The invention relates to compounds useful as PDE10A inhibitors. The invention also relates to pharmaceutical compositions, the use of said compounds as medicament for the treatment of diseases associated with the PDE10A enzyme.

Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and serve as secondary messengers in several cellular pathways. cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes, particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron. A principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. The 11 known families of PDEs are encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both. PDEIOA was identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDEIOA as the first member of the PDEIOA family of PDEs (Fujishige et al, J. Biol. Chem. 274: 18438- 18445, 1999; Loughney, K. et al, Gene 234: 109-117, 1999). The murine homologue has also been cloned (Soderling, S. et al, Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999) and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm. 261 :551- 557, 1999; Fujishige, K. et al., Eur. J. Biochem. 266: 1118-1127, 1999). There is a high degree of homology across species. The mouse PDEIOAI is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDEIOA for cAMP (Km = 0.05 μΜ) is higher than for cGMP (Km = 3 μΜ). However, the approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDEIOA is a unique cAMP- inhibited cGMPase (Fujishige et al, J. Biol. Chem. 274: 18438-18445, 1999).

PDEIOA also is uniquely localized in mammals relative to other PDE families. mRNA for PDEIOA is highly expressed only in testis and brain (Fujishige, K. et al, Eur J Biochem. 266: 1118-1127, 1999; Soderling, S. et al, Proc. Natl. Acad. Sci. 96:7071-7076, 1999; Loughney, K. et al., Gene 234: 109-117, 1999). These initial studies indicated that within the brain, PDEIOA expression is highest in the striatum (caudate and putamen), n. accumbens, and olfactory tubercle. More recently, a detailed analysis has been made of the expression pattern in rodent brain of PDEIOA mRNA (Seeger, T.F. et al., Abst. Soc. Neurosci. 26:345.10, 2000) and PDEIOA protein (Menniti, F.S., Stick, C.A., Seeger, T.F., and Ryan, A.M., immunohistochemical localization of PDEIOA in the rat brain. William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001).

Furthermore, PDEIOA expression has been observed in the pancreas. Pyrazolopyridine derivatives useful in the medical field are described in e.g. WO-A 2006/004188 where pyrazolopyridine derivatives are claimed as dual PDE4 / TNF-alpha inhibitors for the treatment of inflammatory disorders. Because of the emerging disease-related roles of PDEIOA, there is a continuing need for compounds which may be useful for treating and preventing disorders or diseases which respond to inhibition of PDEIOA.

Thus, an object of the present invention is to provide a new class of compounds as PDEIOA inhibitors which may be effective in the treatment of PDEIOA enzyme related diseases and may show improved pharmaceutically relevant properties including activity, ADMET properties and/or reduced side effects, typically potent and selective inhibitors of PDEIOA.

Accordingly, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt, tautomer, prodrug or metabolite thereof, wherein R ¹ , R ² , R ³ are independently selected from the group consisting of H; and C _1-4 alkyl, wherein Ci-4 alkyl is optionally substituted with one or more halogen, which are the same or different; m is 1, 2, or 3; n is 0, 1, 2, or 3;

X is a covalent single bond; O; C(O); C(0)NH; or HC(O);

R ⁴ is H; or T ¹ ; T ¹ is 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T ¹ is optionally substituted with one or more R ⁶ , which are the same or different;

R ⁶ is halogen; CN; C(0)OR ⁷ ; OR ⁷ ; C(0)R ⁷ ; C(0)N(R ⁷ R ^7a ); S(0) ₂ N(R ⁷ R ^7a ); S(0)N(R ⁷ R ^7a ); S(0) ₂ R ⁷ ; S(0)R ⁷ ; N(R ⁷ )S(0) ₂ N(R ^7a R ^7b ); SR ⁷ ; N(R ⁷ R ^7a ); N0 ₂ ; OC(0)R ⁷ ; N(R ⁷ )C(0)R ^7a ; N(R ⁷ )S(0) ₂ R ^7a ; N(R ⁷ )S(0)R ^7a ; N(R ⁷ )C(0)OR ^7a ; N(R ⁷ )C(0)N(R ^7a R ^7b ); OC(0)N(R ⁷ R ^7a ); oxo (=0), where the ring is at least partially saturated; Ci- ₆ alkyl; C ₂ - ₆ alkenyl; or C ₂ - ₆ alkynyl, wherein Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ⁷ , R ^7a , R ^7b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl, wherein Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl are optionally substituted with one or more halogen, which are the same or different, provided that the following compounds are excluded:

4-(difluorom ethyl)- 1 -methyl-6-( 1 -methyl- lH-pyrazol-4-yl)- lH-pyrazolo[3 ,4-b]pyridine; 4-(difluorom ethyl)- 1 , 3 -dimethyl-6-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-pyrazolo [3 ,4-b]pyri dine; 4-(difluoromethyl)-6-( 1 -ethyl- lH-pyrazol-4-yl)- 1 -methyl- 1 H-pyrazolo[3 ,4-b]pyridine;

4-(difluoromethyl)-6-( 1 , 5 -dimethyl- 1 H-pyrazol-4-yl)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyri dine; 4-(difluorom ethyl)- 1 -ethyl-6-( 1 -methyl- lH-pyrazol-4-yl)- lH-pyrazolo[3 ,4-b]pyri dine;

4-(difluoromethyl)-l-ethyl-3-methyl-6-(l -methyl- lH-pyrazol-4-yl)-l H-pyrazolo [3, 4- b]pyridine;

4-(difluoromethyl)-6-( 1 , 5 -dimethyl- 1 H-pyrazol-4-yl)- 1 , 3 -dimethyl- 1 H-pyrazolo [3 ,4- b]pyridine;

4-(difluoromethyl)-6-(l,5-dimethyl-lH-pyrazol-4-yl)-l-ethyl- lH-pyrazolo[3,4-b]pyridine; 4-(difluorom ethyl)- 1 -ethyl-6-( 1 -ethyl- lH-pyrazol-4-yl)- lH-pyrazolo[3 ,4-b]pyridine;

4-(difluoromethyl)-6-( 1 -ethyl-5-methyl- lH-pyrazol-4-yl)- 1 -methyl- 1 H-pyrazolo[3 ,4- b]pyridine;

4-(difluoromethyl)-6-( 1 -ethyl- lH-pyrazol-4-yl)- 1 ,3 -dimethyl- lH-pyrazolo[3 ,4-b]pyri dine; 4-(difluorom ethyl)- 1 -ethyl-6-( 1 -ethyl- lH-pyrazol-4-yl)-3 -methyl- lH-pyrazolo[3 ,4- b]pyridine;

4-(difluoromethyl)-6-(l-ethyl-5-methyl-lH-pyrazol-4-yl)-l,3- dimethyl-lH-pyrazolo[3,4- b]pyridine; 4-(difluorom ethyl)- 1 -ethyl-6-( 1 -ethyl-5-methyl- 1 H-pyrazol-4-yl)- lH-pyrazolo[3 ,4- b]pyridine;

4-(difluoromethyl)-3 -methyl-6-( 1 -methyl- lH-pyrazol-4-yl)- 1 -propyl- lH-pyrazolo[3 ,4- b]pyridine;

4-(difluoromethyl)-6-(l,5-dimethyl-lH-pyrazol-4-yl)-l-eth yl-3-methyl-lH-pyrazolo[3,4- b]pyridine;

l-butyl-4-(difluoromethyl)-3-methyl-6-(l -methyl- lH-pyrazol-4-yl)-lH-pyrazolo[3, 4- b]pyridine;

4-(difluoromethyl)-6-( 1 -ethyl- lH-pyrazol-4-yl)-3 -methyl- 1 -propyl- lH-pyrazolo[3 ,4- b]pyridine;

4-(difluorom ethyl)- 1 -ethyl-6-( 1 -ethyl-5 -methyl- 1 H-pyrazol-4-yl)-3 -methyl- 1 H-pyrazolo [3 ,4- b]pyridine;

1 -butyl-4-(difluoromethyl)-6-( 1 , 5 -dimethyl- 1 H-py razol-4-yl)-3 -methyl- 1 H-pyrazolo [3 ,4- b]pyridine;

4-(difluoromethyl)-6-( 1 -ethyl-5-methyl- lH-pyrazol-4-yl)-3 -methyl- 1 -propyl- 1H- pyrazolo[3,4-b]pyridine;

l-butyl-4-(difluoromethyl)-6-(l-ethyl-lH-pyrazol-4-yl)-3- methyl-lH-pyrazolo[3,4- b]pyridine; and

l-butyl-4-(difluoromethyl)-6-(l-ethyl-5-methyl-lH-pyrazol -4-yl)-3-methyl-lH-pyrazolo[3,4- b]pyridine.

The compounds excluded from the scope of the present invention are known catalogue compounds (Chembridge, Ambinter, Princeton, Chem T&I, Vitas, Interchim and/or TimTec) without any reference to the use as medicament and the treatment of disorders and conditions associated with the PDE10A enzyme and thus are excluded only inasfar as compounds of the present invention as such are concerned.

In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.

Within the meaning of the present invention the terms are used as follows:

"Alkyl" means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified. "Alkenyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified. "Alkynyl" means a straight-chain or branched hydrocarbon chain, that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.

"Ci-4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. - CH ₂ -, -CH2-CH2-, -CH(CH ₃ )-, -CH2-CH2-CH2-, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C ₁ -4 alkyl carbon may be replaced by a substituent as further specified. The term "C ₂ -4 alkyl" is defined accordingly. "Ci-6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C ₁ -4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, - C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci-6 alkyl carbon may be replaced by a substituent as further specified. The term "C _{1 -5} alkyl" is defined accordingly.

"C ₂ -6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH ₂ , -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ -CH ₃ , -CH=CH- CH=CH ₂ , or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C ₂ -6 alkenyl carbon may be replaced by a substituent as further specified. The terms "C ₂ -4 alkenyl" and "C ₂ -5 alkenyl" are defined accordingly.

"C ₂ -6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH ₂ -C≡CH, CH ₂ -CH ₂ -C≡CH, CH ₂ -C≡C-CH ₃ , or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C ₂ -6 alkynyl carbon may be replaced by a substituent as further specified. The terms "C ₂ -4 alkynyl" and "C ₂ -5 alkynyl" are defined accordingly.

"C _{3 -} 7 cycloalkyl" or "C _{3 -} 7 cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified. The term "C ₃ - ₆ cycloalkyl is defined accordingly. "Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

"3 to 7 membered heterocyclyl" or "3 to 7 membered heterocycle" means a ring with 3, 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom and up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0) ₂ -), oxygen and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 3 to 7 membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "4 to 5 membered heterocyclyl" or "4 to 5 membered heterocycle" is defined accordingly. The term "5 to 6 membered heterocyclyl" or "5 to 6 membered heterocycle" is defined accordingly.

"3 to 7 membered saturated heterocyclyl" or "3 to 7 membered saturated heterocycle" means "3 to 7 membered heterocyclyl" or a "3 to 7 membered heterocycle" which is saturated. The term "4 to 5 membered saturated heterocyclyl" or "4 to 5 membered saturated heterocycle" is defined accordingly.

"8 to 11 membered heterobicyclyl" or "8 to 11 membered heterobicycle" means a heterocyclic system of two rings with 8 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0) ₂ -), oxygen and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 8 to 11 membered heterobicycles are imidazo[2, l-b][l,3]oxazole, imidazo[2, l-b][l,3]thiazole, indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 8 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.

"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, - S(0) ₂ -), oxygen and nitrogen (including =N(0)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.

Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.

In preferred embodiments of the present invention, the substituents of formula (I) independently have the following meaning. Hence, one or more of the substituents can have the preferred or more preferred meanings given below.

Preferably, R ¹ is H; CH ₃ ; or CH ₂ CH ₃ . More preferably, R ¹ is CH ₃ .

Preferably, R ² and R ³ are independently selected from the group consisting of H; and CH ₃ . More preferably, R ² and R ³ are CH ₃ .

Preferably, m is 1 or 2.

Preferably, n is 0, 1, or 2. More preferably, n is 0 or 1.

Preferably, X is O.

Preferably, R ⁴ is T ¹ . More preferably, T ¹ is 2-Quinolinyl; 2-Pyridyl; or Imidazo[l,2-a]pyridin- 2-yl and wherein T ¹ is unsubstituted or substituted with one or more R ⁶ , which are the same or different. Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.

Preferred specific compounds of the present invention are selected from the group consisting of

4-(Difluoromethyl)-6-(5 -ethyl- 1 -methyl- lH-pyrazol-4-yl)- 1 -ethyl-3 -methyl- lH-pyrazolo[3 , 4-b]pyridine;

4-(Difluoromethyl)-6-( 1 , 5 -dimethyl- 1 H-pyrazol-4-yl)- 1 -ethyl-3 -methyl- 1 H-pyrazolo [3 , 4- b]pyridine;

2-({2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1 H-pyrazolo [3, 4-b] pyridin- 1 -yljethoxy }methyl)quinoline;

2-{2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1 H-pyrazolo [3, 4- b]pyridin-l -yljethoxy }quinoline;

4-[4-(Difluoromethyl)-l-(2-{imidazo[l,2-a]pyridin-2-ylmethox y}ethyl)-3-methyl-lH- pyrazolo [3 ,4-b]pyridin-6-yl] - 1 , 5 -dimethyl- 1 H-pyrazole;

2-({2-[4-(Difluoromethyl)-6-(l,5-dimethyl-lH-pyrazol-4-yl)-3 -methyl-lH-pyrazolo[3, 4- b]pyridin- 1 -yljethoxy }methyl)pyri dine;

2- [4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4- b]pyridin-l-yl]-N-(quinolin-2-yl)acetamide; and

3- [4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4- b]pyridin-l-yl]-N-(quinolin-2-yl)propionamide.

Prodrugs of the compounds of the invention are also within the scope of the present invention. "Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods. Metabolites of compounds of formula (I) are also within the scope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, e.g. enantiomers, cis/trans isomers, conformers and the like.

Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.

If desired, the isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials. In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art , for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The present invention provides compounds of general formula (I) as PDE10A inhibitors. As described before, Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and serve as secondary messengers in several cellular pathways.

The cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron. A principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11 known families of PDEs encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both.

PDEIOA is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDEIOA as the first member of the PDEIOA family of PDEs (Fujishige et al, J. Biol. Chem. 274: 18438- 18445, 1999; Loughney, K. et al, Gene 234: 109-117, 1999). The murine homologue has also been cloned (Soderling, S. et al, Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999) and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm. 261 :551- 557, 1999; Fujishige, K. et al., Eur. J. Biochem. 266: 1118-1127, 1999). There is a high degree of homology across species. The mouse PDEIOAI is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDEIOA for cAMP (Km = 0.05 μΜ) is higher than for cGMP (Km = 3 μΜ). However, the approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDEIOA is a unique cAMP- inhibited cGMPase (Fujishige et al, J. Biol. Chem. 274: 18438-18445, 1999).

PDEIOA also is uniquely localized in mammals relative to other PDE families. mRNA for PDEIOA is highly expressed only in testis and brain (Fujishige, K. et al, Eur J Biochem. 266: 1118-1127, 1999; Soderling, S. et al, Proc. Natl. Acad. Sci. 96:7071-7076, 1999; Loughney, K. et al., Gene 234: 109-117, 1999). These initial studies indicated that within the brain PDEIOA expression is highest in the striatum (caudate and putamen), n. accumbens, and olfactory tubercle. More recently, a detailed analysis has been made of the expression pattern in rodent brain of PDEIOA mRNA (Seeger, T.F. et al, Abst. Soc. Neurosci. 26:345.10, 2000) and PDEIOA protein (Menniti, F.S., Stick, C.A., Seeger, T.F., and Ryan, A.M., immunohistochemical localization of PDEIOA in the rat brain. William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001).

Furthermore, PDEIOA expression has been observed in the pancreas. Accordingly, another aspect of the present invention is a compound of formula (I)

(I) or a pharmaceutically acceptable salt, tautomer, prodrug or metabolite thereof, wherein R ¹ , R ² , R ³ are independently selected from the group consisting of H; and C _1-4 alkyl, wherein Ci-4 alkyl is optionally substituted with one or more halogen, which are the same or different; m is 1, 2, or 3; n is 0, 1, 2, or 3;

X is a covalent single bond; O; C(O); C(0)NH; or HC(O);

R ⁴ is H; or T ¹ ;

T ¹ is 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T ¹ is optionally substituted with one or more R ⁶ , which are the same or different;

R ⁶ is halogen; CN; C(0)OR ⁷ ; OR ⁷ ; C(0)R ⁷ ; C(0)N(R ⁷ R ^7a ); S(0) ₂ N(R ⁷ R ^7a ); S(0)N(R ⁷ R ^7a ); S(0) ₂ R ⁷ ; S(0)R ⁷ ; N(R ⁷ )S(0) ₂ N(R ^7a R ^7b ); SR ⁷ ; N(R ⁷ R ^7a ); N0 ₂ ; OC(0)R ⁷ ; N(R ⁷ )C(0)R ^7a ; N(R ⁷ )S(0) ₂ R ^7a ; N(R ⁷ )S(0)R ^7a ; N(R ⁷ )C(0)OR ^7a ; N(R ⁷ )C(0)N(R ^7a R ^7b ); OC(0)N(R ⁷ R ^7a ); oxo (=0), where the ring is at least partially saturated; Ci- ₆ alkyl; C ₂ - ₆ alkenyl; or C ₂ - ₆ alkynyl, wherein Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ⁷ , R ^7a , R ^7b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl, wherein Ci_6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl are optionally substituted with one or more halogen, which are the same or different, for use as a medicament, with preferred compounds as mentioned above.

Another aspect of the present invention is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of formula (I) as described for compounds for use as a medicament together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

Another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of formula (I) as described for compounds for use as a medicament for use in a method of treating or preventing diseases and disorders associated with the PDEIOA enzyme.

Another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient, preferably human patient, in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the PDEIOA enzyme, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of formula (I) as described for compounds for use as a medicament or a pharmaceutically acceptable salt thereof. Preferred diseases, disorders or conditions associated with the PDEIOA enzyme are further described below.

Examples are psychotic disorders such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; movement disorders including Parkinson's disease and Huntington's disease.

Examples of psychotic disorders that may be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type. Examples of movement disorders that can be treated according to the present invention include, but are not limited to, Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor. Other disorders that may be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.

A further example is an anxiety disorder or condition in a mammal, including a human. Examples of anxiety disorders that can be treated according to the present invention include, but are not limited to, panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder. A further example is a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human.

Drug addiction, as used herein, means an abnormal desire for a drug and is generally characterized by a compulsion to take the desired drug and episodes of intense drug craving.

A further example is a symptom a deficiency in attention and/or cognition in a mammal, including a human.

Examples of disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present invention are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; and age-related cognitive decline.

A further example is a mood disorder or mood episode in a mammal, including a human. Examples of mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.

A further example is a neurodegenerative disorder or condition in a mammal, including a human. Examples of neurodegenerative disorders and conditions that can be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.

Preferably, the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.

Preferably, the neurodegenerative disorder or condition is Huntington's disease.

Other disorders that may be treated according to the present invention are metabolic syndrome and diabetes. An example of diabetes is type 2 diabetes.

Accordingly, examples are: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age- related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post- psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; dyskinesia associated with dopamine agonist therapy; restless leg syndrome; essential tremor; obsessive/compulsive disorders; Tourette's syndrome and other tic disorders; panic disorder; agoraphobia, a specific phobia; social phobia; acute stress disorder; generalized anxiety disorder; drug addiction, for example an alcohol, amphetamine, cocaine or opiate addiction; metabolic syndrome; diabetes, for example diabetes is type 2 diabetes.

Preferred examples are Schizophrenia, Deficiency in attention / cognition, Huntington's disease, Parkinson's disease and dyskinesia associated with dopamine agonist therapy.

Concerning the above diseases, disorders or conditions associated with the PDEIOA enzyme reference is made to Cantin et al. "PDE-10A inhibitors as insulin secretagogues", Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869 - 2873; Rodefer JS et al, Eur J Neurosci. 2005 Feb, 21(4): 1070-6; Grauer SM et al, J Pharmacol Exp Ther. 2009 Nov, 331(2):574-90, Epub 2009 Aug 6; Siuciak JA et al, Neuropharmacology 2006 Aug, 51(2):386-96, Epub 2006 Jun 15; Schmidt CJ et al, J Pharmacol Exp Ther. 2008 May, 325(2):681-90, Epub 2008 Feb 20; Threlfell S et al, J Pharmacol Exp Ther. 2009 Mar, 328(3):785-95, Epub 2008 Dec 4; Giampa C et al., Neurobiol Dis. 2009 Jun, 34(3):450-6, Epub 2009 Mar 9; Kehler J et al, Expert Opin Ther Pat. 2009 Dec, 19(12): 1715-25.

"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other PDE10A inhibitors.

The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to enable delivery via syringe. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

Starting materials for the synthesis of preferred embodiments of the invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR or can be synthesized using known methods by one skilled in the art. In general, several methods are applicable to prepare compounds of the present invention. In some cases various strategies can be combined. Sequential or convergent routes may be used.

General experimental schemes Some compounds of formula (I) where X is a covalent single bond, n = 0 and R ⁴ = H are commercially available. Alternatively, compounds of formula (I) can be conveniently prepared from pyrazolopyridine (II), according to Scheme 1 below:

X = C(0)NH

Scheme 1: Preparation of a compound of formula (I)

Compounds of formula (I), where X=0 and m=2 can be accessed via silyl ether (III), which is prepared by reaction of pyrazolopyridine (II) and a reagent such as (2-bromoethoxy)(tert- butyl)dimethylsilane in the presence of a suitable base, e.g. sodium hydride in a solvent such as dimethylformamide. Treatment of silyl ether (III) using a reagent such as hydrochloric acid affords alcohol (IV), which can be converted into a compound of formula (I), where X=0 and m=2, by reaction with electrophile (V), where LG denotes a suitable leaving group such as chloro, bromo or alkyl sulfonate, in the presence of a base e.g. sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. A compound of formula (I), where X=C(0) H, can be prepared from acid (VI) and amine (VII) using reagents such as dimethylaminopropyl-ethylcarbodi-imide (EDC), optionally in the presence of hydroxybenzotriazole (HOBt) in a solvent such as dimethylformamide. Acid (VII) is conveniently prepared from pyrrolopyridine (II) using a reagent such as ethyl bromoacetate, ethyl bromopropionate or ethyl bromobutyrate in the presence of a base such as sodium hydride in a suitable solvent e.g. dimethylformamide, followed by ester hydrolysis.

A route to pyrazolopyridine (II) is described in Scheme 2 below:

Scheme 2: Preparation of pyrazolopyridine (II)

Hydroxypyrazolopyridine (X) is prepared by reaction of diethyl oxalacetate sodium salt (VIII) and l-tert-butyl-3-alkyl pyrazol-5-ylamine (IX) in a solvent such as aqueous acetic acid. Hydroxypyrazolopyridine (X) is converted to triflate (XI) by treatment with a triflating reagent such as trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfo namide or triflic anhydride in the presence of a base e.g. triethylamine in a suitable solvent, for example dichloromethane, optionally with a catalyst such as dimethylaminopyridine. Pyrazole-ester (XIII) is prepared by Suzuki coupling of triflate (XI) with boronate (XII) in the presence of a catalyst e.g. tetrakis(triphenylphosphinyl)palladium and a suitable base such as cesium carbonate in a solvent mixture, for example dioxane / water. Alcohol (XIV) is prepared by reduction of pyrazole-ester (XIII) with a reagent such as lithium aluminium hydride in a solvent such as tetrahydrofuran. Oxidation of alcohol (XIV) with a reagent such as Dess- Martin periodinane in a solvent such as dichloromethane produces aldehyde (XV), which can be converted to difluoride (XVI) using a suitable reagent e.g. dimethyl aminosulfur trifluoride. Pyrazolopyridine (II) is accessed by treatment of difluoride (XVI) with an acid such as formic acid, optionally with heating the reaction. Experimental Examples

The following examples are provided to further illustrate details for the preparation and biological evaluation of the compounds of the present invention. The examples are not intended to limit the scope of the invention.

Materials

Human and rat phosphodiesterase PDEIOA (catalytic site) was cloned and purified at Evotec Ltd, UK. Human PDE1B (CatJ: 60011), PDE3A (CatJ: 60030), and PDE4D (CatJ: 60043) were purchased from BPS Bioscience. Reference inhibitors like Tofisopam (Sigma, CatJ: T8200), IBMX (Fluka, Cat.#: 58620), Milrinone (Tocris CatJ: 1504) and Rolipram (Tocris, CatJ: 0905) were obtained from different vendors. The assay was performed in black 384 well plates (Greiner; CatJ: 784076). Standard reagents like Tris buffer (CatJ: 1.08382.2500), MgC12 (CatJ: TA523833 014.1), and Bovine Serum Albumin (CatJ: 1.12018.0100) were purchased from Merck. CaC12 (CatJ: C4901), EGTA (CatJ: E3889), EDTA (CatJ: E5134), Calmodulin (CatJ: P1431), and Brij-35 (CatJ: B4184) were obtained from Sigma and dimethylsulfoxide (CatJ: 41647) was purchased from Fluka.

Methods

Phosphodiesterases (PDEs) hydrolyse the intracellular second messenger signaling molecules cAMP and cGMP. To screen substances for inhibition of cyclic nucleotide hydrolysis by PDEIOA and family members like PDE1B, 3A, and 4D, a competitive fluorescence polarization immunoassay was approached using the TranscreenerTM PDE Assay Kit by BellBrook Labs according the manufacturer instructions. In this assay format an observed fluorescence polarisation signal is reduced upon displacement of an AMP/GMP Alexa633 tracer bound to an antibody by AMP/GMP substrate generated by PDEIOA.

The effect of PDE inhibitors was determined by assaying a fixed amount of enzyme in the presence of varying substance concentrations. The cyclic nucleotide substrate concentration used in the assay was the Km concentration determined for different PDEs (PDEIOA: 3μΜ cGMP; PDE1B: Ι μΜ cGMP; PDE3A: 0.1 μΜ cGMP; PDE4D: 2μΜ cAMP). The enzyme reaction was performed in 384 well plates in a total volume of 15μ1 containing 5μ1 enzyme solution, 5μ1 compound dilution and 5μ1 Detection mix (substrate, Alexa633 tracer and AMP/GMP antibody) in assay buffer (50mM Tris, pH 7.5, lmM EGTA, 5mM MgC12„ 0.01% BSA). Test substances and reference inhibitors like Tofisopam, IBMX, Milrinone or Rolipram were titrated in 100% DMSO at 100 times final concentration and diluted twice in assay buffer to reach final concentration. Compounds were titrated in a seven-point dilution plus control and triplicates of each compound concentration were prepared. The reaction was initiated by adding Detection mix to enzyme and compound, followed by an incubation for 30 min at 30-37 °C resulting in a substrate turnover < 25%. To stop the reaction 20mM EDTA including Brij-35 was added and equilibrated for 60 min at RT. The measurement of the fluorescent polarisation signal was performed with an emission of 620 nm and an excitation of 688 nm using the En Vision (2104 Multilabel Reader) from PerkinElmer. IC50 values of substances and reference inhibitors were calculated using the "Dose-response one site model 205" of the Excel fit programme. Percentage of inhibition was calculated in relation to reference inhibitors like Tofisopam, IBMX, Milrinone or Rolipram assuming them to be full inhibitors.

The specificity of the fluorescence polarisation signal was controlled in a counter assay. In this assay format the compound dilution was added to the PDE1 OA-reaction mix after stopping the reaction with EDTA and the fluorescence polarisation signal was measured as described above.

Examples:

The following Examples serve to illustrate the invention without limiting its scope. Abbreviations used are those conventional in the art.

In the procedures that follow, after each starting material, reference to a description is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to. NMR Methods

NMR Spectroscopy was determined using either a Bruker AVANCE 400 MHz NMR, a Bruker DPX 250 MHz NMR, a Bruker DPX 360 MHz NMR or a Bruker DRX 500 MHz NMR. Values are reported as shifts (in ppm), with zero corresponding to tetramethylsilane as an internal standard. Chemical shifts are reported in ppm ([delta]) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90 C. When more than one conformer was detected the chemical shifts for the most abundant one are reported.

Analytical HPLC-MS

Method A

Column: Atlantis dC18 50mm x 3 mm; 3 μιη

Mobile phase A: 0.1% Formic acid in Water

Mobile phase B: 0.1% Formic acid in Acetonitrile

Flow rate: 0.8 ml/min.

Detection wavelength: Diode array Spectrum 1 max (with scan in the region 210-350nm) Sampling rate: 5

Column temperature: 35°C

Injection volume: 5 μΐ

Eluent: 0 mins 95% solvent A + 5% solvent B, 0.2 mins 95% solvent A + 5% solvent B; 0.2mins to 3.2mins constant gradient from 95% solvent A + 5% solvent B to 5% solvent A and 95% solvent B; 5mins 5% solvent A and 95% solvent B; 5mins to 5.2 mins constant gradient from 5% solvent A and 95% solvent B to 95% solvent A + 5% solvent B; 5.5mins 95% solvent A and 5% Solvent B.

MS detection using Waters LCT or LCT Premier, or ZQ or ZMD

UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV

Method B

Column: Waters Atlantis dC18 (2.1 xlOOmm, 3um column) Flow rate: 0.6 ml/min

Solvent A: 0.1% Formic acid / water

Solvent B: 0.1% Formic acid / acetonitrile

Injection Volume: 3 μΐ

Column temperature: 40°C

UV Detection wavelength: 215nm

Eluent: 0 mins to 5 mins, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5 mins to 5.4 mins, 100% solvent B; 5.4 mins to 5.42 mins, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 5.42 mins to 7.00 mins, 95% solvent A + 5% solvent B

Compound Naming

All compounds are named either using ACD Labs 10.0 naming software (which conforms to IUPAC naming protocols) or by analogy to conventional nomenclature familiar to a skilled practitioner. Some compounds are isolated as TFA salts, which is not reflected by the chemical name. Within the meaning of the present invention the chemical name represents the compound in neutral form as well as its TFA salt or any other salt, especially pharmaceutically acceptable salt, if applicable.

Flash silica gel chromatography was carried out on silica gel 230-400 mesh or on pre-packed silica cartridges.

List of Abbreviations br s broad singlet

Boc tert-butoxycarbonyl

C degrees Celcius

CDC13 deuterated chloroform

d doublet

DCM dichloromethane

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

EDCI.HC1 dimethylaminopropyl-ethylcarbodi-imide hydrochloride Eq. equivalent

EtOAc ethyl acetate

EtOH ethanol

FCC flash column chromatography

HC1 hydrochloric acid

HOBt 1 -hydroxybenzotriazole

HBTU O-benzotriazol- 1 -yl-Ν,Ν,Ν ^" ,ΙΝΓ -tetramethyluronium tetrafluorob orate

HPLC-MS high performance liquid chromatography and mass spectrometry

Li OH lithium hydroxide

MeOH methanol

MeOD deuterated methanol

m multiplet

ml millilitre

mmol/M millimole/molar

MW molecular weight

MR nuclear magnetic resonance

q quartet

Rt retention time

s singlet

t triplet

THF tetrahydrofuran

TLC thin layer chromatography

Intermediate 1: Ethyl l-tert-butyl-6-hydroxy-3 -methyl- lH-pyrazolo [3,4-b]pyridine-4- carboxylate

A stirred solution of diethyl oxalacetate sodium salt (504 mg, 2.4 mmol) and l-tert-butyl-3- methyl pyrazol-5-ylamine (250 mg, 1.63 mmol) in a mixture of acetic acid / water (0.3 mL, 6 mL), was heated at 80 C for 4 h. The reaction mixture was cooled to room temperature and the solid precipitate was filtered off then washed with water (50 mL). The solid was dissolved in ethyl acetate (50 mL) and dried over sodium sulfate. The organic layer was evaporated in vacuo to afford the title compound as a pale yellow solid (240 mg, 53%). HPLC-MS (Method A): MH+ requires m/z=278; Found m/z=278, Rt 3.63 min (100%). 1H MR (300 MHz, CDC13) δ 9.46 (br, 1H), 6.78 (s, 1H), 4.47-4.40 (q, 2H), 2.49 (s, 3H), 1.72 (s, 9H) and 1.44- 1.40 (t, 3H).

Intermediate 2: Ethyl l-tert-butyl-3-methyl-6-[(trifluoromethane)sulfonyloxy]-lH- pyrazolo[3,4-b]pyridine-4-carbox late

To a suspension of ethyl l-tert-butyl-6-hydroxy-3 -methyl- lH-pyrazolo [3,4-b]pyridine-4- carboxylate (prepared in an analogous manner to Intermediate 1, 2.0 g, 7.20 mmol), trifluoro- N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.6 g, 7.27 mmol) and DMAP (88 mg, 0.72 mmol) in dry DCM (50 mL), was added triethylamine (1.01 mL, 7.92 mmol). The resulting reaction mixture was stirred at room temperature for 42 h and concentrated in vacuo. The residue was purified by FCC eluting with 0-2% ethyl acetate in hexane to afford the title compound (2.51 g, 85%). HPLC-MS (Method A): MH+ requires m/z 410; Found m/z=410, Rt 4.82 min (100%). 1H MR (300 MHz, CDC13) δ 7.33 (s, 1H), 4.53-4.46 (q, 2H), 2.68 (s, 3H), 1.77 (s, 9H) and 1.49-1.44 (t, 3H).

Intermediate 3: Ethyl l-tert-butyl-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b] pyridine-4-carboxylate

To a stirred solution of ethyl l-tert-butyl-3-methyl-6-[(trifluoromethane)sulfonyloxy]-lH- pyrazolo[3,4-b]pyridine-4-carboxylate (Intermediate 2, 2.5 g, 6.10 mmol) in a mixture of dioxane: water (4: 1, 200 mL: 50 mL) was added l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.62 g, 7.32 mmol) followed by cesium carbonate (5.0 g, 15.25 mmol). Argon was bubbled into the resulting mixture for 30 min at room temperature and tetrakis(triphenylphosphinyl)palladium (705 mg, 0.61 mmol) was added. The reaction mixture was heated at 90 C for 3h. The mixture was cooled to room temperature, concentrated in vacuo (to remove the dioxane) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC eluting with 0-30% ethyl acetate in hexane to afford the title compound as a light yellow solid (1.2 g, 57%). FIPLC-MS (Method A): MH+ requires m/z = 356; Found m/z=356, Rt = 4.31 min (100%). 1H MR (300 MHz, CDC13) δ: 7.93 (s, 1H), 7.69 (s, 1H), 4.53-4.45 (q, 2H), 3.88 (s, 3H), 2.73 (s, 3H), 2.65 (s, 3H), 1.83 (s, 9H) and 1.49-1.44 (t, 3H).

Intermediate 4: [l-Tert-butyl-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- lH-pyrazolo [3, 4- b] pyridin-4-yl] methanol

To a stirred solution of ethyl l-tert-butyl-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b] pyridine-4-carboxylate (prepared in an analogous manner to Intermediate 3, 5.5 g, 15.5 mmol) in dry THF (200 mL) under argon at 0 C was added dropwise lithium aluminium hydride solution (15.8 mL, 31.0 mmol, 2M in THF). The reaction warmed to room temperature and stirred for 1 h. The mixture was cooled to 0 C and quenched by slow addition of a mixture of THF: water (450 mL: 50 mL) followed by aqueous sodium hydroxide solution (2M). The solid formed was filtered off and washed with ethyl acetate (50 mL). The filtrate was evaporated, water (100 mL) was added to the residue and the aqueous was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo and triturated with pentane to afford the title compound as a white solid (4.4 g, 92%). HPLC-MS (Method A): MH+ requires m/z=314; Found m/z=314, Rt 3.34 min (100%). lH MR (300 MHz, CDC13) δ 7.89 (s, 1H), 7.32 (s, 1H), 5.10-5.08 (d, 2H), 3.84 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H) and 1.82 (s, 9H). Intermediate 5: l-Tert-butyl-6-(l, 5-dimethyl-lH-pyrazol-4-yl)-3-methyl-lH-pyrazolo[3,4- b]pyridine-4-carbaldehyde

To a stirred solution of [l-tert-butyl-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b] pyridin-4-yl] methanol (Intermediate 4, 1.0 g, 3.2 mmol) in DCM (50 mL) at 0 C was added l, l, l-triacetoxy-l, l-dihydro-l,2-benziodoxol-3-one (Dess-Martin Periodinane, 1.63 g, 3.84 mmol). The resulting reaction mixture was warmed to room temperature and stirred for 4 h. Aqueous sodium hydroxide solution was added (5%, 50 mL) and the mixture was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow solid, which was used without further purification (0.8 g, 80%). HPLC-MS (Method A): MH+ requires m/z=312; Found m/z=312, Rt 3.99 min (92%). 1H MR (300 MHz, CDC13) δ 10.48 (s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 3.89 (s, 3H), 2.77 (s, 3H), 2.75 (s, 3H) and 1.85 (s, 9H).

Intermediate 6: 4-[l-Tert-butyl-4-(difluoromethyl)-3-methyl-lH-pyrazolo[3, 4-b]pyridin-6- yl]-l, 5 -dimethyl- lH-pyrazole

1 -Tert-butyl-6-( 1 , 5 -dimethyl- 1 H-pyrazol-4-yl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-4- carbaldehyde (Intermediate 5, 700 mg, 2.25 mmol) was placed in a flask and diethylaminosulfur trifluoride (DAST, 0.76 mL, 5.63 mmol) was added slowly while stirring. The resulting reaction mixture was heated to 58 C for 4 h then cooled to room temperature and quenched by addition of ice water (70 mL). The mixture was basified with aqueous sodium hydroxide solution (5%) and extracted with ethyl acetate (3 x 70 mL). The combined organic extracts were washed with water (70 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC eluting with 0-15% ethyl acetate in hexane to afford the title compound as a white solid (420 mg, 56%). HPLC-MS (Method A): MH+ requires m/z=334; Found m/z=334, Rt 4.18 min (94%). 1H MR (300 MHz, CDC13) δ 7.90 (s, 1H), 7.39 (s, 1H), 7.15- 6.78 (t, 1H), 3.88 (s, 3H), 2.74 (s, 3H), 2.62 (s, 3H) and 1.84 (s, 9H). Intermediate 7: 4-[4-(Difluoromethyl)-3-methyl-lH-pyrazolo[3, 4-b]pyridin-6-yl]-l, 5- dimethyl- lH-pyrazole

A stirred mixture of 4-[l-tert-butyl-4-(difluoromethyl)-3-methyl-lH-pyrazolo[3, 4-b]pyridin- 6-yl]-l, 5 -dimethyl- lH-pyrazole (prepared in an analogous manner to Intermediate 6, 2.0 g, 6.0 mmol) and formic acid (10 mL) in a sealed was heated at 120 C for 24 h. After cooling, the formic acid was evaporated in vacuo. The residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by FCC eluting with 70-80%) ethyl acetate in hexane to afford the title compound as a light yellow solid (0.8 g, 48%>). FIPLC-MS (Method A): MH+ requires m/z=278; Found m/z=278, Rt 2.99 min (95%). 1H MR (300 MHz, CDC13) δ 7.91 (s, 1H), 7.42 (s, 1H), 7.16-6.79 (t, 1H), 3.87 (s, 3H), 2.70 (s, 3H) and 2.66 (s, 3H). Intermediate 8: 4-(l-{2-[(Tert-butyldimethylsilyl)oxy]ethyl}-4-(difluorometh yl)-3-methyl- lH-pyrazolo[3, 4-b]pyridin-6-yl)-l, 5 -dimethyl- lH-pyrazole

To a stirred solution of 4-[4-(difluoromethyl)-3-methyl-lH-pyrazolo[3, 4-b]pyridin-6-yl]-l, 5- dimethyl-lH-pyrazole (Intermediate 7, 700 mg, 2.52 mmol) in dry DMF (10 mL) under argon at 0 C was added sodium hydride (200 mg,) followed by (2-bromoethoxy)(tert- butyl)dimethylsilane (900 mg, 3.76 mmol) and reaction was further stirred at RT for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (3 x 25 mL) and brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by FCC eluting with 0-60% ethyl acetate in hexane to afford the title compound as a viscous yellow liquid (610 mg, 55%). HPLC-MS (Method A): MH+ requires m/z=436; Found m/z=436, Rt 4.83 min (100%). 1H MR (300 MHz, CDC13) δ 7.91 (s, 1H), 7.37 (s, 1H), 7.13-6.77 (t, 1H), 4.61-4.57 (t, 2H), 4.08-4.04 (t, 2H), 3.88 (s, 3H), 2.75 (s, 3H), 2.63 (s, 3H), 0.72 (s, 9H) and -0.12 (s, 6H).

Intermediate 9: 2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3 , 4-b]pyridin- 1 -yl]- 1 -ethanol

To a stirred solution of 4-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-(difluorometh yl)-3- methyl-lH-pyrazolo[3, 4-b]pyridin-6-yl)-l, 5 -dimethyl- IH-pyrazole (Intermediate 8, 610 mg, 1.40 mmol) in THF (10 mL) was added hydrochloric acid (6N, 5 mL). After completion of the reaction, the solvent was removed under reduced pressure and the aqueous layer was basified using saturated aqueous sodium hydrogencarbonate solution (10 mL) and extracted with DCM (20 mL). The organic layer was dried over sodium sulfate and the solvent was removed under vacuum to give the title compound as an off-white solid (360 mg, 80%). HPLC-MS (Method A): MH+ requires m/z=322; Found m/z=322, Rt 3.21 min (100%). 1H MR (300 MHz, CDC13) δ 7.90 (s, 1H), 7.40 (s, 1H), 7.14-6.78 (t, 1H), 4.64-4.61 (t, 2H), 4.14-4.09 (q, 2H), 3.88 (s, 3H), 2.71 (s, 3H) and 2.64 (s, 3H).

Intermediate 10: 2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl] acetic acid

A solution of 4-[4-(difluoromethyl)-3-methyl-lH-pyrazolo[3, 4-b]pyridin-6-yl]-l, 5-dimethyl- lH-pyrazole (prepared in an analogous manner to Intermediate 7, 400 mg, 1.44 mmol) in anhydrous DMF (10 mL) was added to a suspension of sodium hydride (60% in oil, 145 mg, 6.04 mmol) in anhydrous DMF (10 mL) at 0 C and the mixture was stirred under nitrogen for 30 min. Ethyl bromoacetate (290 mg, 1.73 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 h. Water (5 mL) was added to the reaction mixture and further stirred for lh (which caused in situ hydrolysis of the ester to the acid). After completion, DMF was completely removed under pressure. The residue was dissolved in water (10 mL) and washed with ethyl acetate (2 x 10 mL). The aqueous layer was acidified with saturated aqueous citric acid solution (2 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed sequentially with water (2 x 10 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as an off white solid (280 mg, 58%). HPLC-MS (Method A): MH+ requires m/z=336; Found m/z=336, Rt 3.02 min (98%). 1H MR (300 MHz, MeOD) δ 8.06 (s, 1H), 7.65 (s, 1H), 7.39-7.03 (t, 1H), 5.22 (s, 2H), 3.90 (s, 3H), 2.78 (s, 3H) and 2.66 (s, 3H).

Intermediate 11: 3-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl] propanoic acid

The title compound was prepared from 4-[4-(difluoromethyl)-3-methyl-lH-pyrazolo[3, 4- b]pyridin-6-yl]-l, 5-dimethyl- IH-pyrazole (prepared in an analogous manner to Intermediate 7, 480 mg, 1.73 mmol), sodium hydride (60% in oil, 131 mg, 3.28 mmol,) in anhydrous DMF (10 mL) and ethyl 3-bromopropanoate (346 mg, 1.92 mmol) according to the method described for Intermediate 10. Yield: 260 mg, 43%. HPLC-MS (Method A): MH+ requires m/z=350; Found m/z=350, Rt 3.10 min (97%). IH NMR (300 MHz, d6-DMSO) δ 12.38 (IH, br), 8.06 (s, IH), 7.66 (s, IH), 7.57-7.21 (t, IH), 4.64-4.60 (t, 2H), 3.82 (s, 3H), 2.91-2.86 (q, 2H), 2.73 (s, 3H) and 2.52 (s, 3H).

Example 1 : 4-(Difluoromethyl)-6-(5 -ethyl- 1 -methyl- lH-pyrazol-4-yl)- 1 -ethyl-3 -methyl- 1H- pyrazolo[3, 4-b]pyridine

Commercially available, purchased from Chem T and I (UZI/1711674). HPLC-MS (Method B): MH+ requires m/z=320; Found m/z=320, Rt 4.46 min (100%).

Example 2: 4-(Difluoromethyl)-6-( 1,5 -dimethyl- lH-pyrazol-4-yl)-l -ethyl-3 -methyl- 1H- pyrazolo[3, 4-b]pyridine

Commercially available, purchased from Chem T and I (UZI/1712010). HPLC-MS (Method B): MH+ requires m/z=306; Found m/z=306, Rt 4.18 min (100%).

Example 3: 2-({2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]ethoxy}methyl)quinoline

To a stirred solution of 2-[4-(difluoromethyl)-6-(l, 5 -dimethyl- 1 H-pyrazol-4-yl)-3 -methyl- lH-pyrazolo[3, 4-b]pyridin-l-yl]-l-ethanol (Intermediate 9, 60 mg, 0.19 mmol, ) in dry THF (5 mL) under argon at 0 C was added sodium hydride (9 mg,) followed by 2- (chloromethyl)quinoline (37 mg, 2.1 mmol) and reaction was warmed to room temperature and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by FCC eluting with ethyl acetate to afford the title compound as a dark brown semi-solid (17 mg, 19%). HPLC-MS (Method A): MH+ requires m/z=463; Found m/z=463, Rt 3.25 min (100%). 1H MR (300 MHz, CDC13) δ 7.99 (d, 1H), 7.91-7.87 (m, 2H), 7.71-7.63 (m, 2H), 7.48 (t, 1H), 7.24 (t, 1H), 6.94 (t, 1H), 4.79 (s, 2H), 4.74 (t, 2H), 4.11 (t, 2H), 3.81 (s, 3H), 2.69 (s, 3H) and 2.63 (s, 3H). Example 4: 2-{2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]ethoxy}quinoline

The title compound was prepared according to the procedure used for the synthesis of Example 3 using 2-[4-(difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]-l-ethanol (Intermediate 9, 50 mg, 0.16 mmol), 2- chloroquinoline (31 mg, 0.19 mmol) and sodium hydride (10 mg, 0.234 mmol) in dry DMF (3 mL). Yield: 22 mg, 31%. HPLC-MS (Method A): MH+ requires m/z=449; Found m/z=449, Rt 4.36 min (96%). 1H MR (300 MHz, CDC13) δ 7.85-7.81 (m, 2H), 7.67 (d, IH), 7.65- 7.60 (m, 2H), 7.39-7.34 (m, 2H), 6.91 (t, IH), 6.67 (d, IH), 4.99 (t, 2H), 4.94 (t, 2H), 3.77 (s, 3H), 2.62 (s, 3H) and 2.37 (s, 3H).

Example 5: 4-[4-(Difluoromethyl)-l-(2-{imidazo[l,2-a]pyridin-2-ylmethox y}ethyl)-3- methyl-lH-pyrazolo[3,4-b]pyridin-6- -l,5-dimethyl-lH-pyrazole

The title compound was prepared according to the procedure used for the synthesis of Example 3 using 2-[4-(difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]-l-ethanol (Intermediate 9, 50 mg, 0.16 mmol), 2- (chloromethyl)imidazo[l,2-a]pyridine (31 mg, 0.19 mmol) and sodium hydride (10 mg, 0.23 mmol) in dry DMF (2 mL). Yield: 23 mg, 32%. HPLC-MS (Method A): MH+ requires m/z=452; Found m/z=452, Rt 2.99 min (89%). IH MR (300 MHz, CDC13) δ 7.95-7.87 (m, 2H), 7.49 (d, IH), 7.38 (s, IH), 7.14 (m, IH), 6.96 (t, IH), 6.72 (t, IH), 4.72 (s, 2H), 4.70 (t, 2H), 4.11 (t, 2H), 3.85 (s, 3H), 2.71 (s, 3H) and 2.64 (s, 3H).

Example 6: 2-({2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]ethoxy}methyl)pyridine

The title compound was prepared according to the procedure described for the synthesis of Example 3 using 2-[4-(difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- IH- pyrazolo[3, 4-b]pyridin-l-yl]-l-ethanol (Intermediate 9, 50 mg, 0.16 mmol), picolyl chloride (24 mg, 0.19 mmol) and sodium hydride (10 mg, 0.23 mmol) in dry DMF (3 mL). Yield: 20 mg, 31%. HPLC-MS (Method A): MH+ requires m/z=413; Found m/z=413, Rt 3.09 min (92%). 1H MR (300 MHz, CDC13) δ 8.46 (d, 1H), 7.90 (s, 1H), 7.48 (t, 1H), 7.39 (br s, 1H), 7.15-7.10 (m, 2H), 6.96 (t, 1H), 4.74 (t, 2H), 4.64 (s, 2H), 4.08 (t, 2H), 3.86 (s, 3H), 2.71 (s, 3H) and 2.64 (s, 3H).

Example 7: 2-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]-N-(quinolin-2- l acetamide

To a stirred solution of 2-[4-(difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3-methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl] acetic acid (Intermediate 10, 40 mg, 0.12 mmol) in DMF (5 mL) were added HOBt (24 mg, 0.18 mmol) and EDCI.HC1 (35 mg, 0.18 mmol). The resulting solution was stirred for 30 min prior to the addition of 2-aminoquinoline (19 mg, 0.13 mmol), then stirred for 12 at ambient temperature. The solvent was removed under pressure and the residue was dissolved in ethyl acetate (10 mL), washed with water (2 x 10 mL), saturated aqueous sodium hydrogencarbonate solution (2 x 10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by FCC eluting with 0-30% ethyl acetate in hexane to afford the title compound as an off-white semi-solid (25 mg, 45%). HPLC-MS (Method A): MH+ requires m/z=462; Found m/z=462, Rt 3.61 min (100%). 1H MR (300 MHz, DMSO-d6) δ 11.35 (br s, 1H), 8.34 (d, 1H), 8.16 (d, 1H), 8.06 (s, 1H), 7.92-7.84 (m, 2H), 7.76-7.70 (m, 2H), 7.51 (t, 1H), 7.44 (t, 1H), 5.43 (s, 2H), 3.74 (s, 3H), 2.61 (s, 3H) and 2.56 (s, 3H). Example 8: 3-[4-(Difluoromethyl)-6-(l, 5 -dimethyl- lH-pyrazol-4-yl)-3 -methyl- 1H- pyrazolo[3, 4-b]pyridin-l-yl]-N-(quinolin-2-yl)propionamide

To a stirred solution of 3-[4-(difluoromethyl)-6-(l, 5 -dimethyl- 1 H-pyrazol-4-yl)-3 -methyl- lH-pyrazolo[3, 4-b]pyridin-l-yl] propanoic acid (Intermediate 11, 50 mg, 0.14 mmol) in DMF (5 mL) were added HBTU (30 mg, 0.22 mmol), EDCI.HC1 (43 mg, 0.22 mmol). The resulting solution was stirred for 30 min prior to the addition of 2-aminoquinoline (24 mg, 0.17 mmol) then stirred for 12 h. The DMF was removed under pressure; the residue was dissolved in ethyl acetate (10 mL), washed with water (2 x 10 mL), saturated aqueous sodium hydrogencarbonate solution (2 x 10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by FCC eluting with 0-5% MeOH in DCM to afford the title compound (43 mg, 63%). HPLC-MS (Method A): MH+ requires m/z=476; Found m/z=476, Rt 3.59 min (96%). 1H MR (300 MHz, CDC13) δ 8.50 (br s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.87 (s, 1H), 7.75 (m, 2H), 7.65 (t, 1H), 7.26 (s, 1H), 6.92 (t, 1H), 4.91 (t, 2H), 3.84 (s, 3H), 3.13 (t, 2H), 2.75 (s, 3H) and 2.66 (s, 3H).