1-chloro-2- (chloromethyl) benzene, the title compound (16) was isolated as a white solid in 51% yield (98% purity by HPLC). MS (ESI)⁺)：492.1；MS(ESI^-)：490.0。

Example 17: 2- (1, 3-benzothiazol-2-yl) -1-benzyl-4-methyl-5- (tetrahydrofuran) Pyran-2-ylmethyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C17)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 1- (tetrahydrofuran-2-yl) methylamine and (chloromethyl) benzene, the title compound (17) was isolated as a pale brown solid in 61% yield (97% purity by HPLC). MS (ESI)⁺)：473.7；MS(ESI^-)：471.6。

Example 18: 1- (4-chlorobenzyl) -5- [2- (1H-imidazol-4-yl) ethyl]-4-methyl group -2-phenyl-1H-pyrazolo [4,3-c]Pyridine, -3, 6(H, 5H) -dione (C18)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 2- (1H-imidazol-5-yl) ethylamine and 1-chloro-4- (chloromethyl) benzene, the title compound (18) was isolated as a pale brown solid in 63% yield (98% purity by HPLC). MS (ESI)⁺)：461.0；MS(ESI^-)：459.0。

Example 19: 5- (1, 3-benzodioxol-5-ylmethyl) -4-methyl-2- phenyl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C19)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 1- (1, 3-benzodioxol-5-yl) methylamine, the title compound (19) was isolated as a pale brown solid in 78% yield (99% purity by HPLC). MS (ESI)⁺)：376.5；MS(ESI^-)：374.5。

Example 20: 5-benzyl-4-methyl-2-phenyl-1H-pyrazolo [4,3-c]Pyridine compound -3,6(2H,5H) -dione (C)20)Formation of(chemical combination)Substance Ia, scheme 1)

Following the general procedure outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and benzylamine, the title compound (20) was isolated as a pale brown solid in 79% yield (99% purity by HPLC). MS (ESI)⁺)：332.5；MS(ESI^-)：330.4。

Example 21: 5-benzyl-2- (4-fluorophenyl) -4-methyl-1H-pyrazolo [4,3-c]Pyridine (II) Pyridine-3, 6(2H,5H) -dione (C)21)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and benzylamine, the title compound (21) was isolated as a white solid in 86% yield (99% purity by HPLC). MS (ESI)⁺)：350.5；MS(ESI^-)：348.6。

Example 22: 5-benzyl-2- (4-methoxyphenyl) -4-methyl-1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -diones(22)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), with (4-methoxyphenyl) hydrazine, 3-oxoglutaric acidDimethyl ester, 1, 1, 1-triethoxyethane and benzylamine as starting materials, the title compound (22) was isolated as a light brown solid in 78% yield (95% purity by HPLC). MS (ESI)⁺)：362.6；MS(ESI^-)：360.5。

Example 23: 2- (1, 3-benzothiazol-2-yl) -4-methyl-5-morpholin-4-yl-1H-pyri-dine Azolo [4,3-c ] s]Pyridine-3, 6(2H,5H) -diones(23)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and morpholin-4-amine, the title compound (23) was isolated as a pale yellow solid in 81% yield (99% purity by HPLC). MS (ESI)⁺)：384.5；MS(ESI^-)：382.5。

Example 24: 5-benzyl-4-methyl-2- (4-nitrophenyl) -1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -diones(24)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (4-nitrophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and benzylamine, the title compound (24) was isolated as a yellow solid in a yield of 72% (96% purity by HPLC). MS (ESI)⁺)：377.6；MS(ESI^-)：375.5。

Example 25: 2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (3-methylbenzyl) -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -bis Ketones(25)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 3-morpholin-4-ylpropan-1-amine and 1- (chloromethyl) -3-methylbenzene, the title compound (25) was isolated as a white solid in 68% yield (98% purity by HPLC). MS (ESI)⁺)：530.9；MS(ESI^-)：528.6。

Example 26: 2- (1, 3-benzothiazol-2-yl) -1- (4-fluorobenzyl) -4-methyl -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(26)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 3-morpholin-4-ylpropan-1-amine and 1- (chloromethyl) -4-fluorobenzene, the title compound (26) was isolated as a light brown solid in 54% yield (98% purity by HPLC). MS (ESI)⁺)：534.9；MS(ESI^-)：532.6。

Example 27: 2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (4-methylbenzyl) 5- (3-morpholin-4-ylpropyl) -1H-pyrazoleAnd [4,3-c ]]Pyridine-3, 6(2H,5H) -bis Ketones(27)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 3-morpholin-4-ylpropan-1-amine and 1- (bromomethyl) -4-methylbenzene, the title compound (27) was isolated as a light brown solid in 62% yield (98% purity by HPLC). MS (ESI)⁺)：530.8；MS(ESI^-)：528.6。

Example 28: 2- (1, 3-benzothiazol-2-yl) -1- (2-chlorobenzyl) -4-methyl-5-morpholino lin-4-yl-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(28)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, morpholin-4-amine and 1-chloro-2- (chloromethyl) benzene, the title compound (28) was isolated as a pale brown solid in 56% yield (98% purity by HPLC). MS (ESI)⁺)：509.1；MS(ESI^-)：507.0。

Example 29: 2- (1, 3-benzothiazol-2-yl) -1- (4-bromobenzyl) -4-methyl -5- (2-morpholin-4-ylethyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(29)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 2-morpholin-4-ylethylamine and 1-bromo-4- (chloromethyl) benzene, the title compound (29) was isolated as a pale brown solid in 50% yield (98% purity by HPLC). MS (ESI)⁺)：581.7；MS(ESI^-)：579.4。

Example 30: 2- [2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (3-morpholin-4-yl) Propyl) -3, 6-dioxo-2, 3,5, 6-tetrahydro-1H-pyrazolo [4,3-c]Pyridin-1-yl]-N- Phenylacetamides(30)Formation of(Compound Ib, scheme 1)

Following the general procedure outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 3-morpholin-4-ylpropan-1-amine and 2-bromo-N-phenylacetamide, the title compound (30) was isolated as a pale brown solid in 67% yield (98% purity by HPLC). MS (ESI)⁺)：559.8；MS(ESI^-)：557.4。

Example 31: 4-methyl-2-phenyl-5- (tetrahydrofuran-2-ylmethyl) -1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(31)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 1- (tetrahydrofuran-2-yl) methylamine, the title compound (31) was isolated as a white solid in 78% yield (99% purity by HPLC). MS (ESI)⁺)：326.5；MS(ESI^-)：324.4。

Example 32: 2- (1, 3-benzothiazol-2-yl) -4-methyl-5- (2-phenylethyl) -1H- Pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(32)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2-phenylethylamine, the title compound (32) was isolated as a pale brown solid in 64% yield (97% purity by HPLC). MS (ESI)⁺)：403.7；MS(ESI^-)：401.5。

Example 33: 5- [2- (1H-indol-3-yl) ethyl]-4-methyl-2-phenyl-1H-pyrazole And [4,3-c ]]Pyridine-3, 6(2H,5H) -diones(33)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2- (1H-indol-3-yl) ethylamine, the title compound (33) was isolated as a pale brown solid in 82% yield (99% purity by HPLC). MS (ESI)⁺)：335.5；MS(ESI^-)：333.3。

Example 34: 4-methyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo [4,3-c]Pyridine compound -3,6(2H,5H) -dione(34)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and morpholin-4-amine, the title compound (34) was isolated as a white solid in 87% yield (99% purity by HPLC). MS (ESI)⁺)：327.6；MS(ESI^-)：325.4。

Example 35: 2- (1, 3-benzothiazol-2-yl) -1- (2-chlorobenzyl) -4-methyl -5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(35)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 3-morpholin-4-ylpropan-1-amine and 1-chloro-2- (chloromethyl) benzene, the title compound (35) was isolated as a light brown solid in 61% yield (98% purity by HPLC). MS (ESI)⁺)：551.2；MS(ESI^-)：549.4。

Example 36: 5-benzyl-4-ethyl-2- (4-fluorophenyl) -1H-pyrazolo [4,3-c]Pyridine (II) Pyridine-3, 6(2H,5H)) -diketones(36)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and benzylamine, the title compound (36) was isolated as a pale yellow solid in a yield of 80% (96% purity by HPLC). MS (ESI)⁺)：364.5；MS(ESI^-)：362.2。

Example 37: 4-Ethyl-2- (4-fluorophenyl) -5- (2-phenylethyl) -1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(37)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 2-phenylethylamine, the title compound (37) was isolated as a white solid in 83% yield (97% purity by HPLC). MS (ESI)⁺)：378.5；MS(ESI^-)：376.4。

Example 38: 4-Ethyl-2- (4-fluorophenyl) -5-morpholin-4-yl-1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(38)Formation of(Compound Ia, scheme 1)

According to one as outlined in example 7a)The title compound (38) was isolated as a pale brown solid in 77% yield (99% purity by HPLC) from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and morpholin-4-amine as starting materials. MS (ESI)⁺)：358.7；MS(ESI^-)：356.2。

Example 39: 4-methyl-5- (2-morpholin-4-ylethyl) -2-phenyl-1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(39)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 2-morpholin-4-ylethylamine, the title compound (39) was isolated as a pale brown solid in 63% yield (95% purity by HPLC). MS (ESI)⁺)：355.5；MS(ESI^-)：353.5。

Example 40: 4-Ethyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo [4,3-c]Pyridine compound -3,6(2H,5H) -dione (C)40)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and morpholin-4-amine, the title compound (40) was isolated as a white solid in 89% yield (98% purity by HPLC). MS (ESI)⁺)：341.8；MS(ESI^-)：339.4。

Example 41: 2- (2-chlorophenyl) -4-methyl-5- (pyridin-2-ylmethyl) -1H-pyrazole And [4,3-c ]]Pyridine-3, 6(2H,5H) -diones(41)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (2-chlorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 1-pyridin-2-ylmethylamine, the title compound (41) was isolated as a yellow solid in 81% yield (99% purity by HPLC). MS (ESI)⁺)：367.9；MS(ESI^-)：365.7。

Example 42: 4-methyl-2- (2-methylphenyl) -5- (3-morpholin-4-ylpropyl) -1H- Pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -dione (C42)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (2-methylphenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 3-morpholin-4-ylpropan-1-amine, the title compound (42) was isolated as a pale brown solid in a yield of 72% (98% purity by HPLC). MS (ESI)⁺)：383.6；MS(ESI^-)：381.5。

Example 43: 2- (1, 3-benzothiazol-2-yl) -4-methyl-1- (pyridin-2-ylmeth-yl) Yl) -5- (tetrahydrofuran-2-ylmethyl) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) - Diketones(43)Formation of(Compound Ib, scheme 1)

Following the general method outlined in examples 7 and 13, starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane, 1- (tetrahydrofuran-2-yl) methylamine and 2- (chloromethyl) pyridine, the title compound (43) was isolated as a pale brown solid in a yield of 60% (98% purity by HPLC). MS (ESI)⁺)：474.6；MS(ESI^-)：472.5。

Example 44: 2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (pyridin-2-ylmeth-yl) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(44)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 1-pyridin-2-ylmethylamine, the title compound (44) was isolated as a yellow solid in 83% yield (95% purity by HPLC). MS (ESI)⁺)：404.6；MS(ESI^-)：402.5。

Example 45: 2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (3-morpholin-4-ylpropan) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(45)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine, the title compound (45) was isolated as a light brown solid in 82% yield (98% purity by HPLC). MS (ESI)⁺)：440.5；MS(ESI^-)：438.4。

Example 46: 2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (2-methoxyethyl) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(46)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 2-methoxyethylamine, the title compound (46) was isolated as a white solid in 69% yield (97% purity by HPLC). MS (ESI)⁺)：371.4；MS(ESI^-)：369.4。

Example 47: 2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- (4-methylpiperazine-1-) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(47)Formation of) (Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 4-methylpiperazin-1-amine, the title compound (47) was isolated as light brown coloured solidA colored solid in 78% yield (98% purity by HPLC). MS (ESI)⁺)：411.6；MS(ESI^-)：409.4。

Example 48: 2- (1, 3-benzothiazol-2-yl) -4-ethyl-5- [1- (4-methylbenzyl) Piperidin-4-yl radical]-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(48)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) starting from 2-hydrazino-1, 3-benzothiazole, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 1- (4-methylbenzyl) piperidin-4-amine, the title compound (48) was isolated as a yellow solid in 55% yield (92% purity by HPLC). MS (ESI)⁺)：500.6；MS(ESI^-)：498.6。

Example 49: 4-Ethyl-2- (4-fluorophenyl) -5- (pyridin-2-ylmethyl) -1H-pyrazole And [4,3-c ]]Pyridine-3, 6(2H,5H) -diones(49)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 1-pyridin-2-ylmethylamine, the title compound (49) was isolated as a pale yellow solid in 77% yield (99% purity by HPLC). MS (ESI)⁺)：365.5；MS(ESI^-)：363.7。

Examples50: 4-Ethyl-2- (4-fluorophenyl) -5- (3-morpholin-4-ylpropyl) -1H-pyri-dine Azolo [4,3-c ] s]Pyridine-3, 6(2H,5H) -diones(50)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine, the title compound (50) was isolated as a light brown solid in 78% yield (99% purity by HPLC). MS (ESI)⁺)：401.5；MS(ESI^-)：399.3。

Example 51: 4-Ethyl-2- (4-fluorophenyl) -5- (2-methoxyethyl) -1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(51)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (4-fluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 2-methoxyethylamine, the title compound (51) was isolated as a white solid in 76% yield (98% purity by HPLC). MS (ESI)⁺)：332.4；MS(ESI^-)：330.4。

Example 52: 5- (2-morpholin-4-ylethyl) -2-pyridin-2-yl-1H-pyrazolo [4，3-c]Pyridine-3, 6(2H,5H) -diones(52)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from 2-hydrazinopyridine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxymethane and 2-morpholin-4-ylethylamine, the title compound (52) was isolated as a pale yellow solid in 68% yield (97% purity by HPLC). MS (ESI)⁺)：342.5；MS(ESI^-)：340.3。

Example 53: 2, 4-Diphenyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c] Pyridine-3, 6(2H,5H) -diones(53)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from phenylhydrazine, dimethyl 3-oxoglutarate, (triethoxymethyl) benzene and 1-pyridin-3-ylmethylamine, the title compound (53) was isolated as a pale brown solid in 79% yield (96% purity by HPLC). MS (ESI)⁺)：395.5；MS(ESI^-)：393.2。

Example 54: 2- (2-chlorophenyl) -4-ethyl-5- (pyridin-3-ylmethyl) -1H-pyrazole And [4,3-c ]]Pyridine-3, 6(2H,5H) -diones(54)Formation of(Compound Ia, scheme 1)

Following the general method as outlined in example 7a), starting from (2-chlorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 1-pyridin-3-ylmethylamine, the title compound (54) was isolated as a yellow solid in yield74% (purity by HPLC 98%). MS (ESI)⁺)：381.8；MS(ESI^-)：379.6。

Example 55: 4-methyl-2- (2-methylphenyl) -5- (pyridin-2-ylmethyl) -1H-pyrane Azolo [4,3-c ] s]Pyridine-3, 6(2H,5H) -diones(55)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (2-methylphenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxyethane and 1-pyridin-2-ylmethylamine, the title compound (55) was isolated as a yellow solid in 63% yield (98% purity by HPLC). MS (ESI)⁺)：347.5；MS(ESI^-)：345.6。

Example 56: 4-Ethyl-5- (3-morpholin-4-ylpropyl) -2- [4- (trifluoromethyl) benzene Base of]-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(56)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) with [4- (trifluoromethyl) phenyl ]]Hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine as starting materials, the title compound (56) was isolated as a yellow solid in 59% yield (96% purity by HPLC). MS (ESI)⁺)：451.5；MS(ESI^-)：449.4。

Example 57: 4-Ethyl-5- (3-morpholin-4-ylpropan)Base) -2- [4- (trifluoromethoxy) Phenyl radical]-1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(57)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) with [4- (trifluoromethoxy) phenyl ]]Hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine as starting materials, the title compound (57) is isolated as a yellow solid in 67% yield (97% purity by HPLC). MS (ESI)⁺)：467.4；MS(ESI^-)：465.6。

Example 58: 2- (2, 5-difluorophenyl) -4-ethyl-5- (3-morpholin-4-ylpropyl) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(58)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a) starting from (2, 5-difluorophenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine, the title compound (58) was isolated as a yellow solid in 71% yield (98% purity by HPLC). MS (ESI)⁺)：419.7；MS(ESI^-)：417.3。

Example 59: 4-Ethyl-2- (2-methoxyphenyl) -5- (3-morpholin-4-ylpropan) Radical) -1H-pyrazolo [4,3-c]Pyridine-3, 6(2H,5H) -diones(59)Formation of(Compound Ia, scheme 1)

Following the general procedure as outlined in example 7a), starting from (2-methoxyphenyl) hydrazine, dimethyl 3-oxoglutarate, 1, 1, 1-triethoxypropane and 3-morpholin-4-ylpropan-1-amine, the title compound (59) was isolated as a pale yellow solid in 67% yield (99% purity by HPLC). MS (ESI)⁺)：413.6；MS(ESI^-)：411.7。

Example 60: determination of the level of reactive oxygen species in different cell cultures

The compounds of the invention are tested for their activity in inhibiting or reducing the formation of Reactive Oxygen Species (ROS) by oxygen in cells. By different techniques such as nitroblue tetrazolium, AmplexRed reagent, chemiluminescence (luminol), and diethyl 2 ', 7' -dichlorodihydrofluorescein (H) in the following cell cultures₂DCF-DA), the activity of the compounds was tested according to the protocol detailed below.

Human microglial cell line

Human microglia cell line (HMC3, human microglia clone 3) was cultured in MEM (Eagle minimal basal medium) containing 10% FBS with 50U/ml penicillin G sodium, 50. mu.g/ml streptomycin sulfate (Janabi et al, 1995, Neurosci Lett 195: 105) and incubated at 37 ℃ for 24 hours. Adding IFN-gamma (human IFN-gamma, Roche.11040596001) into culture medium to final concentration of 10ng/ml for 24h, and detecting O₂ ^-And (4) forming.

Human Umbilical Vein Endothelial Cell (HUVEC)

HUVECs were cultured in endothelial cell basal medium supplemented with hydrocortisone (1. mu.g/mL, CalbioChem), bovine brain extract (12. mu.g/mL), gentamicin (50. mu.g/mL, CalbioChem), amphotericin B (50ng/mL, CalBioChem), EGF (10ng/mL) and 10% FCS until the fourth passage. Unless otherwise stated, when the fifth passage begins, cells were cultured in the absence of EGFWith lower concentration FCS (2%). All experiments were performed using fifth generation cells. OxLDL (oxidized modified low-density lipoprotein) or its buffer solution is used as a control, and is incubated with cells for 24h, and then O is detected₂ ^-And (4) forming.

HL-60 cell

At 37 ℃ and 5% CO₂Human acute myeloid leukemia cell line HL-60 was cultured in RPMI 1640(Invitrogen) supplemented with 10% heat-inactivated calf serum, 2mM glutamine, 100U/mL penicillin (Sigma) and 100. mu.g streptomycin (Sigma) in a humidified gas environment. By reacting Me₂SO (final concentration 1.25% v/v, 6 days) was added to the medium to differentiate HL 60 into the neutrophil phenotype.

1. Nitrogen Blue Tetrazole (NBT)

Intracellular and extracellular peroxides were measured by colorimetric methods using a quantitative nitroblue tetrazolium (NBT) assay. The SOD-inhibitable conversion of NBT to formazan, a blue precipitate, in the presence of superoxide anion was determined using a Fluostar Optima spectrometer (BMG labtech). After incubation with the appropriate stimulus, cells were trypsinized (1X trypsin-EDTA), collected by centrifugation and washed with PBS to remove medium. Mixing 5X10⁵Individual cells were plated on 48-well culture plates and incubated in Hank's balanced salt solution with or without 800U/mL SOD containing 0.5mg/mL NBT. As a control, DPI was used at a final concentration of 10. mu.M. After 2.5h, the cells were fixed and washed with methanol to remove the unreduced NBT. The reduced formazan was then dissolved in 230. mu.l of 2M potassium hydroxide and 280. mu.l of dimethyl sulfoxide. The absorbance was measured at 630 nm. For the calculation, the absorbance at 630nm was individually calibrated for each well. For each time point, the average of 4 blank values was subtracted from each calibration value. NOX activity is expressed as "%" corresponding to activity in control cells. The residual activity of DPI-treated cells is typically < 10%.

2.Amplex Red

Extracellular hydrogen peroxide was measured using Amplex UltraRed (Molecular Probes). Cells were trypsinized (1 × trypsin-EDTA), collected by centrifugation and resuspended in HBSS supplemented with 1% glucose. Cells were seeded into black 96-well plates at a density of 50000 cells in 200 μ l of test buffer (HBSS 1% glucose with or without the presence of a compound of the invention containing 0.005U/mL horseradish peroxidase (Roche) and 50 μ M Amplex Red). As a control, DPI was included at a final concentration of 10. mu.M. The plates were placed in a fluorescence-optimized fluorescence plate reader and maintained at 37 ℃ during 20 min. Fluorescence was measured for 15min using excitation and emission wavelengths of 544nm and 590nm, respectively. NOX activity was expressed as "%" of activity in control cells. The residual activity of DPI-treated cells is typically < 10%.

The percentage of NOX activity inhibition determined by Amplex Red using DMSO-differentiated HL 60 cells as described above is summarized in table 1 below:

TABLE 1

Compound n degree	Inhibition (%)
		(1)	53
(9)	51
		(12)	60

The IC of NOX activity determined by Amplex Red using DMSO-differentiated HL 60 cells as described above is summarized in Table 2 below₅₀：

TABLE 2

Compound n degree	IC₅₀(μM)
		(1)	1.1
(9)	8.4
		(10)	4.0
(12)	6.4
		(14)	13.8
(21)	13.4
		(23)	14.5
(30)	12.9
		(31)	14.5
(36)	4.3
		(44)	4.3
(46)	2.7
		(53)	4.4

3. Chemiluminescence (luminol)

ROS was determined using the chemiluminescent probe luminol (luminol). Cells were cultured and plated for Amplex Red, but Amplex Red reagent was replaced with 10 μ g/mL luminol (Sigma 09235). Luminescence was recorded continuously for 60 minutes at 37 ℃ using the luminescence function of a FluoStar Optima fluorescence plate reader. For each time point, the average of 4 blank values was subtracted from each calibrated value. NOX activity is expressed as "%" relative to activity in control cells. Residual activity of cells treated with DPI is typically < 10%.

4.2 ', 7' -dichlorodihydrofluorescein diethyl ester (H)₂DCF-DA)

HUVECs were plated on coverslips and allowed to stand overnight in 0.5% BSA before stimulation with TGF-. beta.s. Cells were loaded with 5 μ M CM-H2 DCFDA in phenol red-free medium for 10 min in the dark and then treated with TGF-. beta.s (R & D Systems) in the presence or absence of the compounds of the invention. Cells were then visualized by immunofluorescence microscopy after fixation and staining of nuclei with DAPI or examined for cell viability using confocal microscopy. DCF fluorescence was visualized at the 488nm excitation wavelength and at the 515-540nm emission wavelength. To avoid photo-oxidation of the indicator dye, images were acquired using a single fast scan of the same parameters for all samples. For the calculation, the absorbance at 540nm was individually calibrated for each well to the absorbance at 540 nm. For each time point, the average of 4 blank values was subtracted from each calibration value. NOX activity is expressed as "%" relative to activity in control cells. Residual activity of cells treated with DPI is typically < 10%.

Claims

1. Pyrazolo pyridine derivatives of formula (I) and pharmaceutically acceptable salts thereof for use as medicaments,

wherein G is₁Selected from H, optionally C₁-C₆Alkyl-substituted phenyl C₁-C₆Alkyl, and C substituted by-C (O) NRR₁-C₆Alkyl, wherein R and/or R' are independently selected from H and phenyl; g₂Selected from phenyl and benzothiazole, optionally substituted with halogen; g₃Is selected from C₁-C₆Alkyl and phenyl; g₄Selected from the group consisting of₁-C₆Alkyl, morpholinyl, tetrahydrofuryl, phenyl, thienyl, indolyl, pyridinyl or C₁-C₆Alkoxy-substituted C₁-C₆Alkyl, piperazinyl C optionally substituted by acyl₁-C₆Alkyl, and morpholinyl; g₅Is H, wherein the acyl group is-C (O) R 'and the R' is C₁-C₆An alkyl group.

2. The pyrazolopyridine derivative of claim 1, wherein G is₁Is H.

3. The pyrazolopyridine derivative of claim 1, wherein G is₁Is optionally substituted by C₁-C₆Alkyl-substituted phenyl C₁-C₆An alkyl group.

4. The pyrazolopyridine derivative of claim 1, wherein G is₁Is C substituted by-C (O) NRR₁-C₆Alkyl, wherein R and R' are as defined in claim 1.

5. The pyrazolopyridine derivative of claim 1, wherein G is₃Is C₁-C₆An alkyl group.

6. The pyrazolopyridine derivative of claim 1, wherein G is₃Is phenyl.

7. The pyrazolopyridine derivative of claim 1, wherein G is₄Is optionally substituted by C₁-C₆Alkyl, morpholinyl, tetrahydrofuryl,Phenyl, thienyl, indolyl, pyridyl or C₁-C₆Alkoxy-substituted C₁-C₆An alkyl group.

8. The pyrazolopyridine derivative of claim 1, wherein G is₄Is piperazinyl C optionally substituted by acyl₁-C₆Alkyl, wherein the acyl group is-C (O) R 'and the R' is C₁-C₆An alkyl group.

9. The pyrazolopyridine derivative of claim 1, wherein G is₄Is morpholinyl.

10. The pyrazolopyridine derivative according to claim 1, which is selected from the group consisting of:

5-benzyl-4-methyl-2-phenyl-1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione;

2- (2-chlorophenyl) -4-ethyl-5- (pyridin-3-ylmethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione; and

2- (2, 5-difluorophenyl) -4-ethyl-5- (3-morpholin-4-ylpropyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione.

11. A pharmaceutical composition comprising at least one derivative of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

12. A pyrazolo pyridine derivative and pharmaceutically acceptable salts thereof selected from the group consisting of:

4-ethyl-2- (4-fluorophenyl) -5- (2-methoxyethyl) -1H-pyrazolo [4,3-c ] pyridine-3, 6(2H,5H) -dione; and