WO2004089471A2 - NEW PYRAZOLO[1,5-a] PYRIMIDINES DERIVATIVES AND PHARMACEUTICAL USE THEREOF - Google Patents

NEW PYRAZOLO[1,5-a] PYRIMIDINES DERIVATIVES AND PHARMACEUTICAL USE THEREOF Download PDF

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WO2004089471A2
WO2004089471A2 PCT/DK2004/000253 DK2004000253W WO2004089471A2 WO 2004089471 A2 WO2004089471 A2 WO 2004089471A2 DK 2004000253 W DK2004000253 W DK 2004000253W WO 2004089471 A2 WO2004089471 A2 WO 2004089471A2
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Prior art keywords
pyrazolo
methanone
pyrimidin
trifluoromethyl
phenyl
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PCT/DK2004/000253
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French (fr)
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WO2004089471A3 (en
Inventor
Henrik Sune Andersen
Gita Camilla Tejlgaard Kampen
Inge Thøger Christensen
John Patrick Mogensen
Annette Rosendal Larsen
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Novo Nordisk A/S
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Priority to EP04725889A priority Critical patent/EP1615697A2/en
Priority to JP2006504356A priority patent/JP2006522749A/en
Publication of WO2004089471A2 publication Critical patent/WO2004089471A2/en
Publication of WO2004089471A3 publication Critical patent/WO2004089471A3/en
Priority to US11/254,118 priority patent/US20070270408A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to use of substituted pyrazolo[1 ,5-a]pyrimidines and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSD1).
  • the present invention also relates to novel substituted pyrazolo[1 ,5-a]pyrimidines, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the present compounds modulate the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
  • the metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide.
  • the metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally es- calating.
  • glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes.
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSD1) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 11 ⁇ HSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J.
  • 11 ⁇ HSDI The role of 11 ⁇ HSDI in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific 11 ⁇ HSDI inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • 11 ⁇ HSDI knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
  • mice that overexpress 11 ⁇ HSDI in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin.
  • 11 ⁇ HSDI modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems.
  • 11 ⁇ HSDI promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci.
  • WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
  • substituted pyrazolo[1 ,5-a]pyrimidines that modulate the activity of 11 ⁇ HSDI leading to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of 11 ⁇ HSDI leading to decreased intracellular concentrations of active glucocorticoid.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 ⁇ HSDI .
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C C 6 straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 6 branched saturated hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), te/t-butyl (.-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like.
  • alkenyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and branched C 3 -C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C 4 -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
  • saturated or partially saturated cyclic, bicyclic or tricyclic ring system represents but are not limit to aziridinyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, phthalimide, 1 ,2,3,4-tetrahydro-quinolinyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, 6-aza-bicyclo[3.2.1 Joctane, and indolinyl.
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • cycloalkylalkyl (e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • cycloalkenyl (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohep- tenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
  • heteroalkyl (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S0 2 .
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an “alkyl” group.
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • hetaryloxy e.g. 2-pyridyloxy and the like
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • arylalkyloxy represents an arylalkyl group as defined below attached through an oxygen bridge.
  • hetarylalkyloxy (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
  • alkylthio (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
  • arylthio e.g. benzenthiol, naphthylthiol and the like
  • arylthioalkyl e.g. methylsulfanyl benzene, ethylsulfanyl naphthalene and the like
  • alkyl group having the indicated number of carbon atoms.
  • hetarylthioalkyl e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyl- isoquinoline and the like
  • aryloxyalkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
  • aryloxyaryl e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like
  • aryloxyaryl represents an aryloxy group as defined above attached through an “aryl” group as defined below.
  • arylalkyloxyalkyl e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like
  • arylalkyloxyalkyl represents an arylalkyloxy group as defined above attached through an "alkyl” group having the indicated number of carbon atoms.
  • hetaryloxyalkyl e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like
  • hetarylalkyloxyalkyl (e.g. 4-methoxymethyl-pyrimidine, 2-methoxymethyl- quinoline and the like) represents a hetarylalkyloxy group as defined above attached through an "alkyl” group having the indicated number of carbon atoms.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • arylalkyl represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • heteroarylalkyl and “hetaralkyl” (e.g.
  • (2-furyl) methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • arylcarbonyl e.g. benzoyl
  • arylcarbonyl represents an aryl group as defined below attached through a carbonyl group.
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • hetarylcarbonyl represents a hetaryl group as defined below attached through a carbonyl group.
  • carbonylalkyl e.g. acetyl and the like
  • alkylcarbonylalkyl e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like
  • alkylcarbonylalkyl represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylalkyl e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like
  • arylcarbonylalkyl represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • hetarylcarbonylalkyl e.g. 1-pyhdin-2-yl-propan-1-one, 1-(1-/-/-imidazol-2- yl)-propan-1-one and the like
  • arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
  • hetarylalkylcarbonyl (e.g. imidazolylpentylcarbonyl and the like) represents an hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylcarboxy e.g. benzoic acid and the like
  • arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylalkylcarboxyalkyl e.g. benzylcarboxymethyl, phenylpropylcar- boxypropyl and the like
  • arylalkylcarboxyalkyl represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • hetarylcarboxy e.g. pyridine-2-carboxylic acid and the like
  • hetarylcarboxy represents a hetarylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylcarbonylamino e.g. methylcarbonylamino, cyclopentylcarbonyl- aminomethyl, methylcarbonylaminophenyl
  • alkylcarbonylamino represents an "alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.
  • the nitrogen atom may itself be substituted with an alkyl or aryl group.
  • alkylcarbonylaminoalkyl e.g.N-propyl-acetamide, N-butyl-propionamide and the like
  • alkylcarbonylaminoalkyl represents an “alkylcarbonylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonylamino e.g. phenylacetamide, 3phenyl-propionamide and the like
  • arylalkylcarbonylamino represents an “arylalkylcarbonyl” group as defined above attached through an amino group.
  • arylalkylcarbonylaminoalkyl e.g. N-ethyl-phenylacetamide, N-butyl-3- phenyl-propionamide and the like
  • arylalkylcarbonylaminoalkyl represents an “arylalkylcarbonylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylamino e.g. benzamide, naphthalene-1-carboxylic acid amide and the like
  • arylcarbonylaminoalkyl e.g. N-propyl-benzamide, N-Butyl-naphthalene-
  • 1-carboxylic acid amide and the like represents an "arylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • aryl includes but is not limited to a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • aryll includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
  • aryl2 includes phenyl, biphenyl, naphthyl, and anthracenyl.
  • heteroaryl includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl
  • treatment is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • pharmaceutically acceptable is defined as being suitable for administration to humans without adverse events.
  • prodrug is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
  • the present invention provides the use of a substituted pyrazolo[1 ,5- a]pyrimidine, a pro-drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tauto eric forms for a) modulation of the activity of 11 ⁇ HSDI ;or b) inhibition of 11 ⁇ HSDI , in a patient in need thereof.
  • the present invention provides the use of a substituted pyra- zolo[1 ,5-a]pyrimidine, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 ⁇ HSDI ; or b) inhibit 1 1 ⁇ HSDI , in a patient in need thereof.
  • the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine or a prodrug thereof is of the general formula (I)
  • R 3 and R 5 independently are hydrogen, NR 13 R 14 trihalomethyl, trihalomethoxy, CrC 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkyloxy, C C 6 alkylthio, aryl, arylC C 6 alkyl, hetaryl or hetarylC C 6 alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 ;
  • R 6 and R 7 independently are C ⁇ C 6 alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C 10 cycloalkyl, arylC C 6 alkyl or hetarylCrC 6 alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, halo, hydroxy, oxo, C C 6 alkyloxy, arylCrCealkyloxy, hetarylC C 6 alkyloxy, C CealkyloxyC Cealkyl, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 alkyl- carbonyl, hetarylCrC 6 alkylcarbonyl, C C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C 10 cycloalkyl, C 3 - C 10 hetocycloalkyl, C C 6 alkyl, C C 6 alkyloxy, trihalomethyl, trihalomethoxy, arylC C 6 alkyloxy, hetarylC C 6 alkyloxy, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 alkylcar- bonyl, hetarylC ⁇ -C 6 alkylcarbonyl, C C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C 6 - alkylcarboxy, hetary!C ⁇ -C 6 alkylcarboxy, C r C 6 alkylcarbonylamino or arylC C 6 alkylcarbonyl- amino; R 10 is
  • R 11 is CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetarylC C 6 alkyl, C C 6 alkyl- carbonylCrC 6 alkyl, CrC 6 alkyloxy, aryloxy, C C 6 alkyloxy, arylcarbonyl, arylCrC 6 alkyl- carbonyl, hetarylcarbonylCrC 6 alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 12 is CrCealkylcarbonylaminoCrCealkyl, arylcarbonylaminoCrC 6 alkyl or arylC C 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, C C 6 alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrCealkylcarbonyl;
  • R 15 is hydrogen, C 3 -C 10 cycloalkyl, C C 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylCrC 6 alkyl, C C 6 alkyloxyalkyl or arylC C 6 alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the invention provides the present use of a substituted pyrazolo[1,5-a]pyrimidines, or a prodrug thereof of the general formula (I)
  • R 3 and R 5 independently are hydrogen, NR 13 R 14 trihalomethyl, trihalomethoxy, CrC 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetaryl- CrC 6 alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 ;
  • R 6 and R 7 independently are C C 6 alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C 10 cycloalkyl, arylCrC 6 alkyl or hetarylCrC 6 alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylC C 6 alkyloxy, CrC 6 - alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetarylcarboxy,
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C 10 cycloalkyl, C 3 - C 10 hetocycloalkyl, CrC 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C 6 alkylcarboxy, hetarylCrC 6 alkylcarboxy, CrC 6 alkylcarbonylamino or arylCrC 6 alkylcarbonyl- amino;
  • R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, C C 6 alkyl, C C 6 alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, het- arylCrCealkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, C C 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkylcarboxy;
  • R 11 is C ⁇ -C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetarylC C 6 alkyl, C r C ⁇ alkyl- carbonylC C 6 alkyl, C C ⁇ alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyICrC 6 - alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 12 is CrCealkylcarbonylaminoCrCealkyl, arylcarbonylaminoCrC 6 alkyl or arylC C 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, C C 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC 6 alkyloxy, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkyl- carboxy, arylcarboxy, hetarylcarboxy, arylCrC 6 alkylcarboxy;
  • R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylC r C 6 alkyl, CrC 6 alkyloxyalkyl or arylCrC 6 alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 3 and R 5 independently are hydrogen, trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrC 6 alkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 .
  • R 3 and R 5 independently are hydrogen, trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrC 6 alkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 6 and R 7 independently are CrC 6 alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C 10 cycloalkyl, arylC C 6 alkyl or hetarylCrC 6 alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 .
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I)
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylCrC 6 alkyl, halo, hydroxy, oxo, C r C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylC C 6 alkyloxy, CrCealkyloxyCrC-ealkyl, C C 6 alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbon
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylC C 6 alkyloxy, hetarylCrC 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl.
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 8 and R 9 inde- pendently are hydrogen, halo, hydroxy, oxo, cyanoC 3 -C 10 cycloalkyl, C 3 -C 10 hetocycloalkyl, C C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, arylCrCealkyloxy, hetarylCrC 6 alkyloxy.
  • the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 0 is hy- drogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkyl, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkylcarboxy.
  • R 0 is hy- drogen, halo, cyano
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 11 is CrCealkyl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, CrC 6 alkyloxy, aryloxy, CrC 6 alkyloxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 .
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 12 is CrC 6 - C 6 alkylcarbonylaminoCrC 6 alkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkylcarbonyl- aminoCrC 6 alkyl.
  • the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 13 and R 14 independently are hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, Ci-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl.
  • the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, C C 6 alkyloxyalkyl or arylCrC 6 alkyloxyalkyl.
  • the invention provide the present use of substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of general formula (I) selected from the group consisting of:
  • the invention provides the present use of substituted pyra- zolo[1 ,5-a]pyrimidines, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 4, examples 4-2 through 4-214, example 5 and examples 5-2 through 5-126, a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the present invention provides substituted pyrazolo[1 ,5- ajpyrimidines, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 4, examples 4-2 through 4-214, example 5 and examples 5-2 through 5-126, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium tetif-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, ami- noacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • esters for instance methyl esters, ethyl esters, te/t-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • esters for instance methyl esters, ethyl esters, te/t-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • 'modified compounds' for instance methyl esters, ethyl esters, te/t-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the invention alters, and more specifically, reduces the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
  • the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of
  • the present compounds may be applicable for the treatment, pre- vention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia
  • asthma cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid re- ceptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g.
  • glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & trans- plantation e.g.
  • cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.
  • the invention relates to a compound according to the invention for use as a pharmaceutical composition.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
  • the patient is treated with a compound according to the invention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
  • the pharmaceutical composition is for oral, nasal, trans- dermal, pulmonal or parenteral administration.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDI is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDI is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonal, or parenteral.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratios.
  • Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, agents modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone
  • the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), e.g. Asp B28 human insulin, US 5,504,188 (Eli Lilly), e.g. Lys B28 Pro 629 human insulin, EP 368 187 (Aventis), e.g.
  • GLP-1 glucagon like peptide-1
  • GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorpo- rated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPAR ⁇ modulators, PPAR ⁇ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp B28 human insulin, Lys B28 Pro 629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • insulin an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp B28 human insulin, Lys B28 Pro 629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide e.g. metformin.
  • the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
  • a meglitinide e.g. repaglinide or senaglinide.
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an ' antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
  • an ' antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator
  • the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, ⁇ 2-receptor blockers e.g.
  • S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine
  • loop-diuretics e.g. bumetanide, furosemide and torasemide
  • potassium sparing diuretics e.g. amiloride, spironolactone
  • endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551 , CM 034, S-0139 and YM-598
  • endothelin antagonists e.g. bosentan and J-104133
  • renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g.
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.
  • adenosine A1 antagonists such as naftopidil, N-0861 and FK-352
  • thromboxane A2 antagonists such as KT2-962
  • endopeptidase inhibitors e.g. ecadotril
  • nitric oxide agonists such as LP-805
  • dopamine D1 antagonists e.g. MYD-37
  • dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor
  • prostacyclin agonists such as treprostinil, beraprost
  • PGE1 agonists e.g.
  • ecraprost Na7K + ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • the present compounds may be administered in combination with one or more glucocorticoid receptor agonists.
  • glucocorticoid receptor agonists are betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and analogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021 , NS-126, P-4112, P-4114, RU-24858 and T-25 series.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and gran- ules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 200 mg, e.g. about 100 mg.
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid.
  • pharmaceutically acceptable salts refers to non-toxic salts of the compounds for use according to the present invention which are generally prepared by reaction of the free base with a suitable organic or inorganic acid or by reaction of the acid with a suitable organic or inorganic base.
  • a compound for use according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • a compounds for use according to the present invention contains a free acid
  • such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
  • solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media em- ployed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to pro- vide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for exam- pie, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
  • Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsule wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • Oily suspensions may be formulated by suspending the active ingredient in a vegeta- ble oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavouring, and colouring agents may also be present.
  • the pharmaceutical compositions comprising a compound for use according to the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, leci- thin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of i ⁇ jectables.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • Such materials in- elude cocoa butter and polyethylene glycols, for example.
  • topical applications For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the present invention are contemplated.
  • topical applications shall include mouth washes and gargles.
  • the compounds for use according to the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • solvates may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
  • a pharmaceutical composition comprising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liq- uid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg
  • the compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof.
  • mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. Any novel feature or combination of features described herein is considered essential to this invention.
  • the present invention also relate to the below methods of preparing the compounds of the invention.
  • Microwave oven synthesis The reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry®.
  • Preparative HPLC Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % in 15 min, MeCN, 0.1 % TFA, flow rate of 15 ml/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze dried.
  • CDCI 3 Deuterio chloroform
  • DIPEA Diisopropylethylamine DMSO-d 6 : Hexadeuterio dimethylsulfoxide
  • HOBT 1-Hydroxy-benzotriazole
  • EDAC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
  • General method D By allowing a pyrazolo[1 ,5-a]pyrimidines (III) or (IV) wherein R 3 , R 4 and R 5 are as defined above and one of R 16 and R 17 are OH or SH and the other are hydrogen or halo to react with a halo-ester (IX); wherein hal is halo, R 15 is as defined above and n is 1 to 6, in a solvent such as MeOH, EtOH, /-PrOH, DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g.
  • 2A 1 H NMR (400 MHz, CDCI 3 ) ⁇ 2.68 (s, 3H), 3.98 (s, 3H), 6.92 (s, 1 H), 7.17 (s, 1 H), 7.56- 7.59 (m, 3H), 8.10 (m, 2H).
  • 2B 1 H NMR (400 MHz, CDCI 3 ) ⁇ 2.93 (s, 3H), 4.04 (s, 3H), 7.24 (s, 1 H), 7.30 (s, 1 H), 7.52- 7.54 (m, 3H), 8.10 (m, 2H).

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Abstract

The use of substituted pyrazolo[1,5-a]pyrimidines for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and the use of these compounds as phar-maceutical compositions are described. Also a novel class of substituted pyrazolo[1,5-a]pyrimidines their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described The present com-pounds are modulators and more specifically inhibitors of the activity of 11βHSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Description

PHARMACEUTICAL USE OF SUBSTITUTED PYRAZOLO[1,5- a]PYRIMIDINES
FIELD OF THE INVENTION
The present invention relates to use of substituted pyrazolo[1 ,5-a]pyrimidines and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11βHSD1).
The present invention also relates to novel substituted pyrazolo[1 ,5-a]pyrimidines, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds. The present compounds modulate the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
BACKGROUND OF THE INVENTION
The metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide. The metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally es- calating.
In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around 70%o of people with type 2 diabetes additionally have hypertension once again leading to increased mortality of cardiovascular diseases.
In the clinical setting, it has long been known that glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes.
11 β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. Thus, 11 βHSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J.
Biol. Chem., 266, 16653 (1991); Bujalska et al., Endocrinology, 140, 3188 (1999); Whorwood et al., J. Clin. Endoc noi. Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000); Da- vani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al., Hypertension; 31., 459 (1998); Rauz et al., Invest. Ophthalmol. Vis. Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450 (1990)).
The role of 11 βHSDI in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific 11 βHSDI inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, 11 βHSDI knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol. Conversely, mice that overexpress 11 βHSDI in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003); Walker et al., J. Clin. Endocrinol. Metab., 80, 3155 (1995); Morton et al., J. Biol. Chem. 276, 41293 (2001); Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997); Masuzaki et al., Science, 294, 2166 (2001)).
The more mechanistic aspects of 11 βHSDI modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. 11 βHSDI promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002); Brindley & Salter, Prog. Lipid Res., 30, 349 (1991)).
WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 β-hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
We have now found substituted pyrazolo[1 ,5-a]pyrimidines that modulate the activity of 11 βHSDI leading to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of 11 βHSDI leading to decreased intracellular concentrations of active glucocorticoid. Thus, the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g. the metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), im- paired fasting glucose (IFG), dyslipidemia, obesity, hypertension, diabetic late complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis, neurodegenerative and psychiatric disorders, and adverse effects of treatment or therapy with glucocorticoid receptor agonists. One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 βHSDI .
DEFINITIONS
In the following structural formulas and throughout the present specification, the following terms have the indicated meaning: The term "halo" includes fluorine, chlorine, bromine, and iodine.
The term "trihalomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
The term "trihalomethoxy" includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy. The term "alkyl" includes C C6 straight chain saturated and methylene aliphatic hydrocarbon groups, C3-C6 branched saturated hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), te/t-butyl (.-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like. The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and branched C3-C6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-C6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
The term "saturated or partially saturated cyclic, bicyclic or tricyclic ring system" represents but are not limit to aziridinyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, phthalimide, 1 ,2,3,4-tetrahydro-quinolinyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, 6-aza-bicyclo[3.2.1 Joctane, and indolinyl.
The term "cycloalkyl" (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like) represents a saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "cycloalkylalkyl" (e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "cycloalkenyl" (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohep- tenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "hetcycloalkyl" (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S02.
The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an "alkyl" group.
The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge. The term "hetaryloxy" (e.g. 2-pyridyloxy and the like) represents a hetaryl group as defined below attached through an oxygen bridge.
The term "arylalkyloxy" (e.g. phenethyloxy, naphthylmethyloxy and the like) represents an arylalkyl group as defined below attached through an oxygen bridge.
The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
The term "alkylthio" (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
The term "arylthio" (e.g. benzenthiol, naphthylthiol and the like) represents an aryl group as defined below attached through a sulphur bridge. The term "arylthioalkyl" (e.g. methylsulfanyl benzene, ethylsulfanyl naphthalene and the like) represents an arylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms.
The term "hetarylthioalkyl" (e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyl- isoquinoline and the like) represents a hetarylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms. The term "aryloxyalkyl" (e.g. phenoxymethyl, naphthyloxyethyl and the like) represents an aryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "aryloxyaryl" (e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like) represents an aryloxy group as defined above attached through an "aryl" group as defined below.
The term "arylalkyloxyalkyl" (e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like) represents an arylalkyloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms. The term "hetaryloxyalkyl" (e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like) represents a hetaryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "hetarylalkyloxyalkyl" (e.g. 4-methoxymethyl-pyrimidine, 2-methoxymethyl- quinoline and the like) represents a hetarylalkyloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "arylalkyl" (e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like ) represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above. The term "hetarylalkyl" and "hetaralkyl" (e.g. (2-furyl) methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "alkylcarbonyl" (e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "arylcarbonyl" (e.g. benzoyl) represents an aryl group as defined below attached through a carbonyl group.
The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like) represents a hetaryl group as defined below attached through a carbonyl group.
The term "carbonylalkyl" (e.g. acetyl and the like) represents a carbonyl group attached through alkyl group as defined above having the indicated number of carbon atoms. The term "alkylcarbonylalkyl" (e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylcarbonylalkyl" (e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like) represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "hetarylcarbonylalkyl" (e.g. 1-pyhdin-2-yl-propan-1-one, 1-(1-/-/-imidazol-2- yl)-propan-1-one and the like) represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like) represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "hetarylalkylcarbonyl" (e.g. imidazolylpentylcarbonyl and the like) represents an hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylcarboxy" (e.g. benzoic acid and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylalkylcarboxy" (e.g. benzylcarboxy, phenylpropylcarboxy and the like) represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylalkylcarboxyalkyl" (e.g. benzylcarboxymethyl, phenylpropylcar- boxypropyl and the like) represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "hetarylcarboxy" (e.g. pyridine-2-carboxylic acid and the like) represents a hetarylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "hetarylalkylcarboxy" (e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like) represents a hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "alkylcarbonylamino" (e.g. methylcarbonylamino, cyclopentylcarbonyl- aminomethyl, methylcarbonylaminophenyl) represents an "alkylcarbonyl" group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term "alkylcarbonylaminoalkyl" (e.g.N-propyl-acetamide, N-butyl-propionamide and the like) represents an "alkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylalkylcarbonylamino" (e.g. phenylacetamide, 3phenyl-propionamide and the like) represents an "arylalkylcarbonyl" group as defined above attached through an amino group.
The term "arylalkylcarbonylaminoalkyl" (e.g. N-ethyl-phenylacetamide, N-butyl-3- phenyl-propionamide and the like) represents an "arylalkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylcarbonylamino" (e.g. benzamide, naphthalene-1-carboxylic acid amide and the like) represents an "arylcarbonyl" group as defined above attached through an amino group. The term "arylcarbonylaminoalkyl" (e.g. N-propyl-benzamide, N-Butyl-naphthalene-
1-carboxylic acid amide and the like) represents an "arylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "aryl" includes but is not limited to a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
The term "aryll" includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
The term "aryl2" includes phenyl, biphenyl, naphthyl, and anthracenyl. The term "hetaryl" includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), ben- zo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6- benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-ben- zo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro- benzo-[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thio- phenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3- dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thio- phenyl), 7-(2,3-dihydro-benzo[b]thiophenyl)), 4,5,6, 7-tetrahydro-benzo[b]thiophenyl (2-
(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 3-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 4-(4,5,6,7- tetrahydro-benzo[b]thiophenyl), 5-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 6-(4,5,6,7- tetrahydro-benzo[b]thiophenyl), 7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)), thieno[2,3- bjthiophenyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl (4-(4,5,6,7-tetrahydro-thieno[2,3- cjpyridyl), 5-4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 6-(4,5,6,7-tetrahydro-thieno[2,3- cjpyridyl), 7-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4- indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4- isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1 ,3-dihydro-isoindolyl (1 -(1 ,3-dihydro- isoindolyl), 2-(1 ,3-dihydro-isoindolyl), 3-(1 ,3-dihydro-isoindolyl), 4-(1 ,3-dihydro-isoindolyl), 5- (1 ,3-dihydro-isoindolyl), 6-(1 ,3-dihydro-isoindolyl), 7-(1 ,3-dihydro-isoindolyl)), indazole (1- indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1- benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7- benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1 -benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6- benzothiazolyl, 7-benzothiazolyl), benzo-[1 ,2,5]oxadiazolyl, (4-benzo[1 ,2,5]oxadiazole, 5- benzo[1 ,2,5joxadiazole), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).
Certain of the above defined terms may occur more than once in the structural for- mulae, and upon such occurrence each term shall be defined independently of the other.
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different. The term "treatment" is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
The term "pharmaceutically acceptable" is defined as being suitable for administration to humans without adverse events.
The term "prodrug" is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides the use of a substituted pyrazolo[1 ,5- a]pyrimidine, a pro-drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tauto eric forms for a) modulation of the activity of 11 βHSDI ;or b) inhibition of 11 βHSDI , in a patient in need thereof.
In another aspect, the present invention provides the use of a substituted pyra- zolo[1 ,5-a]pyrimidine, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDI ; or b) inhibit 1 1 βHSDI , in a patient in need thereof.
In another embodiment, the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine or a prodrug thereof is of the general formula (I)
Figure imgf000010_0001
wherein R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, C02R15, NR6C(=0)R11, OR12 or SR12;
R3 and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, Cι-C6alkyloxy, C C6alkylthio, aryl, arylC C6alkyl, hetaryl or hetarylC C6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylC C6alkyl, hetarylC C6alkyl, hydroxy, d-Cealkyloxy, arylC C6alkyloxy, hetarylC C6alkyloxy, or Cι-C6alkyloxyCrC6alkyl, wherein the alkyl, alkynyl, alkenyl, cycloal- kyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are CτC6alkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylC C6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C6alkyl, aryl, hetaryl, arylC C6alkyl, halo, hydroxy, oxo, C C6alkyloxy, arylCrCealkyloxy, hetarylC C6alkyloxy, C CealkyloxyC Cealkyl, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkyl- carbonyl, hetarylCrC6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C6alkylcarboxy or hetarylCι-C6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-C10cycloalkyl, C3- C10hetocycloalkyl, C C6alkyl, C C6alkyloxy, trihalomethyl, trihalomethoxy, arylC C6alkyloxy, hetarylC C6alkyloxy, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcar- bonyl, hetarylCι-C6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C6- alkylcarboxy, hetary!Cι-C6alkylcarboxy, CrC6alkylcarbonylamino or arylC C6alkylcarbonyl- amino; R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C C6alkyl, C C6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrC6alkyloxy, hetarylC C6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC-ι-C6alkyl- carbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylC C6alkylcarboxy;
R11 is CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylC C6alkyl, C C6alkyl- carbonylCrC6alkyl, CrC6alkyloxy, aryloxy, C C6alkyloxy, arylcarbonyl, arylCrC6alkyl- carbonyl, hetarylcarbonylCrC6alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is CrCealkylcarbonylaminoCrCealkyl, arylcarbonylaminoCrC6alkyl or arylC C6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, C C6alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrCealkylcarbonyl;
R15 is hydrogen, C3-C10cycloalkyl, C C6alkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, C C6alkyloxyalkyl or arylC C6alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of a substituted pyrazolo[1,5-a]pyrimidines, or a prodrug thereof of the general formula (I)
Figure imgf000012_0001
wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, NC(=0)R11, OR12 or SR12;
R3and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetaryl- CrC6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8; R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, C Cβalkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, hydroxy, CrC6alkyloxy, arylCrCealkyloxy, hetarylC C6alkyloxy, or CrCealkyloxyd-Cealkyl, wherein the alkyl, alkynyl, alkenyl, cycloal- kyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are C C6alkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylCrC6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylC C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, hetarylC C6alkyloxy, CrC6- alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkyl- carboxy or hetarylC C6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-C10cycloalkyl, C3- C10hetocycloalkyl, CrC6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C6alkylcarboxy, hetarylCrC6alkylcarboxy, CrC6alkylcarbonylamino or arylCrC6alkylcarbonyl- amino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, C C6alkyl, C C6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, het- arylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, C C6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R11 is Cι-Cβalkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylC C6alkyl, CrCβalkyl- carbonylC C6alkyl, C Cβalkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyICrC6- alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is CrCealkylcarbonylaminoCrCealkyl, arylcarbonylaminoCrC6alkyl or arylC C6alkyl- carbonylaminoCrC6alkyl;
R13 and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, C C6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkyl- carboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy;
R15 is hydrogen, C3-C10cycloalkyl, CrC6alkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, CrC6alkyloxyalkyl or arylCrC6alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R1 and R2 independently are hydrogen and/or C(=0)NR6R7. In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R3 and R5 independently are hydrogen, trihalomethyl, CrC6alkyl, CrC6alkyloxy, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8. In another embodiment, the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R4 is hydrogen, cyano, halo, C(=0)NR6R7, CrC6alkyl, aryl, hetaryl, arylC C6alkyl, hetarylC C6alkyl, hydroxy, CrC6alkyloxy, arylC C6alkyloxy, hetarylCrC6alkyloxy, wherein the alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R6 and R7 independently are CrC6alkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylC C6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10. In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylCrC6alkyl, halo, hydroxy, oxo, Cr C6alkyloxy, arylCrC6alkyloxy, hetarylC C6alkyloxy, CrCealkyloxyCrC-ealkyl, C C6alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkyl- carboxy.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylC C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylC C6alkyloxy, hetarylCrC6alkyloxy, CrC6alkyloxyCrC6alkyl.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R8 and R9 inde- pendently are hydrogen, halo, hydroxy, oxo, cyanoC3-C10cycloalkyl, C3-C10hetocycloalkyl, C C6alkyl, CrC6alkyloxy, trihalomethyl, arylCrCealkyloxy, hetarylCrC6alkyloxy.
In another embodiment, the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R 0 is hy- drogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, CrC6alkyl, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R11 is CrCealkyl, arylCrC6alkyl, hetarylCrC6alkyl, CrC6alkyloxy, aryloxy, CrC6alkyloxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R12 is CrC6- C6alkylcarbonylaminoCrC6alkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkylcarbonyl- aminoCrC6alkyl.
In another embodiment, the invention provides the present use of a substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R13and R14 independently are hydrogen, C3-C10cycloalkyl, CrC6alkyl, Ci-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl.
In another embodiment, the invention provides the present use of a substituted pyrazolo[1 ,5-a]pyrimidine, or a prodrug thereof of the general formula (I) wherein R15 is hydrogen, C3-C10cycloalkyl, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, C C6alkyloxyalkyl or arylCrC6alkyloxyalkyl.
In another embodiment, the invention provide the present use of substituted pyra- zolo[1 ,5-a]pyrimidine, or a prodrug thereof of general formula (I) selected from the group consisting of:
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1-yl-)methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl-)methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyhmidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-
1-yl-)methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide;
Azepan-1-yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl)methanone;
3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-carboxylic acid cyclohexyl- amide;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperidin-1-yl)methanone;
5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl amide;
[5-(-4-Ethoxy-phenyl-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-yl])-piperidin-1-yl-methanone; Azepan-1 -yl-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl amide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]methanone; Azepan-1 -yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone
Azepan-1-yl-(5,7-diphenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone;
[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl] methanone;
5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1 -yl)- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
5-Thiophen-2-yl -7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 ,3-dimethyl-1r-/- pyrazol-4-ylmethyl)-methyl amide; 5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl amide; 5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
(5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone
(2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)methanone; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone; 5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of substituted pyra- zolo[1 ,5-a]pyrimidines, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 4, examples 4-2 through 4-214, example 5 and examples 5-2 through 5-126, a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention provides substituted pyrazolo[1 ,5- ajpyrimidines, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 4, examples 4-2 through 4-214, example 5 and examples 5-2 through 5-126, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like. Examples of cationic amino acids include lysine, arginine, histidine and the like. Further, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium tetif-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used. The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in "Enantiomers, Racemates and Resolu- tion" (Wiley Interscience, 1981). More specifically the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, ami- noacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
Various polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
It is a well known problem in drug discovery that compounds, such as enzyme inhibitors, may be very potent and selective in biochemical assays, yet be inactive in vivo. This lack of so-called bioavailability may be ascribed to a number of different factors such as lack of or poor absorption in the gut, first pass metabolism in the liver and/or poor uptake in cells. Although the factors determining bioavailability are not completely understood, there are many examples in the scientific literature - well known to those skilled in the art - of how to modify compounds, which are potent and selective in biochemical assays but show low or no activity in vivo, into drugs that are biologically active.
It is within the scope of the invention to modify the compounds of the present inven- tion, termed the Original compound', by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated.
Examples of said modifications, which are not intended in any way to limit the scope of the invention, include changing of one or more carboxy groups to esters (for instance methyl esters, ethyl esters, te/t-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters). Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'.
The invention also encompasses active metabolites of the present compounds. The compounds according to the invention alters, and more specifically, reduces the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
Accordingly, the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of autoimmune diseases, adverse effects of glucocorticoid receptor agonist treatment of inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse effects of glucocorticoid receptor agonist treatment as a part of cancer chemotherapy, adverse effects of glucocorticoid receptor agonist treatment for surgical/post-surgical or other trauma, adverse effects of glucocorticoid receptor agonist therapy in the context of organ or tissue transplantation or adverse effects of glucocorticoid receptor agonist treatment in other diseases, disorders or conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
More specifically the present compounds may be applicable for the treatment, pre- vention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arryth- mia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurode- generative and psychiatric disorders, Alzheimers disease, neuronal death, impaired cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsia, ad- diction to chemical substances, disorders of intraocular pressure, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate T helper-1/T helper-2 polarisation, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasitic infestations, suboptimal responses to immunizations, immune dysfunction, partial or complete baldness, or other diseases, disorders or conditions that are influenced by intracel- lular glucocorticoid levels and any combination thereof, adverse effects of glucocorticoid receptor agonist treatment of allergic-inflammatory diseases such as asthma and atopic dermatitis, adverse effects of glucocorticoid receptor agonist treatment of disorders of the respiratory system e.g. asthma, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid re- ceptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g. reactive arthritis, rheumatoid arthritis, Sjόgren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schonlein pur- pura, Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoido- sis, dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects of glucocorticoid re- ceptor agonist treatment of endocrinological diseases such as hyperthyroidism, hypoaldos- teronism, hypopituitarism; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases e.g. hemolytic anemia, thrombocytopenia, paroxysmal nocturnal he- moglobinuria; adverse effects of glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & trans- plantation e.g. trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tra- cheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, kerato- plasty, lens implantation and other procedures where immunosuppression with glucocorticoid receptor agonists is beneficial; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms or adverse effects to glucocorticoid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects. Accordingly, in a further aspect the invention relates to a compound according to the invention for use as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents. The pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
In another embodiment, the patient is treated with a compound according to the invention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
In yet another embodiment, the pharmaceutical composition is for oral, nasal, trans- dermal, pulmonal or parenteral administration.
Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial.
The invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
Thus, in a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above. In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders. In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
In another embodiment of the present invention, the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonal, or parenteral.
In still a further aspect of the invention the present compounds are administered in combination with one or more further active substances in any suitable ratios. Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, agents modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), e.g. NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), e.g. AspB28 human insulin, US 5,504,188 (Eli Lilly), e.g. LysB28 Pro629 human insulin, EP 368 187 (Aventis), e.g. Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorpo- rated herein by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPARα modulators, PPARδ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates, anion exchangers, compounds lowering food intake, bile acid resins, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells.
In one embodiment, the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human in- sulin, AspB28 human insulin, LysB28 Pro629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
In a further embodiment the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguanide e.g. metformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
In still another embodiment the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
In yet another embodiment the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor e.g. miglitol or acarbose. In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide. In still another embodiment the present compounds are administered in combination with an'antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine. In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
Further, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, β2-receptor blockers e.g. S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, bamidipine, efonodipine, iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, furnidipine, α-blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, diuretics such as thiazides/sulphonamides (e.g. bendro- flumetazide, chlorothalidone, hydrochlorothiazide and clopamide), loop-diuretics (e.g. bumetanide, furosemide and torasemide) and potassium sparing diuretics (e.g. amiloride, spironolactone), endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551 , CM 034, S-0139 and YM-598, endothelin antagonists e.g. bosentan and J-104133, renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g. OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g. fenoldopam and ketanserin, adenosine A1 antagonists such as naftopidil, N-0861 and FK-352, thromboxane A2 antagonists such as KT2-962, endopeptidase inhibitors e.g. ecadotril, nitric oxide agonists such as LP-805, dopamine D1 antagonists e.g. MYD-37, dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists such as treprostinil, beraprost, PGE1 agonists e.g. ecraprost, Na7K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
Furthermore, the present compounds may be administered in combination with one or more glucocorticoid receptor agonists. Examples of such glucocorticoid receptor agonists are betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and analogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021 , NS-126, P-4112, P-4114, RU-24858 and T-25 series.
It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
PHARMACEUTICAL COMPOSITIONS
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and gran- ules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 200 mg, e.g. about 100 mg. For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds for use according to the present invention which are generally prepared by reaction of the free base with a suitable organic or inorganic acid or by reaction of the acid with a suitable organic or inorganic base. When a compound for use according to the present invention, contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compounds for use according to the present invention, contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention. For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media em- ployed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
The pharmaceutical compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to pro- vide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for exam- pie, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsule wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegeta- ble oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavouring, and colouring agents may also be present. The pharmaceutical compositions comprising a compound for use according to the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, leci- thin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of iηjectables.
The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials in- elude cocoa butter and polyethylene glycols, for example.
For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the present invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles.
The compounds for use according to the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
In addition, some of the compounds for use according to the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liq- uid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite@IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg
* Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating.
The compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. Any novel feature or combination of features described herein is considered essential to this invention.
The present invention also relate to the below methods of preparing the compounds of the invention.
The present invention is further illustrated in the following representative examples which are, however, not intended to limit the scope of the invention in any way.
EXAMPLES
The following examples and general procedures refer to intermediate compounds and final products identified in the specification and in the synthesis schemes. The preparation of the compounds of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chroma- tography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C18 4 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
Microwave oven synthesis: The reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry®.
Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % in 15 min, MeCN, 0.1 % TFA, flow rate of 15 ml/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze dried.
The abbreviations as used in the examples have the following meaning:
TLC: Thin layer chromatography
CDCI3: Deuterio chloroform
CD3OD: Tetradeuterio methanol
DIPEA: Diisopropylethylamine DMSO-d6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-Hydroxy-benzotriazole EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Scheme 1 Methode A
Figure imgf000036_0001
Figure imgf000036_0002
R« IX
V
Figure imgf000036_0003
General method A:
By allowing a 1 ,3 dicarbonylderivativ (I), wherein R3, R4 and R5 are as defined above, to react with a 5-amino-pyrazole (II), wherein R16 and R17 independently are selected from the group consisting of hydrogen, hal, C02R15, N02, OH or SH, wherein R15 are defined as above, in AcOH at elevated temperature or in a solvent such as EtOH, toluene and the like, catalysed by a base such as with piperidine at elevated temperature, affording the two regio isomeric compounds (III) and (IV), wherein R3, R4, R5, R16 and R17 are as defined above; the two regio-isomers (III) and (IV) can be separated by methods known those skilled in the art.
General method B:
By allowing a pyrazolo[1 ,5-a]pyrimidines (III) or (IV) wherein R3, R4 and R5 are as defined above and one of R16 and R17 are C02R15, wherein R15 are defined as above and the other is hydrogen, is transformed into the corresponding acid by methods known to those skilled in the art and coupled with an amine (V) wherein R6 and R7 are as defined above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording pyrazolo[1 ,5-a]pyrimidines (VI) and/or (VII), wherein R1, R2, R3, R4 and R5 are defined as above. General method C:
By allowing a pyrazolo[1 ,5-a]pyrimidines (III) or (IV) wherein R3, R4 and R5 are as defined above and one of R16 and R17 are OH or SH and the other are hydrogen or halo, to react with a halo-amide (VIII), wherein hal is halo, R6 and R7 are as defined above and n is 1 to 6, in a solvent such as MeOH, EtOH, /-PrOH, DMF, DMSO, NMP, acetone, THF, di- chloromethane and the like under basic conditions (e.g. triethylamine, K2C03, NaOH, NaH, n- BuLi and the like) affording pyrazolo[1 ,5-a]pyrimidines (VI) and/or (VII), wherein R1, R2, R3 , R4 and R5 are defined as above.
General method D: By allowing a pyrazolo[1 ,5-a]pyrimidines (III) or (IV) wherein R3, R4 and R5 are as defined above and one of R16 and R17 are OH or SH and the other are hydrogen or halo to react with a halo-ester (IX); wherein hal is halo, R15 is as defined above and n is 1 to 6, in a solvent such as MeOH, EtOH, /-PrOH, DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. triethylamine, K2C03, NaOH, NaH, n-BuLi and the like) affording a pyrazolo[1 ,5-a]pyrimidines with a ester group. This is transformed into the corresponding acid by methods known to those skilled in the art and coupled with an amine (V), wherein R6 and R7 are as defined above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording pyrazolo[1 ,5-a]pyrimidines (VI) and/or (VII), wherein R1, R2, R3, R4 and R5 are defined as above.
Example 1 (General method (A))
5-Methyl-7-trifluoromethyl-pyrazolof1 ,5-a1pyrimidine-2-carboxylic acid methyl ester
Figure imgf000037_0001
A mixture of 5-amino-1/-/-pyrazole-3-carboxylic acid methyl ester (0.99 g, 7.0 mmol) and 1 ,1 ,1-triflouro-2,4-pentanedione (1 ,08 g, 7.0 mmol) in acetic acid (20ml) was refluxed in a reaction flask for 16 hrs. The reaction mixture was cooled to room temperature, the solid product filtered off and dried in vacuo affording 0.74 g (41 %) of the title compound as a solid. 1H NMR (400 MHz, CDCI3) δ 2.72 (s, 3H), 4.01 (s, 3H), 7.18 (s, 1 H), 8.27 (s, 1 H). Example 2 (General method (A))
2A: 5-Methyl-7-phenyl-pyrazolof1 ,5-a1pyrimidine-2-carboxylic acid methyl ester
2B: 7-Methyl-5-phenyl-pyrazolof1 ,5-a1pyrimidine-2-carboxylic acid methyl ester
Figure imgf000038_0001
2B A mixture of 5-amino-1 H-pyrazole-3-carboxylic acid methyl ester (0.55 g, 3.9 mmol) and 1-Benzoylacetone (0.63 g, 3.9 mmol) in acetic acid (10 ml) was heated to 140 °C in a sealed tube for 2 hrs. using a microwave oven. The reaction mixture was cooled to room temperature and the volatiles evaporated in vacuo. The crude product was purified by sili- cagel chromatography using DCM as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording the two region-isomeric product 2A (570 mg, 55%) and 2B (150 mg, 15%).
2A: 1H NMR (400 MHz, CDCI3) δ 2.68 (s, 3H), 3.98 (s, 3H), 6.92 (s, 1 H), 7.17 (s, 1 H), 7.56- 7.59 (m, 3H), 8.10 (m, 2H). 2B: 1H NMR (400 MHz, CDCI3) δ 2.93 (s, 3H), 4.04 (s, 3H), 7.24 (s, 1 H), 7.30 (s, 1 H), 7.52- 7.54 (m, 3H), 8.10 (m, 2H).
Example 3 (General method (B))
(5-methyl-7-trifluorornethyl-pyrazoloH ,5-alpyrimidin-2-vD- (piperidin-1 -vDmethanone
Figure imgf000038_0002
To 5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl es- ter (648 mg, 2.5 mmol) in ethanol (35 ml) was added 1 N NaOH (5 ml) and the resulting mixture stirred at room temperature for 3.5 hrs. The solvent was removed in vacuo and to the residue was added 1 N HCI (6ml). The solid 5-methyl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid was collected by filtration and dried in vacuo. A mixture of 5- methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid; (98 mg, 0.4 mmol), HOBT (59 mg, 0.44 mmol), EDAC (84 mg, 0.44 mmol) and diisopropylethylamine (57 mg, 0.44 mmol) in THF (5 ml) was stirred at room temperature for 30 min. and then added 2- methylpiperidine (38 mg, 0.44 mmol) and stirred for 16 hrs. The reaction mixture was quenched by addition of water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic phase dried (MgS04), filtered and the volatiles evaporated in vacuo affording 106 mg (85%) of the title compound as a solid.
1H NMR (400 MHz, CDCI3) δ 1.63 (m, 2H), 1.71 (m, 4H), 2.70 (s, 3H), 3.76 (m, 4H), 7.03 (s, 1 H), 7.09 (s, 1 H).
Example 4 (General method (B)) (5-methyl-7-phenyl-pyrazolof1 ,5-alpyrimidine-2-carboxylic acid cyclohexyl-methyl amide
Figure imgf000039_0001
To 5-methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester (300 mg, 1.12 mmol) in ethanol (100 ml) was added 1N NaOH (4 ml) and stirred at room temperature for 16 hrs. The solvent was removed in vacuo and to the residue was added 1 N HCI (6 ml). The solid 5-methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (284 mg, 99%) was collected by filtration and dried in vacuo. A mixture of 5-methyl-7-phenyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid; (284 mg, 1.1 mmol), HOBT (167 mg, 1.23 mmol), EDAC (237 mg, 1.23 mmol) and diisopropylethylamine (159 mg, 1.23 mmol) in THF (5 ml) was stirred at room temperature for 30 min. and then added N-methyl-cyclohexylamine (127 mg, 1.21 mmol) and stirred for 16 hrs. The reaction mixture was quenched by addition of water and extracted with EtOAc (2 x 50 ml). The combined organic phases were dried (MgS04), filtered and the volatiles evaporated in vacuo affording 386 mg (94 %) of the title compound as a solid.
1H NMR (400 MHz, CDCI3) δ 1.05 (m, 2H), 1.55 (m, 2H) 1.65-1.80 (m, 4H), 2.67 (s, 3H), 3.00 (s, 3H) 3.26 (m, 1 H), 6.85 (s, 1 H) 6.96 (s, 1 H), 7.54 (m, 3H), 8.02 (m, 2H). Mp:158 - 162 °C
The following compounds were made in a similar way as described in Example 4 above
Figure imgf000040_0001
,5-
,5-
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl- -31 433.39 pyrazo!o[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1 - yl)-methanone
[5-(3,4-DichIoro-phenyI)-7-trifluoromethyl- -32 457.29 pyrazolo[1 ,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1 -yl)- methanone
3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl- -33 489.89 pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(2- pyridin-2-yl-ethyl)-amide
[3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl- -34 445.23 pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl- -35 462.88 pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl- -36 550.37 pyrazolo[1 ,5-a]pyrimidin-2-yl]-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-methanone
(4-Benzoyl-piperazin-1-yl)-[3-chloro-5-(4-chloro- -37 548.36 phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
-
,5-
Figure imgf000052_0001
Figure imgf000053_0001
,5-
H-
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
,5-
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
-
,5-
-
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
,5-
,5-
Figure imgf000065_0001
,5-
,5-
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
-
Figure imgf000069_0001
Figure imgf000070_0001
,5-
,5-
Figure imgf000071_0001
Example 5
(5-Phenyl-7-trifluoromethyl-pyrazoloπ ,5-alpyrimidin-3-yl)-(1 ,3,3-t methyl-6-aza- bicyclo[3.2.11oct-6-yl)-methanone
Figure imgf000072_0001
A mixture of 5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid
(108 mg, 0.35 mmol), HOBT (52 mg, 0.39 mmol), EDAC (74 mg, 0.39 mmol) and DIPEA (50 mg, 0.39 mmol) in THF (5 ml) was stirred at room temperature for 30 min. and then added 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (59 mg, 0.39 mmol) and stirred for 16 hrs. The reaction mixture was quenched by addition of water and extracted with EtOAc (2 x 50 ml). The combined organic phases were dried (MgS04), filtered and the volatiles evaporated in vacuo affording 160 mg (~100 %) of the title compound as a solid. LC/MS m/z: 443 H+ 1H NMR (400 MHz, CDCI3) δ 0.89 - 1.19 (m, 9H), 1.22 - 1.95 (m, 5.5H), 2.26 (m, 0.5H), 3.36 (d, 0.5H), 3.54 (d, 0.5H), 3.73 (q, 1 H), 4.60 (m, 0.5 H), 4.76 (m, 0.5H), 7.56 (m, 3H), 7.71 (s, 1 H), 8.14 (t, 2H), 8.50 (d, 1 H). Calculated for C24H25F3N40; C 65.15 %; H 5.69 %; N 12.66 %; Found C 65.27 %; H 5.97 %; N 12.32.
The following compounds were made in a similar way as described in example 5 above
Figure imgf000072_0002
Figure imgf000073_0001
,5-
es¬
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
(2,6-Dimethyl-piperidin-1-yl)-(5-thiophen-2-yl-7- -28 408.45 trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone
[5-(4-Methoxy-phenyl)-7-trifluoromethyl- -29 419.41 pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl- piperazin-1 -yl)-methanone
(4-Methyl-piperazin-1-yl)~(5-thiophen-2-yl-7- -30 395.41 trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone
[5-(4-Bromo-phenyl)-7-trifluoromethyl- -31 468.28 pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl- piperazin-1 -yl)-methanone
(Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-p-tolyl- -32 429.45 7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone
[5-(4-Bromo-phenyl)-7-trifluoromethyl- -33 494.32 pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
(1-
ben¬
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
ben¬
Figure imgf000092_0001
PHARMACOLOGICAL METHODS
11 βHSDI enzyme assay
Materials
3H-cortisone and anti-rabbit Ig coated scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, β-NADPH was from Sigma and rabbit anti- cortisol antibodies were from Fitzgerald. An extract of yeast transformed with h-11 βHSDI (Hult et al., FEBS Lett; 441 , 25 (1998)) was used as the source of enzyme. The test compounds were dissolved in DMSO (10 mM). All dilutions were performed in a buffer containing 50 mM TRIS-HCI (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical Co), 0.1 % BSA (Sigma Chemical Co), 0.01 %> Tween-20 (Sigma Chemical Co) and 0.005% bacitracin (Novo Nordisk A/S), pH=7.4. Optiplate 96 wells plates were supplied by Packard. The amount of 3H- cortisol bound to the SPA beads was measured on TopCount NXT, Packard.
Methods h-11 βHSDI , 120 nM 3H-cortisone, 4 mM β-NADPH, antibody (1 :200), serial dilutions of test compound and SPA particles (2 mg/well) were added to the wells. The reaction was initiated by mixing the different components and was allowed to proceed under shaking for 60 min at 30°C. The reaction was stopped be the addition of 10 fold excess of a stopping buffer containing 500 μM carbenoxolone and 1 μM cortisone. Data was analysed using GraphPad Prism software.
Table 1
Inhibition of 11 βHSDI by compounds of the invention
Figure imgf000093_0001

Claims

1. Use of a substituted pyrazolo[1 ,5-a]pyrimidine, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms, for a) modulation of the activity of 11 βHSDI; or b) inhibition of 11 βHSDI , in a patient in need thereof.
2. Use of a substituted pyrazolo[1 ,5-a]pyrimidine, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDI ; or b) inhibit 11 βHSDI , in a patient in need thereof.
3. The use according to claim 1 or 2, wherein the substituted pyrazolo[1 ,5-a]pyrimidine or a prodrug thereof is of the general formula (I)
Figure imgf000094_0001
wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, C02R15, NR6C(=0)R11, OR12 or SR12;
R3 and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, CrCβalkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, C C6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, or CrCealkyloxyCrC6alkyl, wherein the alkyl, alkynyl, alkenyl, cycloal- kyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are CrCealkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylCrC6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylC C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylC C6alkyloxy, CrC6- alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkyl- carboxy or hetarylC C6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-C10cycloalkyl, C3- C10hetocycloalkyl, C C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C6- alkylcarboxy, hetarylC C6alkylcarboxy, CrC6alkylcarbonylamino or arylCrC6alkylcarbonyl- a ino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C C6alkyl, C C6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylC C6alkyloxy, hetaryl- CrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy; R11 is CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylC C6alkyl, hetarylCrC6alkyl, CrC6alkyl- carbonylC C6alkyl, CrC6alkyloxy, aryloxy, CrC6alkyioxy, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is CrCealkylcarbonylaminoCrCealkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, CrC6alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrCealkylcarbonyl;
R15 is hydrogen, C3-C10cycloalkyl, CrC6alkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, CrC6alkyloxyalkyl or arylCrC6alkyloxyalkyl; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
4. The use according to any of the claims 1-3, wherein the substituted pyrazolo[1 ,5- a]pyrimidine or a prodrug thereof is of the general formula (I)
Figure imgf000096_0001
wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, NC(=0)R11, OR12 or SR 12.
R3 and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetaryl- CrC6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, hydroxy, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, or CrCealkyloxyCrCealkyl, wherein the alkyl, alkynyl, alkenyl, cycloal- kyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are C C6alkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylCrC6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylCr C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, Cr CealkyloxyCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkyl- carbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCr C6alkylcarboxy or hetarylCrC6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-C10cycloalkyl, C3- C10hetocycloalkyl, CrC6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6- alkylcarboxy, hetarylCrC6alkylcarboxy, CrC6alkylcarbonylamino or arylC C6alkyl- carbonylamino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C C6alkyl, CrC6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCr C6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy;
R11 is d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylC C6alkyl, CrC6alkyl- carbonylC C6alkyl, CrC6alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6- alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9; R12 is CrCealkylcarbonylaminoCrC-ealkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, CrC6alkyloxy, tri- halomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy;
R 5 is hydrogen, C3-C10cycloalkyl, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylC C6alkyl, C C6alkyloxyalkyl or arylCrC6alkyloxyalkyl; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
5. The use according to any of the claims 1-4, wherein in formula (I) R1 and R2 independently are hydrogen and/or C(=0)NR6R7.
6. The use according to any of the claims 1-5 wherein in formula (I) R3 and R5 independently are hydrogen, trihalomethyl, CrC6alkyl, CrC6alkyloxy, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8.
7. The use according to any of the claims 1-6, wherein in formula (I) R4 is hydrogen, cyano, halo, C(=0)NR6R7, C C6alkyl, aryl, hetaryl, arylC C6alkyl, hetarylC C6alkyl, hydroxy, C C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, wherein the alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9.
8. The use according to any of the claims 1-7, wherein in formula (I) R6 and R7 independently are CrC6alkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylCrC6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10.
9. The use according to any of the claims 1-7, wherein in formula (I) R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, halo, hydroxy, oxo, CrCealkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrC6alkyIoxyCr C6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkylcarboxy;
10. The use according to any of the claims 1-9, wherein in formula (I) R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyanoC3-C10cycloalkyl, C3-C 0hetocycloalkyl, C C6alkyl, CrCealkyloxy, trihalomethyl, arylCrCealkyloxy, hetarylCrCealkyloxy.
11. The use according to any of the claims 1-10 wherein in formula (I) R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C 0hetcycloalkyl, CrC6alkyl, C C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrCealkylcarbonyl, C C6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy.
12. The use according to any of the claims 1-11 , wherein in formula (I) R11 is CrC6alkyl, arylCrC6alkyl, hetarylCrC6alkyl, CrC6alkyloxy, aryloxy, CrC6alkyloxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9.
13. The use according to any of the claims 1-12, wherein in formula (I) R 2 is CrC6alkyl- carbonylaminoCrC6alkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkylcarbonylaminoCr
Cβalkyl.
14. The use according to any of the claims 1-13, wherein in formula (I) R13and R14 independently are hydrogen, C3-C10cycloalkyl, C C6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl.
15. The use according to any of the claims 1-14, wherein in formula (I) R15 is hydrogen, C3- C10cycloalkyl, CrCealkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, C C6alkyloxyalkyl or arylC C6alkyloxyalkyl.
16. The use according to any of the claims 1-15, wherein the substituted pyrazolo[1 ,5- ajpyrimidine or a prodrug thereof is selected from the group consisting of:
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl-)methanone; (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl-)methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin- 1-yl-)methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 , 5-a]pyrimidin-3-yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl)methanone;
3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-carboxylic acid cyclohexyl- amide; (7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperidin-1 -yl)methanone;
5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl amide;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-yl]-piperidin-1 -yl-methanone;
Azepan-1-yl-(3-bromo-5-furan-2-yl-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl amide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]methanone;
Azepan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone; Azepan-1 -yl-(5,7-diphenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone; (2,6-Dimethyl-piperidin-1-yl-)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl] methanone;
5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1 -yl)- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
5-Thiophen-2-yl -7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 ,3-dimethyl-1 H- pyrazol-4-yl-methyl)methyl amide; 5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
5-Naphthalen-1-yl-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl amide; 5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
(5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone
(2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a!]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
17. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
18. The use according to any of the claims 1-16 for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or dis- eases of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
19. The use according to any of the claims 1-16, for the preparation of a composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
20. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
21. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
22. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
23. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
24. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
25. The use according to any of the claims 1-24, wherein the pharmaceutical composition is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
26. The use according to any of the claims 1-25 wherein the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 2000 mg/day, pref- erably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day of the compound.
27. A method for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
28. The method according to claim 27 wherein the treatment, prevention and/or prophylaxis is of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
29. The method according to claim 27 or 28, wherein the condition, disorder or disease is the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
30. The method according to claim 27 or 28, wherein the condition, disorder or disease is type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
31. The method according to claim 27 or 28, for the delaying or prevention of the progression from IGT to type 2 diabetes.
32. The method according to claim 27 or 28, for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
33. The method according to claim 27 or 28, wherein the condition, disorder or disease is diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
34. The method according to claim 27 or 28, wherein the condition, disorder or disease is neurodegenerative and psychiatric disorders.
35. The method according to claim 27 or 28, for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
36. A substituted pyrazolo[1 ,5-a]pyrimidine or a prodrug thereof the general formula (I) which is:
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester; 5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester; 7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester;
(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- (piperidin-1 -yl)methanone; (5-methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
37. A substituted pyrazolo[1 ,5-a]pyrimidine or a prodrug thereof the general formula (I) which is:
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(5, 7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone;
5,7-Diphenyl-pyrazolo[1 ,5~a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
5-Naphthalen-1 -yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
[7-(4-Ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
(2-Methyl-piperidin-1-yl)-(7-phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyhmidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
(6-Bromo-3-chloro-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(6-Bromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(6-Bromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(3,6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3, 6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1- yl)-methanone; 3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide;
[3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-[4-(2-methoxy- phenyl)-piperazin-1-yl]-methanone;
(4-Benzoyl-piperazin-1-yl)-[3-chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
4-(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carbonyl)-piperazine-
1-carboxylic acid ethyl ester;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-1 - methyl-3,4-dihydro-1 H-isoquinolin-2-yl)-methanone; [4-(Furan-2-carbonyl)-piperazin-1-yl]-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(2-methoxy- phenyl)-piperazin-1-yl]-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
(3,4-Dihydro-2/-/-quinolin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl)-methanone; (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-pipehdin-1- yl)-methanone;
3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone;
(3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -yl]-methanone;
(3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1- yl)-methanone; [3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Azepan-1 -yl-[3-chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj- methanone; [3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-
1 -yl-methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
[4-(2-Chloro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyhmidin-
2-yl)-methanone; (4-Methyl-piperazin-1 -yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2r - quinolin-1-yl)-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
[4-(Furan-2-carbonyl)-piperazin-1-yl]-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
[5-(4-Nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl-methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(4-Methyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -yl]-methanone; [4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4- yl-methanone; [4-(4-Fluoro-phenyl)-piperazin-1-yl]-(7-methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(4-Benzoyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-
1-yl)-methanone;
(2-Ethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(4-Phenyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1 -yl- methanone;
(5, 7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl)-methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-
1-yl)-methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -yl]-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone; Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Azepan-1 -yl-[3-bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (2,6-Dimethyl-piperidin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl]-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-phenyl-piperazin-1-yl)- methanone;
(3,4-Dihydro-1f -isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; Morpholin-4-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
(Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone; (Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
[5-(4-Fluoro-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3-dimethyl-1 H- pyrazol-4-ylmethyl)-methyl-amide;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5-dimethyl-
1/-/-pyrazol-4-ylmethyl)-methyl-amide; 5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(1 ,3,5- trimethyl-1 /-/-pyrazol-4-ylmethyl)-amide;
3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid
(1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-methyl-amide;
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3- dimethyl-1 H-pyrazol-4-ylmethyl)-methyl-amide;
5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3- dimethyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
(2,5-Dimethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; 5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(1 ,3,5- trimethyl-1 r-/-pyrazol-4-ylmethyl)-amide;
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5- dimethyl-1H-pyrazol-4-ylmethyl)-methyl-amide; (2,4-Dimethyl-piperidin-1 -yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone; (3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperidin-1-yl)-methanone;
(4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
(4-Methyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
Azepan-1-yl-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(4-Benzoyl-piperazin-1-yl)-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; [5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Azepan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(3,4-dihydro- 2/-/-quinolin-1-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1- yl)-methanone; (4-Benzoyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl-methanone;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone;
Azepan-1-yl-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyhmidin-2- yl)-methanone;
Azepan-1-yl-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H- isoquinolin-2-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone; Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Azepan-1 -yl-(5-benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; [3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone; [5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-benzyl-piperazin- 1-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-methanone; [3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(2,6-Dimethyl-piperidin-1-yl)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(3, 6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
Azepan-1-yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
Azepan-1-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; Azepan-1-yl-[5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; [5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1 -yl- methanone;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3,4-Dihydro-1 /- -isoquinolin-2-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone; (4-Benzyl-piperazin-1-yl)-(3-chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyhmidin-2- yl)-methanone;
[3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl- methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)- methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1-yl)- methanone;
[3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone; [4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(4-Phenyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; (4-Benzyl-piperazin-1 -yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; [5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl-methanone; (3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl]-methanone;
Azepan-1 -yl-[5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; (4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1-yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
[3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperidin-1 -yl)-methanone; [3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(3,4-dihydro-
2H-quinolin-1 -yl)-methanone;
3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
[3-Chloro-5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1-yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
Azepan-1 -yl-(3-chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Azepan-1 -yl-[3-chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone; [5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-
1-yl)-methanone;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1-yl)-methanone;
Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; Morpholin-4-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
[3-Bromo-5-(4-bromo-thiophen-2-yl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2/-/- quinolin-1-yl)-methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl- methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone; 7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
(2,6-Dimethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
Azepan-1 -yl-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-phenyl-piperazin-1-yl)- methanone;
(2-Ethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj- methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
(5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6- yl)-methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
(4-Phenyl-piperazin-1-yl)-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
Pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-(2-hydroxy-ethyl)-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-1H- isoquinolin-2-yl)-methanone; (5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-ylj- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
3-yl]-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone; Azepan-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1 -yl- methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; 4-(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperazine-1-carboxylic acid ethyl ester;
(3,4-Dihydro-1 -/-isoquinolin-2-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
[4-(3-Chloro-phenyl)-piperazin-1-yl]-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(4-Methyl-piperidin-1-yl)-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
[4-(2-Methoxy-phenyl)-piperazin-1-yl]-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-methanone; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1 -yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(2,6-Dimethyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl-piperazin-1- yl)-methanone;
(4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl-piperazin-1-yl)- methanone; (Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone; 1-[5-(3-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperidine-4- carboxylic acid ethyl ester; 4-[5-(3-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperazine-1- carboxylic acid ethyl ester; (3,4-Dihydro-2H-quinolin-1 -yl)-[5-(3-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-[5-(3-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 ,3-dimethyl-1 H- pyrazol-4-ylmethyl)-methyl-amide;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5-trimethyl-
1 /-/-pyrazol-4-ylmethyl)-amide;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-imidazol-1-yl)- methanone; [7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
1 -[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-1 H-indole-3- carboxylic acid methyl ester;
[4-(4-Chloro-phenyl)-piperazin-1-yl]-[7-difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-piperidin-1-yl)- methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-5-methyl-1/-/- pyrazol-4-ylmethyl)-methyl-amide; 1-(7-Difluoromethyl-5-methyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperidine-4-carboxylic acid amide;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-ethyl-imidazol-1-yl)-methanone;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)- methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-[4-(furan-2-carbonyl)- piperazin-1 -yl]-methanone;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-3-methyl-1/-/- pyrazol-4-ylmethyl)-methyl-amide; [7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone; (7-Difluoromethyl-5-methyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1-yl-(7-difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1-methyl-1 -/- pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3-methyl-piperidin-1-yl)-methanone; (7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-ethyl-piperazin-1 -yl)-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5- trimethyl-1/-/-pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methyl-2H-pyrazole-3- carbonyl)-piperazin-1 -yl]-methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl-amide;
7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-3- methyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(4-pyrazol-1-yl- benzyl)-amide;
Azepan-1 -yl-(5-cyclopropyl-7-difluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yI]-methanone;
(3,4-Dihydro-2/-/-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)- methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
Azepan-1 -yl-(5-benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; (5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-2H-quinolin- 1-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone;
Azepan-1 -yl-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1-yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(3,4-Dihydro-1 /-/-isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; Azepan-1 -yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2/-/-quinolin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-benzyl-piperazin-
1-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone; (5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl- methanone; Morpholin-4-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
(4-Benzyl-piperazin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(4-Methyl-piperazin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
Azepan-1 -yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1 -yl- methanone;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; (4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(5-Furan-2-yl-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yi-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl)-methanone; (4-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yI)- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
Piperidin-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-ylj- methanone; (2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
Azepan-1 -yl-[5-(4-methoxyrphenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone; 5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1 -yl- methanone;
[5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pipehdin-1 -yl- methanone; Azepan-1 -yl-[5-(4-chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
[5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl- piperazin-1 -yl)-methanone; Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide; (4-Benzyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
MorphoJin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
38. A compound according to claim 36 or 37, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial.
39. A compound according to claim 36 or 37, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
40. A compound according to claim 36 or 37, which is an agent useful for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
41. A compound according to claim 36 or 37, which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
42. A compound according to claim 36 or 37, which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
43. A compound according to claim 36 or 37, which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
44. A compound according to claim 36 or 37, which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
45. A pharmaceutical composition comprising, as an active ingredient, at least one com- pound according to claim 36 or 37, together with one ore more pharmaceutically acceptable carriers or excipients.
46. The pharmaceutical composition according to claim 45 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
47. The pharmaceutical composition according to claim 45 or 46 in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to claim 36 or 37.
48. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial.
49. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
50. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceuti- cal composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
51. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceuti- cal composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
52. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
53. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
54. A use of a compound according to claim 36 or 37, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
55. A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11 βHSDI is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
56. The method according to claim 55 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
PCT/DK2004/000253 2003-04-11 2004-04-06 NEW PYRAZOLO[1,5-a] PYRIMIDINES DERIVATIVES AND PHARMACEUTICAL USE THEREOF WO2004089471A2 (en)

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Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007025892A1 (en) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag 11-beta-hydroxysteroid dehydrogenase-1-inhibitor-diabetes-type 2-1
WO2007051811A2 (en) * 2005-11-01 2007-05-10 Transtech Pharma Pharmaceutical use of substituted amides
US7217838B2 (en) 2005-01-05 2007-05-15 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
WO2008015270A1 (en) * 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, a process for their preparation and their use as medicine
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
WO2008056176A1 (en) * 2006-11-10 2008-05-15 Scottish Biomedical Limited Pyrazolopyrimidines as phosphodiesterase inhibitors
WO2008134035A1 (en) * 2007-04-27 2008-11-06 Panacos Pharmaceuticals, Inc. Alpha-unsubstituted arylmethyl piperazine pyrazolo[1,5-a] pyrimidine amide derivatives
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US7511175B2 (en) 2005-01-05 2009-03-31 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
EP2085398A1 (en) 2008-02-01 2009-08-05 Merz Pharma GmbH & Co. KGaA Pyrazolopyrimidines, a process for their preparation and their use as medicine
US7632838B2 (en) 2006-02-07 2009-12-15 Wyeth 11-beta HSD1 inhibitors
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2012078855A1 (en) * 2010-12-08 2012-06-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012139876A1 (en) 2011-04-14 2012-10-18 Merz Pharma Gmbh & Co. Kgaa Enteric formulations of metabotropic glutamate receptor modulators
EP2527337A1 (en) * 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2013087808A1 (en) 2011-12-15 2013-06-20 Merz Pharma Gmbh & Co. Kgaa Pharmaceutical composition comprising a pyrazolopyrimidme and cyclodextrin
WO2013087815A1 (en) 2011-12-15 2013-06-20 Merz Pharma Gmbh & Co. Kgaa Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof
US8513263B2 (en) 2008-10-22 2013-08-20 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
US8524894B2 (en) 2009-06-04 2013-09-03 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
WO2013144172A1 (en) 2012-03-29 2013-10-03 Boehringer Ingelheim International Gmbh Novel pyrazolopyrimidines
US8637526B2 (en) 2008-10-31 2014-01-28 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
CN103764166A (en) * 2011-06-22 2014-04-30 通用医疗公司 Treatment of proteinopathies
US8716345B2 (en) 2005-01-05 2014-05-06 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8791123B2 (en) 2009-07-09 2014-07-29 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
US8999998B2 (en) 2009-07-02 2015-04-07 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9227975B2 (en) 2008-09-22 2016-01-05 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2B]pyridazine compounds
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
EP3417912A1 (en) 2005-12-23 2018-12-26 ARIAD Pharmaceuticals, Inc. Bicyclic heteroaryl compounds
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
EP3373920A4 (en) * 2015-11-13 2019-07-17 Pietro Paolo Sanna Methods and compositions for treating alcohol use disorders
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
EP3576737A4 (en) * 2017-02-06 2021-04-21 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase activity
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US11155560B2 (en) 2018-10-30 2021-10-26 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US11426420B2 (en) 2017-04-07 2022-08-30 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
WO2022255408A1 (en) * 2021-06-02 2022-12-08 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[1,5-a]pyrimidine compound for the treatment of dermal disorders
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006522750A (en) * 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Combination therapy using 11β-hydroxysteroid dehydrogenase type 1 inhibitors and antihypertensive agents to treat metabolic syndrome and related diseases and disorders
WO2004089415A2 (en) * 2003-04-11 2004-10-21 Novo Nordisk A/S COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST
EP2362730A4 (en) 2008-11-21 2012-08-29 High Point Pharmaceuticals Llc Adamantyl benzamide compounds
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482555A (en) * 1982-03-16 1984-11-13 Farmitalia Carlo Erba S.P.A. Substituted 1H-pyrazolo (1,5-a) pyrimidines and process for their preparation
US5169850A (en) * 1990-01-22 1992-12-08 American Cyanamid Company N-(dialkylamino)methylene)-substituted pyrazolo(1,5-a)-pyrimidine-3-carboxamides and N-(dialkylamino)methylene-substituted-4,5-dihydropyrazolo-(1,5-a)-pyrimidine-3-carboxamides
US5602137A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh Pyrimidine compounds and their use as pharmaceuticals
US6124289A (en) * 1996-07-24 2000-09-26 Dupont Pharmaceuticals Co. Azolo triazines and pyrimidines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002053466A (en) * 2000-08-08 2002-02-19 Otsuka Pharmaceut Factory Inc Apoptosis regulating agent
JP2002212076A (en) * 2000-11-17 2002-07-31 Ishihara Sangyo Kaisha Ltd Prophylactic or therapeutic agent for diabetes comprising condensed heterocyclic compound or its salt
JP2003286171A (en) * 2002-03-28 2003-10-07 Sumitomo Pharmaceut Co Ltd Par inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482555A (en) * 1982-03-16 1984-11-13 Farmitalia Carlo Erba S.P.A. Substituted 1H-pyrazolo (1,5-a) pyrimidines and process for their preparation
US5169850A (en) * 1990-01-22 1992-12-08 American Cyanamid Company N-(dialkylamino)methylene)-substituted pyrazolo(1,5-a)-pyrimidine-3-carboxamides and N-(dialkylamino)methylene-substituted-4,5-dihydropyrazolo-(1,5-a)-pyrimidine-3-carboxamides
US5602137A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh Pyrimidine compounds and their use as pharmaceuticals
US6124289A (en) * 1996-07-24 2000-09-26 Dupont Pharmaceuticals Co. Azolo triazines and pyrimidines

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE COLUMBUS, OHIO, US; April 2003 (2003-04), XP002292075 & "Pharma Library Collection" April 2003 (2003-04), *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2002, XP002292071 & 2002, INTERCHIM INTERMEDIATES *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; April 2003 (2003-04), XP002292072 & "cHEMDIV. INC. PRODUCT LIBRARY" April 2003 (2003-04), *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; April 2003 (2003-04), XP002292073 & "AsInEx Express Gold collection" April 2003 (2003-04), *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; April 2003 (2003-04), XP002292074 & "ChemStar Product List" April 2003 (2003-04), *
DATABASE WPI Section Ch, Week 200412 Derwent Publications Ltd., London, GB; Class B02, AN 2004-112780 XP002292087 & JP 2003 286171 A (SUMITOMO SEIYAKU KK) 7 October 2003 (2003-10-07) -& JP 2003 286171 A (SUMITOMO PHARMACEUT CO LTD) 7 October 2003 (2003-10-07) *

Cited By (134)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US9133145B2 (en) 2004-04-29 2015-09-15 Abbvie Inc. Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US8314270B2 (en) 2005-01-05 2012-11-20 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
USRE41135E1 (en) 2005-01-05 2010-02-16 Abbott Laboratories Inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 enzyme
US9290444B2 (en) 2005-01-05 2016-03-22 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7217838B2 (en) 2005-01-05 2007-05-15 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7855308B2 (en) 2005-01-05 2010-12-21 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US8993632B2 (en) 2005-01-05 2015-03-31 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7511175B2 (en) 2005-01-05 2009-03-31 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8716345B2 (en) 2005-01-05 2014-05-06 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7528282B2 (en) 2005-01-05 2009-05-05 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
EP2527337A1 (en) * 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
WO2007025892A1 (en) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag 11-beta-hydroxysteroid dehydrogenase-1-inhibitor-diabetes-type 2-1
WO2007051811A2 (en) * 2005-11-01 2007-05-10 Transtech Pharma Pharmaceutical use of substituted amides
WO2007051811A3 (en) * 2005-11-01 2008-01-24 Novo Nordisk As Pharmaceutical use of substituted amides
EP3417912A1 (en) 2005-12-23 2018-12-26 ARIAD Pharmaceuticals, Inc. Bicyclic heteroaryl compounds
EP3747441A1 (en) 2005-12-23 2020-12-09 ARIAD Pharmaceuticals, Inc. Bicyclic heteroaryl compounds
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7632838B2 (en) 2006-02-07 2009-12-15 Wyeth 11-beta HSD1 inhibitors
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
US9464072B2 (en) 2006-04-07 2016-10-11 Abbvie Inc. Treatment of central nervous system disorders
EP2351568A2 (en) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Uses of dpp-iv inhibitors
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
EP2295439A1 (en) 2006-08-04 2011-03-16 Merz Pharma GmbH & Co. KGaA Substituted pyrazolopyrimidines, a process for their preparation and their use as medicine
WO2008015271A1 (en) * 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, a process for their preparation and the use as a medicine
TWI399376B (en) * 2006-08-04 2013-06-21 Merz Pharma Gmbh & Co Kgaa Substituted pyrazolopyrimidines, a process for their preparation and their use as medicine
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
US7985753B2 (en) 2006-08-04 2011-07-26 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-A]pyrimidines as metabotropic glutamate receptor modulators
WO2008015270A1 (en) * 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, a process for their preparation and their use as medicine
WO2008015269A1 (en) * 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolopyrimidines, a process for their preparation and their use as medicine
WO2008056176A1 (en) * 2006-11-10 2008-05-15 Scottish Biomedical Limited Pyrazolopyrimidines as phosphodiesterase inhibitors
WO2008134035A1 (en) * 2007-04-27 2008-11-06 Panacos Pharmaceuticals, Inc. Alpha-unsubstituted arylmethyl piperazine pyrazolo[1,5-a] pyrimidine amide derivatives
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
EP2085398A1 (en) 2008-02-01 2009-08-05 Merz Pharma GmbH & Co. KGaA Pyrazolopyrimidines, a process for their preparation and their use as medicine
US10011604B2 (en) 2008-09-22 2018-07-03 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9227975B2 (en) 2008-09-22 2016-01-05 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2B]pyridazine compounds
US10590139B2 (en) 2008-09-22 2020-03-17 Array Biopharma Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9796723B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US8865698B2 (en) 2008-10-22 2014-10-21 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
US11267818B2 (en) 2008-10-22 2022-03-08 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10774085B2 (en) 2008-10-22 2020-09-15 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US10047097B2 (en) 2008-10-22 2018-08-14 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9127013B2 (en) 2008-10-22 2015-09-08 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9676783B2 (en) 2008-10-22 2017-06-13 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US10005783B2 (en) 2008-10-22 2018-06-26 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9447104B2 (en) 2008-10-22 2016-09-20 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
US8513263B2 (en) 2008-10-22 2013-08-20 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8637526B2 (en) 2008-10-31 2014-01-28 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US8822452B2 (en) 2009-06-04 2014-09-02 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
US8524894B2 (en) 2009-06-04 2013-09-03 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
US8999998B2 (en) 2009-07-02 2015-04-07 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US10251889B2 (en) 2009-07-09 2019-04-09 Array BioPharm Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8791123B2 (en) 2009-07-09 2014-07-29 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9682979B2 (en) 2009-07-09 2017-06-20 Array Biopharma, Inc. Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors
US10758542B2 (en) 2009-07-09 2020-09-01 Array Biopharma Inc. Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors
US9782415B2 (en) 2009-07-09 2017-10-10 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9796724B2 (en) 2009-07-09 2017-10-24 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9750744B2 (en) 2010-05-20 2017-09-05 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9840519B2 (en) 2010-05-20 2017-12-12 Array Biopharma, Inc. Macrocyclic compounds as TRK kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9718822B2 (en) 2010-05-20 2017-08-01 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
US9902741B2 (en) 2010-05-20 2018-02-27 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
EP3366688A1 (en) * 2010-12-08 2018-08-29 The U.S.A. as represented by the Secretary, Department of Health and Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US9353117B2 (en) 2010-12-08 2016-05-31 The United States Of America As Represented By The Secretary, Dept. Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
CN103534255B (en) * 2010-12-08 2016-12-21 美国健康及人类服务部 Substituted pyrazolopyrimidine as glucocerebrosidase activator
KR101931224B1 (en) * 2010-12-08 2018-12-20 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 Substituted pyrazolopyrimidines as glucocerebrosidase activators
US20140249145A1 (en) * 2010-12-08 2014-09-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv Substituted pyrazolopyrimidines as glucocerebrosidase activators
AU2011338377B2 (en) * 2010-12-08 2016-08-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US9974789B2 (en) 2010-12-08 2018-05-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
KR20140010012A (en) * 2010-12-08 2014-01-23 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 Substituted pyrazolopyrimidines as glucocerebrosidase activators
CN103534255A (en) * 2010-12-08 2014-01-22 美国健康及人类服务部 Substituted pyrazolopyrimidines as glucocerebrosidase activators
WO2012078855A1 (en) * 2010-12-08 2012-06-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
US10925874B2 (en) 2010-12-08 2021-02-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
JP2013544893A (en) * 2010-12-08 2013-12-19 ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ Substituted pyrazolopyrimidines as glucocerebrosidase activators
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012139876A1 (en) 2011-04-14 2012-10-18 Merz Pharma Gmbh & Co. Kgaa Enteric formulations of metabotropic glutamate receptor modulators
CN103764166A (en) * 2011-06-22 2014-04-30 通用医疗公司 Treatment of proteinopathies
US9845327B2 (en) 2011-06-22 2017-12-19 The General Hospital Corporation Treatment of proteinopathies
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013087815A1 (en) 2011-12-15 2013-06-20 Merz Pharma Gmbh & Co. Kgaa Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof
WO2013087808A1 (en) 2011-12-15 2013-06-20 Merz Pharma Gmbh & Co. Kgaa Pharmaceutical composition comprising a pyrazolopyrimidme and cyclodextrin
US9029360B2 (en) 2012-03-29 2015-05-12 Boehringer Ingelheim International Gmbh Pyrazolopyrimidines as metabotropic glutamate 5 receptor antagonists
WO2013144172A1 (en) 2012-03-29 2013-10-03 Boehringer Ingelheim International Gmbh Novel pyrazolopyrimidines
US9815832B2 (en) 2013-02-19 2017-11-14 Pfizer Inc. Azabenzimidazole compounds
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9604984B2 (en) 2014-05-23 2017-03-28 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
US10669279B2 (en) 2014-08-06 2020-06-02 Pfizer Inc. Imidazopyridazine compounds
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US10077269B2 (en) 2014-08-06 2018-09-18 Pfizer Inc. Imidazopyridazine compounds
US10172861B2 (en) 2014-11-16 2019-01-08 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10813936B2 (en) 2014-11-16 2020-10-27 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-YL)-pyrazolo[1,5-A]pyrimidin-3-YL)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10799505B2 (en) 2014-11-16 2020-10-13 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10285993B2 (en) 2014-11-16 2019-05-14 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10907215B2 (en) 2015-10-26 2021-02-02 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10724102B2 (en) 2015-10-26 2020-07-28 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10378068B2 (en) 2015-10-26 2019-08-13 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10655186B2 (en) 2015-10-26 2020-05-19 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
EP3373920A4 (en) * 2015-11-13 2019-07-17 Pietro Paolo Sanna Methods and compositions for treating alcohol use disorders
US11484535B2 (en) 2016-04-04 2022-11-01 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10668072B2 (en) 2016-04-04 2020-06-02 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10588908B2 (en) 2016-04-04 2020-03-17 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US11191766B2 (en) 2016-04-04 2021-12-07 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
US11718589B2 (en) 2017-02-06 2023-08-08 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase
EP3576737A4 (en) * 2017-02-06 2021-04-21 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase activity
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
US11426420B2 (en) 2017-04-07 2022-08-30 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
US11155560B2 (en) 2018-10-30 2021-10-26 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
US11845754B2 (en) 2018-10-30 2023-12-19 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators
WO2022255408A1 (en) * 2021-06-02 2022-12-08 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[1,5-a]pyrimidine compound for the treatment of dermal disorders

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