JP2009541481A - Tricyclic heteroaryl compounds as PDE10 inhibitors - Google Patents

Abstract

The present invention relates to tricyclic heteroaryl compounds of formula (I) which serve as effective phosphodiesterase (PDE) inhibitors. The present invention also relates to compounds that are selective inhibitors of PDE10. The invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds in methods of treating certain central nervous system (CNS) disorders or other disorders. The invention also relates to methods of treating neurodegenerative and psychiatric disorders, such as psychosis and disorders involving cognitive deficits as symptoms.
[Chemical 1]

Description

  The present invention relates to tricyclic heteroaryl compounds that serve as effective phosphodiesterase (PDE) inhibitors. The present invention also relates to compounds that are selective inhibitors of PDE10. The invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds in methods of treating certain central nervous system (CNS) disorders or other disorders. The invention also relates to methods of treating neurodegenerative and psychiatric disorders, such as psychosis and disorders involving cognitive deficits as symptoms.

  Phosphodiesterase (PDE) is a type of intracellular enzyme involved in the hydrolysis of nucleotide cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl cyclase and guanylyl cyclase, respectively, and serve as second messengers in various cellular pathways.

  cAMP and cGMP function as intracellular second messengers that regulate many intracellular processes, particularly in neurons of the central nervous system. In neurons, this includes activation of cAMP and cGMP-dependent kinases, as well as the subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission and neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is suggested by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least 10 adenylyl cyclase families, 2 guanylyl cyclases, and 11 phosphodiesterases. In addition, various different types of neurons are known to express each of these classes of multiple isozymes, and there is ample evidence for compartmentalization and functional specificity of the various different isozymes within a given neuron. is there.

  The primary mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11 known PDE families encoded by 21 different genes. Each gene typically results in multiple splice variants that further contribute to the diversity of isozymes. The PDE family is functionally distinguished based on cyclic nucleotide substrate specificity, regulatory mechanisms, and sensitivity to inhibitors. Furthermore, PDE is specifically expressed throughout the body including the central nervous system. As a result of these specific enzyme activities and localization, a variety of different PDE isozymes can perform specific physiological functions. Further, compounds that can selectively inhibit specific PDE families or isozymes can provide specific therapeutic effects, fewer side effects, or both.

  PDE10 is identified as a unique family based on primary amino acid sequence and specific enzyme activity. Homology screening of the EST database revealed mouse PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. 274: 18438-18445, 1999; Loughney, K. et al., Gene. 234: 109-117, 1999). This mouse 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 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. Mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDE10 for cAMP (Km = 0.05 μM) is higher than the affinity for cGMP (Km = 3 μM). However, Vmax is about 5 times greater in cGMP than cAMP, suggesting that PDE10 is a unique cAMP-inhibiting cGMPase (Fujishige et al., J. Biol. Chem. 274: 18438-18445, 1999).

  PDE10 family polypeptides exhibit low sequence homology compared to previously identified PDE families and are insensitive to certain inhibitors known to be specific for other PDE families It has been shown. US Pat. No. 6,350,603, which is hereby incorporated by reference.

  PDE10 is also uniquely localized in mammals compared to other PDE families. PDE10 mRNA is highly expressed only in the 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 early studies show that in the brain, PDE10 expression is highest in the striatum (caudate nucleus and putamen), nucleus accumbens, and olfactory nodule. More recently, PDE10 mRNA (Seeeger, TF et al., Abst. Soc. Neurosci. 26: 345.10, 2000), and PDE10 protein (Menniti, FS, Stick, CA, Seeger, T. et al.). F., and Ryan, AM, Immunohistochemical localization of PDE10 in the brain brain, William Harvey Research Conference “Phosphosterase in Health and Month, 12 A detailed analysis of the expression pattern in the brain was performed.

  Various therapeutic uses of PDE inhibitors have been reported, including overt lung disease, allergy, hypertension, angina, congestive heart failure, depression, and erectile dysfunction (hereby incorporated by reference) WO01 / 41807A2) as a part of the book.

  The use of selected benzimidazoles and related heterocyclic compounds in the treatment of ischemic heart conditions has been disclosed based on PDE inhibition related to cGMP activity. US Pat. No. 5,693,652, which is hereby incorporated by reference.

  US 2003/0032579 discloses a method for treating certain neurological and psychiatric disorders with the selective PDE10 inhibitor papaverine. In particular, the method relates to psychotic disorders such as schizophrenia, paranoid disorders, and drug-induced psychosis; anxiety disorders such as panic disorder and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease.

  WO 2005/120514 discloses a method for treating obesity-related and metabolic syndrome-related conditions by administering a PDE10 inhibitor.

  A compound of formula I, or a pharmaceutically acceptable salt thereof,

式中、環２は、単環式アリールまたは単環式ヘテロアリールであり、前記環２は、少なくとも１つのＲ^５で置換されていてもよく、
ＨＥＴ^３は、８、９、または１０員二環式ヘテロアリールであり、前記ＨＥＴ^３は、少なくとも１つのＲ^６で置換されていてもよく、
Ｒ^１はそれぞれ、ハロゲン、ヒドロキシル、シアノ、Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、Ｃ_１からＣ_８アルコキシ、Ｃ_１からＣ_８ハロアルキル、Ｃ_３からＣ_８シクロアルキル、Ｃ_３からＣ_７ヘテロシクロアルキル、Ｃ_１からＣ_８アルキルチオ、−ＮＲ^３Ｒ^３、Ｃ_１からＣ_８ハロアルキル、−Ｓ（Ｏ）_ｒ−Ｒ^３、−Ｃ（Ｏ）−ＮＲ^３Ｒ^３、およびヘテロ原子で置換されたＣ_１からＣ_８アルキルからなる群から独立して選択され、ヘテロ原子は、窒素、酸素、および硫黄からなる群から選択され、ヘテロ原子は、水素、Ｃ_１からＣ_８アルキル、Ｃ_３からＣ_８シクロアルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、およびＣ_１からＣ_８ハロアルキルからなる群から選択される１つまたは複数の置換基でさらに置換されていてもよく、
Ｒ^３はそれぞれ、水素、Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、Ｃ_１からＣ_８ハロアルキル、Ｃ_３からＣ_８シクロアルキルからなる群から独立して選択され、
Ｒ^５はそれぞれ、ハロゲン、ヒドロキシル、シアノ、−ＮＲ^８Ｒ^８、Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、Ｃ_１からＣ_８アルコキシ、Ｃ_３からＣ_８シクロアルキル、Ｃ_１からＣ_８アルキルチオ、およびＣ_１からＣ_８ハロアルキルからなる群から独立して選択され、
Ｂ^３およびＢ^４は、Ｈｅｔ^３の隣接する原子であり、Ｂ^３は炭素であり、Ｂ^４は窒素であり、
ＸおよびＸ^１は、酸素、硫黄、Ｃ（Ｒ^２）_２、およびＮＲ^２からなる群からそれぞれ独立して選択され、ただしＸまたはＸ^１の少なくとも１つはＣ（Ｒ^２）_２であり、
Ｒ^２はそれぞれ、水素、Ｃ_１からＣ_８アルキル、−Ｃ_３からＣ_８シクロアルキル−Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルキニル、Ｃ_２からＣ_８アルケニル、Ｃ_１からＣ_８ハロアルキル、およびＣ_３からＣ_８シクロアルキルからなる群から独立して選択され、
ＡおよびＡ^１は、酸素、Ｓ（Ｏ）_ｒ、Ｃ（Ｒ^９）_２、およびＮＲ^９からなる群からそれぞれ独立して選択され、ただしＡまたはＡ^１の少なくとも１つはＣ（Ｒ^９）_２であり、
Ｒ^６はそれぞれ、ハロゲン、ヒドロキシル、シアノ、Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、Ｃ_１からＣ_８アルコキシ、Ｃ_１からＣ_８ハロアルキル、Ｃ_１からＣ_８アルキルチオ、Ｃ_３からＣ_８シクロアルキル、−ＮＲ^７Ｒ^７、Ｃ_１からＣ_８ハロアルキル、−Ｓ（Ｏ）_ｒ−Ｒ^７、−Ｃ（Ｏ）−ＮＲ^７Ｒ^７、ヘテロ原子で置換されたＣ_１からＣ_８アルキルからなる群から独立して選択され、ヘテロ原子は、窒素、酸素、および硫黄からなる群から選択され、ヘテロ原子は、水素、Ｃ_１からＣ_８アルキル、Ｃ_１からＣ_８シクロアルキル、Ｃ_２からＣ_８アルケニル、Ｃ_２からＣ_８アルキニル、およびＣ_１からＣ_８ハロアルキルからなる群から選択される置換基でさらに置換されていてもよいか、
または２つのＲ^６は、それらが結合している原子と共に、Ｃ_４からＣ_１０シクロアルキル、Ｃ_４からＣ_１０シクロアルケニル、（４〜１０員）ヘテロシクロアルキル、または（４〜１０員）ヘテロシクロアルケニル環を形成してもよく、
Ｒ^７はそれぞれ、水素およびＣ_１からＣ_８アルキルからなる群から独立して選択され、
Ｒ^８はそれぞれ、水素、Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルケニル、およびＣ_２からＣ_８アルキニルからなる群から独立して選択され、
Ｒ^９はそれぞれ、水素、Ｃ_１からＣ_８アルキル、−Ｃ_３からＣ_８シクロアルキル−Ｃ_１からＣ_８アルキル、Ｃ_２からＣ_８アルキニル、Ｃ_２からＣ_８アルケニル、Ｃ_１からＣ_８ハロアルキル、およびＣ_３からＣ_８シクロアルキルからなる群から独立して選択され、
ｎ＝０または１であり、ｍ＝１または２であり、ｐ＝０、１、２、または３であり、ｒ＝０、１、または２である。

Wherein ring 2 is monocyclic aryl or monocyclic heteroaryl, said ring 2 may be substituted with at least one R ⁵ ;
HET ³ is an 8, 9, or 10 membered bicyclic heteroaryl, said HET ³ may be substituted with at least one R ⁶ ,
R ¹ is halogen, hydroxyl, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₃ to C, respectively. ₈ cycloalkyl, C ₃ to C ₇ heterocycloalkyl, C ₁ to C ₈ alkylthio, —NR ³ R ³ , C ₁ to C ₈ haloalkyl, —S (O) _r —R ³ , —C (O) —NR Independently selected from the group consisting of ³ R ³ , and C ₁ to C ₈ alkyl substituted with a heteroatom, wherein the heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the heteroatom is hydrogen, The group consisting of C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, and C ₁ to C ₈ haloalkyl May be further substituted with one or more substituents selected from
Each R ³ is independently selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ haloalkyl, C ₃ to C ₈ cycloalkyl And
R ⁵ is halogen, hydroxyl, cyano, —NR ⁸ R ⁸ , C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₃ to C _{8, respectively.} Independently selected from the group consisting of cycloalkyl, C ₁ to C ₈ alkylthio, and C ₁ to C ₈ haloalkyl;
B ³ and B ⁴ are adjacent atoms of Het ³ , B ³ is carbon, B ⁴ is nitrogen,
X and X ¹ are each independently selected from the group consisting of oxygen, sulfur, C (R ² ) ₂ , and NR ² , provided that at least one of X or X ¹ is C (R ² ) ₂ ;
R ² is hydrogen, C ₁ to C ₈ alkyl, —C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₂ to C ₈ alkynyl, C ₂ to C ₈ alkenyl, C ₁ to C ₈ haloalkyl, respectively. And independently selected from the group consisting of C ₃ to C ₈ cycloalkyl,
A and A ¹ are each independently selected from the group consisting of oxygen, S (O) _r , C (R ⁹ ) ₂ , and NR ⁹ , provided that at least one of A or A ¹ is C (R ⁹ ) ₂
R ⁶ is halogen, hydroxyl, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₁ to C, respectively. ₈ alkylthio, C ₃ to C ₈ cycloalkyl, —NR ⁷ R ⁷ , C ₁ to C ₈ haloalkyl, —S (O) _r —R ⁷ , —C (O) —NR ⁷ R ⁷ , substituted with heteroatoms is selected from C ₁ was independently from the group consisting of C ₈ alkyl, heteroatoms are nitrogen, oxygen, and is selected from the group consisting of sulfur, the heteroatom is hydrogen, C ₈ alkyl from C _1, C ₁ to C ₈ cycloalkyl, _{C 8} alkenyl, further substituted with a substituent selected from _{C 2 C 8} alkynyl, and from the group of _{C 1} consisting _{C 8} haloalkyl from _{C 2} Or it may also be,
Or two R ⁶ together with the atoms to which they are attached, C ₄ to C ₁₀ cycloalkyl, C ₄ to C ₁₀ cycloalkenyl, (4 to 10 membered) heterocycloalkyl, or (4 to 10 membered) hetero. May form a cycloalkenyl ring,
Each R ⁷ is independently selected from the group consisting of hydrogen and C ₁ to C ₈ alkyl;
Each R ⁸ is independently selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, and C ₂ to C ₈ alkynyl;
R ⁹ is hydrogen, C ₁ to C ₈ alkyl, —C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₂ to C ₈ alkynyl, C ₂ to C ₈ alkenyl, C ₁ to C ₈ haloalkyl, respectively. And independently selected from the group consisting of C ₃ to C ₈ cycloalkyl,
n = 0 or 1, m = 1 or 2, p = 0, 1, 2, or 3, and r = 0, 1, or 2.

  The present invention provides a compound of formula I as described above, or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, HET ³ is selected from the group consisting of:

式中、Ｙはそれぞれ、ＣＨ、ＣＲ^６、または窒素からなる群から独立して選択され、Ｚは、酸素または硫黄である。

Wherein Y is each independently selected from the group consisting of CH, CR ⁶ , or nitrogen, and Z is oxygen or sulfur.

In other embodiments, all Ys of the HET ³ groups are each independently CH or CR ⁶ .

In another embodiment, HET ³ is selected from the group consisting of:

  In other embodiments, Ring 2 is selected from the group consisting of phenyl, 4-pyridyl, 4-pyridazinyl, and isoxazolyl.

  In other embodiments, Ring 2 is 4-pyridyl.

In other embodiments, X ¹ is C (R ² ) ₂ and X is oxygen.

  In other embodiments, m and n are both 1.

In other embodiments, A and A ¹ are oxygen and C (R ⁹ ) ₂ , respectively.

  The compounds of formula I can have optical centers and therefore can occur in various enantiomeric and diastereomeric configurations. The present invention includes all enantiomers, diastereomers, other stereoisomers, and racemates and racemic mixtures of such compounds of formula I, as well as other mixtures of those stereoisomers.

  Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof.

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate , Cansylate, citrate, cyclamate, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, Hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mandelate, mesylate, Methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyro Glutamate, salicylate, Karin, stearate, succinate, sulfonate, stannate, tartrate, tosylate, trifluoroacetate and Kishinoho salts, (xinofoate) are included.

  Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. The

  Acid and base hemi-salts such as hemisulfate and hemi-calcium salts can also be formed.

  For a review of these and other suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of the compounds of formula I can be prepared by one or more of the following three methods.
(I) by reacting a compound of formula I with the desired acid or base;
(Ii) Opening a suitable ring precursor, such as a lactone or lactam, by removing the acid or base labile protecting group from the appropriate precursor of the compound of formula I or using the desired acid or base Or (iii) by converting one salt of a compound of formula I to another salt by reaction with a suitable acid or base or by a suitable ion exchange column.

  All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to nearly non-ionized.

  The compounds of the present invention can exist in a continuous solid state from fully amorphous to fully crystalline. The term “amorphous” refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically such materials do not exhibit a characteristic X-ray analysis pattern and are more formally considered liquid while exhibiting solid properties. Heating causes a change from solid to liquid properties, which is characterized by a state change that is typically second order ("glass transition"). The term “crystalline” refers to a solid phase in which the material has a regular X-ray analysis pattern with a regular ordered internal structure at the molecular level and with distinct peaks. Such materials also exhibit liquid properties when fully heated, but the change from solid to liquid is typically characterized by a phase change that is first order ("melting point").

  The compounds of the invention can also exist in unsolvated forms as well as solvated forms. As used herein, the term “solvate” is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term “hydrate” is used.

  A currently accepted classification system for organic hydrates is to define isolated sites, channels, or metal ion coordination hydrates; R. See Morris' Polymorphism in Pharmaceutical Solids (edited by HG Brittain, Marcel Dekker, 1995). Isolated site hydrates are those in which water molecules are each isolated from direct contact with each other through the intervention of organic molecules. In channel hydrates, water molecules are present in lattice channels where the water molecules are adjacent to each other. In metal ion coordination hydrate, water molecules are bound to metal ions.

  When the solvent or water is strongly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water binding is weak, such as channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and drying conditions. In such cases, non-stoichiometry is the standard.

The compounds of the present invention can also exist in an intermediate state (mesophase or liquid crystal) when subjected to suitable conditions. The intermediate state is intermediate between the true crystalline state and the true liquid state (molten or solution). The intermediate form resulting from the temperature change is called “thermotropic” and the result of the addition of a second component such as water or other solvent is called “lyotropic”. Compounds that have the potential to form lyotropic mesophases are termed “amphiphilic” and are either ionic (such as —COO ⁻ Na ⁺ , —COO ⁻ K ⁺ , or —SO ₃ ⁻ Na ⁺ ) or nonionic (—N ^- N ⁺ _{(CH 3)} consisting of molecules with ₃ etc.) polar head group. Further information can be found in Crystals and the Polarizing Microscope, N.C. H. Harthorne and A.H. See Stuart, 4th edition (Edward Arnold, 1970).

  Hereinafter, all references to compounds of formula I include references to salts, solvates, multicomponent complexes, and liquid crystals thereof, and solvates, multicomponent complexes, and liquid crystals of salts thereof.

  The compounds of the invention include compounds of formula I as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof as defined below (including optical, geometric, and tautomeric forms) As well as isotopically-labelled compounds of formula I.

  As noted, so-called “prodrugs” of compounds of Formula I are also within the scope of the present invention. For example, certain derivatives of compounds of formula I that may have little or no pharmacological activity per se have formula I that have the desired activity when administered in or on the body, for example by hydrolysis. Can be converted to Such derivatives are referred to as “prodrugs”. Additional information regarding the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella), and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (edited by E. B. Roche, American Pharma).

  Prodrugs according to the present invention can be prepared, for example, using suitable functional groups present in compounds of formula I, for example in Design of Prodrugs, H.M. It can be generated by replacement with certain parts known to those skilled in the art as “pro-parts” as described in Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the present invention include, but are not limited to:
(I) When the compound of formula I contains a carboxylic acid functional group (—COOH), the ester, for example, the hydrogen of the carboxylic acid functional group of the compound of formula I is replaced with (C ₁ -C ₈ ) alkyl. The compound,
(Ii) when the compound of formula I contains an alcohol function (—OH), the ether, for example the hydrogen of the alcohol function of the compound of formula I, is replaced with (C ₁ -C ₆ ) alkanoyloxymethyl And (iii) if the compound of formula I contains a primary or secondary amino function (—NH ₂ or —NHR, where R ≠ H), its amide, eg optionally A compound wherein one or both hydrogens of the amino function of the compound of formula I are replaced with (C ₁ -C ₁₀ ) alkanoyl.

  Further examples of substituents according to the foregoing examples and other types of prodrug examples can be found in the aforementioned references.

  In addition, certain compounds of formula I can themselves act as prodrugs of other compounds of formula I.

Further included within the scope of the invention are metabolites of compounds of Formula I, ie, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the present invention include, but are not limited to:
(I) when the compound of formula I contains a methyl group, its hydroxymethyl derivative (—CH ₃ —> — CH ₂ OH),
(Ii) when the compound of formula I contains an alkoxy group, its hydroxy derivative (-OR->-OH),
(Iii) when the compound of formula I contains a tertiary amino group, its secondary amino derivative (—NR ¹ R ² —> — NHR ¹ or —NHR ² ),
(Iv) when the compound of formula I contains a secondary amino group, its primary derivative (—NHR ¹ —> — NH ₂ ),
(V) when the compound of formula I contains a phenyl moiety, its phenol derivative (-Ph->-PhOH), and (vi) when the compound of formula I contains an amide group, its carboxylic acid derivative (-CONH _2- > COOH).

  Compounds of formula I that contain one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula I contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Tautomerism (“tautomerism”) can occur when structural isomers are interconvertible by a low energy barrier. This can take the form of proton tautomerism in compounds of the formula I containing, for example, an imino, keto or oxime group, or so-called valence tautomerism in compounds containing aromatic moieties. As a result, a single compound can exhibit multiple types of isomerism.

  All stereoisomers, geometric isomers, and tautomeric forms of compounds of Formula I, as well as mixtures of one or more of them, are encompassed by the present invention, including compounds that exhibit multiple types of isomerism. The Also included are acid addition or base salts in which the counter ion is optically active (eg, d-lactate or l-lysine) or racemic (eg, dl-tartrate or dl-arginine).

  Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

  Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or racemates (or salts or salts using, for example, chiral high pressure liquid chromatography (HPLC)). Resolution of racemic derivatives) is included.

  Alternatively, the racemate (or racemic precursor) is converted to a suitable optically active compound, such as an alcohol, or a base or acid such as 1-phenylethylamine or tartaric acid when the compound of formula I contains an acidic or basic moiety. Can be reacted. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. it can.

  The chiral compounds of the present invention (and their chiral precursors) can be obtained from 0 to 50% by volume isopropanol, typically 2% to 20%, and 0 to 5% by volume using chromatography, typically HPLC. Can be obtained in an enantiomerically enriched form in an asymmetric resin using a mobile phase consisting of an alkylamine, typically a hydrocarbon containing 0.1% diethylamine, typically heptane or hexane. The enriched mixture is obtained by concentration of the eluent.

  When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound described above (true racemate) in which one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate in which two forms of crystals each containing a single enantiomer are produced in equimolar amounts.

  Both crystalline forms present in the racemic mixture have the same physical properties, but may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art, e.g., Stereochemistry of Organic Compounds, E.I. L. Eliel and S.M. H. See Wilen (Wiley, 1994).

  The present invention relates to all pharmaceuticals in which one or more atoms have been replaced with atoms having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number found primarily in nature. Including pharmaceutically acceptable isolabeled compounds of formula I.

Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, isotopes of carbon, such as ² H and ³ H, isotopes of chlorine, such as ¹¹ C, ¹³ C, and ¹⁴ C. ^body, such as 36 Cl, isotopes of ^fluorine, such as ¹⁸ F, isotopes of ^iodine, such as ¹²³ I and ¹²⁵ I, isotopes of ^nitrogen, such as ¹³ N and ¹⁵ N, oxygen ^isotope, 15 ^O, 17 O, And ¹⁸ O, phosphorus isotopes, ³² P and the like, and sulfur isotopes, ³⁵ S and the like are included.

Certain isotopically-labelled compounds of Formula I, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavy isotopes such as deuterium, ie ² H, may provide certain therapeutic benefits resulting from higher metabolic stability, eg, increased in vivo half-life, or reduced dosage requirements And therefore may be preferred in certain situations.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

  Isotopically labeled compounds of formula I can be substituted for previously unlabeled reagents by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples and Preparations below. Generally, it can be prepared using an isotope labeling reagent suitable for the above.

Pharmaceutically acceptable solvates in accordance with the invention, for example D _{2 O,} d 6 _- acetone, d _6-DMSO, good solvates solvent of crystallization substituted isotopes are included .

  Certain embodiments of the present invention include compounds exemplified in the following examples, and pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs thereof, and Includes those other derivatives.

  The invention also encompasses certain psychotic disorders and conditions such as schizophrenia, paranoid disorders, and drug-induced psychosis; anxiety disorders such as panic disorder and obsessive compulsive disorder; and Parkinson's disease and Huntington's disease A pharmaceutical composition for treating movement disorders, comprising a certain amount of a compound of formula I effective to inhibit PDE10.

  In other embodiments, the invention also includes psychotic disorders and conditions such as schizophrenia, paranoid disorders, and drug-induced psychosis; anxiety disorders such as panic disorder and obsessive compulsive disorder; and Parkinson's disease and Huntington's disease A pharmaceutical composition comprising an amount of a compound of formula I effective to treat said disorder or condition.

  Examples of psychotic disorders that can be treated according to the present invention include, but are not limited to, eg, delusional, dismantled, strained, indistinguishable, or residual schizophrenia; Schizophrenia-like disorders; for example, paranoid or depressive schizophrenic disorder; paranoid disorders; substance-induced psychotic disorders such as alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine Included are induced psychosis; delusional personality disorder; and schizophrenic personality disorder.

  Examples of movement disorders that can be treated according to the present invention include, but are not limited to, Huntington's disease, and aberrant motility associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor. Is included.

  Other disorders that can be treated according to the present invention are obsessive / compulsive disorders, Tourette's syndrome, and other tic disorders.

  In another embodiment, the invention provides a method of treating an anxiety disorder or condition in a mammal comprising administering to said mammal an amount of a compound of formula I effective to inhibit PDE10. Relates to the method of including.

  The present invention also provides a method of treating an anxiety disorder or condition in a mammal comprising administering to said mammal an amount of a compound of formula I effective to treat said disorder or condition. I will provide a.

  Examples of anxiety disorders that can be treated according to the present invention include, but are not limited to, panic disorder; agoraphobia; specific phobia; social phobia; obsessive compulsive disorder; Disorders include: acute stress disorder; and generalized anxiety disorder.

  The present invention further provides a method of treating drug addiction, such as alcohol, amphetamine, cocaine, or opium addiction, in mammals, including humans, wherein the mammal is an amount effective to treat drug addiction A method comprising administering a compound of formula I:

  The invention also provides a method of treating drug addiction, such as alcohol, amphetamine, cocaine, or opium addiction, in mammals, including humans, wherein the mammal has an amount effective to inhibit PDE10. There is provided a method comprising administering a compound of formula I.

  As used herein, “drug addiction” refers to an abnormal desire for a drug and is generally characterized by a motivational disorder such as an impulsive compulsion trying to take a desired drug and episodes of intense drug craving.

  The invention further provides a method of treating a disorder, including a lack of attention and / or cognition as a symptom, in a mammal, including a human, wherein the mammal has an amount effective to treat the disorder. There is provided a method comprising administering a compound of formula I.

  The present invention also provides a method of treating a disorder or condition comprising a lack of attention and / or cognition as a symptom in a mammal, including a human, wherein the mammal is an amount effective to inhibit PDE10. A method comprising administering a compound of formula I:

  The present invention is also a method of treating a disorder or condition that includes a lack of attention and / or cognition as a symptom in a mammal, including a human, and is effective for treating said disorder or condition in said mammal. There is provided a method comprising administering an amount of a compound of formula I.

  The phrase “lack of attention and / or cognition” as used herein for “disorders involving attention and / or lack of cognition as a symptom” refers to a particular individual compared to other individuals of the same age population Refers to subnormal functioning of one or more cognitive aspects such as memory, intelligence, or learning and logic ability. “Lack of attention and / or cognition” also refers to a decline in function in any particular individual of one or more cognitive aspects, such as occurs with age-related cognitive decline.

  Examples of disorders that include as a symptom a lack of attention and / or cognition that can be treated according to the present invention include dementia such as Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia, intracranial tumors Or dementia related to brain trauma, dementia related to Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorder such as reading disorder, arithmetic disorder Or written disability; attention deficit / hyperactivity disorder; and age-related cognitive decline.

  The invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, wherein the mammal is provided with an amount of a compound of formula I effective to treat the disorder or episode. A method comprising administering is provided.

  The present invention is also a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to the mammal an amount of a compound of formula I effective to inhibit PDE10. A method comprising:

  Examples of mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, mild, moderate, or severe forms of major depression episodes, mania or mixed mood episodes, hypomania mood Episodes; Depressive episodes with atypical features; Depressive episodes with melancholic features; Depressive episodes with tension-type features; Mood episodes with postpartum onset; Depression after stroke; Major depression Disorders: Dysthymia Disorders; Minor Depressive Disorders; Premenstrual Discomfort Mood Disorders; Postpsychotic Depressive Disorders in Schizophrenia; Major Depressive Disorders Associated with Psychiatric Disorders such as Delusional Disorder Bipolar disorders such as bipolar I disorder, bipolar type II disorder, and mood circulatory disorder are included.

  The present invention further provides a method of treating a neurodegenerative disorder or condition in mammals, including humans, wherein said mammal is provided with an amount of a compound of formula I effective to treat said disorder or condition. A method comprising administering is provided.

  The present invention is further a method of treating a neurodegenerative disorder or condition in mammals, including humans, wherein said mammal is administered an amount of a compound of formula I effective to inhibit PDE10. A method comprising:

  As used herein, unless otherwise indicated, a “neurodegenerative disorder or condition” refers to a disorder or condition resulting from neuronal dysfunction and / or death in the central nervous system. Treatment of these disorders and conditions prevents dysfunction or death of neurons at risk in these disorders or conditions and / or compensates for loss of function due to dysfunction or death of neurons at risk As such, it can be facilitated by administration of agents that can enhance the function of damaged or normal neurons. As used herein, the term “neurotrophic agent” refers to a substance or agent that has some or all of these properties.

  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 such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related Dementia and frontotemporal dementia; neurodegeneration associated with brain trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizures; Neurodegeneration associated with poisoning; and multiple system atrophy.

  In one embodiment of the invention, the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in mammals, including humans.

  In a further embodiment of the invention, the neurodegenerative disorder or condition is Huntington's disease.

  The present invention also provides a pharmaceutical composition for treating psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, and drug addiction, said disorder or Pharmaceutical compositions comprising an amount of a compound of formula I effective to treat a condition are provided.

  The invention also provides a method of treating a disorder selected from psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders, wherein the disorders are treated There is provided a method comprising administering an amount of a compound of formula I effective to treat.

  The invention also relates to dementia, Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or brain trauma, Huntington's disease or Parkinson's disease Dementia, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorders such as reading disorders, math disorders, or written expression disorders; Age-related cognitive decline, mild, moderate, or severe major depression episodes; mania or mixed mood episodes; mild mood episodes; depression episodes with atypical features; depression episodes with melancholic features; tension Depressive episodes with type characteristics; mood episodes with postpartum onset; poststroke depression; major depressive disorder; mood modulation Disorders; minor depression disorder; premenstrual dysphoric disorder; postpsychotic depressive disorder in schizophrenia; major depressive disorder associated with psychotic disorder including delusional disorder or schizophrenia; bipolar type I disorder Bipolar type II disorder, bipolar disorder including mood circulation disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related dementia, frontotemporal dementia; Associated neurodegeneration; Neurodegeneration associated with stroke; Neurodegeneration associated with cerebral infarction; Hypoglycemia-induced neurodegeneration; Neurodegeneration associated with epileptic seizures; Neurodegeneration associated with neurotoxin poisoning; Multiple system atrophy, delusions Type, dismantled type, tension type, indistinguishable type, or residual type; schizophrenia-like disorder; delusional or depressive type schizophrenic emotional disorder; delusional disorder; substance-induced psychotic disorder, alcohol, amphet A method of treating a disorder selected from the group consisting of psychosis induced by min, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; delusional personality disorder; and schizophrenic personality disorder provide.

  The present invention is also a method of treating psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, and drug addiction, and is effective in inhibiting PDE10 There is provided a method comprising administering an amount of a compound of formula I.

  Unless otherwise indicated herein, the term “alkyl” includes saturated monovalent hydrocarbon groups having straight or branched chain moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

  Unless otherwise indicated herein, the term “alkenyl” includes an alkyl moiety having at least one carbon-carbon double bond, wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

  Unless otherwise indicated herein, the term “alkynyl” includes alkyl moieties having at least one carbon-carbon triple bond, where alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

  Unless otherwise indicated herein, the term “alkoxy” as used herein, alone or as part of another group, refers to an alkyl group attached to an oxygen atom.

  Unless otherwise indicated herein, the term “alkylthio” as used herein alone or as part of another group includes any of the above alkyl groups attached through a sulfur atom.

  The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.

  Unless otherwise indicated herein, the term “haloalkyl” refers to at least one halo group attached to an alkyl group. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, and fluoromethyl groups.

  Unless otherwise indicated herein, the term “cycloalkyl” includes non-aromatic saturated cyclic alkyl moieties, wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

  Unless otherwise indicated herein, the term “aryl” includes organic groups derived from aromatic hydrocarbons by removing one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. “Aryl” includes fused ring groups wherein at least one ring is aromatic.

  As used herein, the terms “heterocycle”, “heterocycloalkyl”, and like terms are each preferably one or more heteroatoms, preferably 1 to 4, preferably selected from oxygen, sulfur, and nitrogen. Refers to a non-aromatic cyclic group containing 1 heteroatom. The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydro Thiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro [4.5 Decyl, 1,4-dioxaspiro [4.4] nonyl, 1,4-dioxaspiro [4.3] octyl, and 1,4-dioxaspiro [4.2] heptyl.

  As used herein, the term “heteroaryl” refers to an aromatic group containing one or more heteroatoms (preferably oxygen, sulfur and nitrogen), preferably 1 to 4 heteroatoms. A polycyclic group containing one or more heteroatoms in which at least one ring of the group is aromatic is a “heteroaryl” group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzoimidazolyl, cindazolyl , Indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydro Isoquinolyl, tetrahydroisoquinolyl, benzene Zofuriru, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.

  Unless otherwise indicated herein, the term “one or more” substituents or “at least one” substituent refers to from 1 to the maximum number of possible substituents based on the number of available attachment sites. Point to.

Unless otherwise indicated, all groups described above derived from hydrocarbons, carbon atoms from about 1 to about 20 _(e.g., C 1 _{-C 20 alkyl,} C 2 _{-C 20 alkenyl,} C 3 _{-C 20} Cycloalkyl, 3-20 membered heterocycloalkyl, C ₆ -C ₂₀ aryl, 5-20 membered heteroaryl, etc.), or 1 to about 15 carbon atoms (eg, C ₁ -C ₁₅ alkyl, C _2- C _{15 alkenyl,} C 3 _{-C 15} cycloalkyl, 3-15 membered _{heterocycloalkyl,} C 6 _{-C 15} aryl, 5-15 membered heteroaryl, etc.), or carbon atoms from 1 to about 12 or from 1, It can have up to about 8 carbon atoms, or from 1 to about 6 carbon atoms.

  “Neurotoxin poisoning” refers to poisoning by a neurotoxin. A neurotoxin is any chemical or substance that can cause neuronal death and thus neurological damage. An example of a neurotoxin is alcohol, which, when abused by pregnant women, can result in alcoholism and neurological damage known as fetal alcohol syndrome in newborns. Examples of other neurotoxins include, but are not limited to, kainic acid, domoic acid, and achromelic acid; certain pesticides, such as DDT; certain insecticides, such as organophosphates; Volatile organic solvents such as hexacarbon (eg toluene); heavy metals (eg lead, mercury, arsenic and phosphorus); aluminum; certain chemicals used as weapons such as agent orange or nerve gas; and Neurotoxic antitumor agents are included.

  As used herein, a compound of formula I includes all pharmaceutically acceptable salts thereof.

As used herein, the term “selective PDE10 inhibitor” refers to a substance, such as an organic molecule, that effectively inhibits PDE10 family enzymes to a greater extent than PDE1-9 family or PDE11 family enzymes. In one embodiment, a selective PDE10 inhibitor is about 1/10 _{K i 'having} its substance for inhibition of any other PDE enzyme, a substance having a _{K i} for inhibition of PDE10, for example with organic molecules is there. In other words, the substance inhibits PDE10 activity to the same extent at a concentration of about 1/10 or less than that required for any other PDE enzyme.

In general, a substance is considered to effectively inhibit PDE10 activity if it has a K _i of about 10 μM or less, preferably about 0.1 μM or less.

  A “selective PDE10 inhibitor” can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity with the ability to inhibit PDE enzymes of other PDE families. For example, substances are analyzed for their ability to inhibit PDE10 activity in addition to PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11 be able to.

  The term “treating” as in “a method of treating a disorder” refers to the progression of the disorder to which such term applies, or to ameliorate, alleviate or inhibit the symptoms of one or more of the disorder. To do. As used herein, this term also refers to the prevention of a disorder, including preventing the onset of the onset of the disorder or any symptom associated with the disorder, as well as the disorder or any Also included is reducing the severity of symptoms. As used herein, “treating” also refers to preventing the recurrence of a disorder.

  For example, as used herein, “treating schizophrenia, or schizophrenia-like disorder or schizophrenic emotional disorder” refers to one or more symptoms (positive, negative, and other related features) of the disorder. It also includes treating, for example treating the associated delusions and / or hallucinations. Other examples of schizophrenia and symptoms of schizophrenia-like disorders and schizophrenic emotional disorders include disorganized conversations, flattening of emotions, allergies, loss of pleasantness, disproportionate feelings, discomfort (eg, depression, anxiety) Or forms of anger), and some signs of cognitive impairment.

  As used herein, the term “mammal” refers to any member of the “mammal web” and includes, but is not limited to, humans, dogs, and cats.

  The compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents. The pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like. Accordingly, the compounds of the present invention may be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation. Can be formulated in a form suitable for administration by.

  For oral administration, the pharmaceutical composition comprises a binder (eg, pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); a filler (eg, lactose, microcrystalline cellulose, or calcium phosphate); a lubricant (eg, Conventional with pharmaceutically acceptable excipients such as disintegrants (eg, potato starch or sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate); It may take the form of, for example, a tablet or capsule prepared by means. The tablets can be coated by methods well known in the art. Liquid dosage forms for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product consisting of water or other suitable vehicle prior to use. Such liquid preparations include suspending agents (eg, sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, or ethyl alcohol). ); And preservatives (eg, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid) and the like, and can be prepared by conventional means.

  For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner.

  The compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

  If a product solution is required, the product solution is isolated in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex. These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.

  The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.

  For intranasal administration or administration by inhalation, the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane. Conveniently delivered as an aerosol spray presentation from a pressurized container or nebulizer using difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.

  Aerosol formulations for treating the aforementioned conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows. The total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg. Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.

  Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula I per dose.

Assay methods can be used to screen substances for inhibition of cyclic nucleotide hydrolysis by PDE10 and other gene families of PDEs. Cyclic nucleotide substrate concentration used in the assay is 1/3 of the K _m concentration, allowing comparison IC ₅₀ values between different enzymes. PDE activity is measured using a method based on a scintillation proximity assay (SPA) previously described (Fawcett et al., 2000). The effect of a PDE inhibitor is determined by assaying a fixed amount of enzyme (PDE 1-11) in the presence of various substance concentrations and low substrates such that the IC ₅₀ approximates K _i (1/3 Km). CGMP or cAMP in a 3: 1 ratio of unlabeled and [ ³ H] labeled at concentration). The final assay volume is made up to 100 μl with assay buffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl ₂ , 1 mg / ml bovine serum albumin]. The reaction was initiated with the enzyme and incubated at 30 ° C. for 30-60 minutes to obtain <30% substrate turnover and 50 μl yttrium silicate SPA beads (Amersham) (each unlabeled cyclic nucleotide against PDE 9 and 11). Stop at 3 mM). The plate is resealed and shaken for 20 minutes, after which the beads are allowed to settle for 30 minutes in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT). Radioactivity units can be converted to percent of activity relative to the non-inhibited control (100%) and plotted against inhibitor concentration, inhibitor IC ₅₀ values can be obtained using the Microsoft Excel extended function “Fit Curve”. Obtainable.

Using such an assay, compounds of the present invention were determined to have an IC ₅₀ of less than about 10 micromolar for inhibition of PDE10 activity.

  The invention also relates to the preparation of compounds of formula I.

  The following schemes illustrate various methods for preparing the compounds of the present invention. It should be noted that the various substituents exemplified in the scheme (eg, R, X, A, etc.) are for illustrative purposes only and should be confused with those listed above and in the claims. Rather, they may be independent of them.

  Scheme 1 illustrates the preparation of pyrazole tricyclic classes of compounds of the present invention. Treatment of the acid with thionyl chloride provides the desired acid chloride. O, N-dimethylhydroxylamine hydrochloride is added to obtain the coupled Weinreb amide (Weinreb et al., Tet Lett., 1981, 22 (39) 3815). Anions are generated from heteroarylmethyl such as 4-picoline and LDA, or substituted toluene and n-butyllithium, followed by the addition of Weinreb amide to give the ketone. The ketone is then treated with dimethoxymethyl-dimethylamine at reflux to form the enaminone intermediate. Treatment with 2-hydrazinylethanol gives the pyrazole compound. Cyclization with heating with various bases such as potassium t-butoxide provides a 7-membered ring system. The 8-membered ring can be formed using hydrazinyl propanol. Alkylation of the substituted arylphenol with 2-methylchloroquinoline provides the desired ether. This quinoline can be replaced using the chemistry shown in Scheme 3 and Scheme 4.

  Scheme 2 illustrates a method for synthesizing all carbon 7 and 8 membered rings. The chemistry is the same as shown in Scheme 1 except that the starting halide is bromine or iodine. The hydrazine used is 1-allylhydrazine (7-membered) or 1- (but-3-enyl) hydrazine (8-membered). The halogen is then coupled by palladium catalyzed Stille coupling with vinyl stannane. Ring-closing metathesis (see Grubbs et al., Tetrahedron, 2004, pages 7117-7140) provides 7- or 8-membered tricyclic nuclei. Hydrogenation reduces the olefin and removes the benzyl protecting group. Alkylation with a heteroaryl halide gives the final compound.

  Many 8-9 membered heteroarylbenzyl halides or alcohols are commercially available or known from the literature. A common method for those skilled in the art to produce these intermediates is the reduction of esters, acids, or aldehydes to form alcohols. One common procedure is to oxidize the benylic site with selenium dioxide to give the aldehyde, which is subsequently reduced with sodium borohydride. Benzyl halides can be formed by halogenation (see Syn. Comm. 1995, 25 (21) 3427-3434). These analogs can then be coupled to phenol by alkylation or Mitsunobu reaction.

  Many 10-membered heteroaryl halides or alcohols are commercially available or known from the literature. A common method for those skilled in the art to produce these intermediates is the reduction of esters, acids, or aldehydes to form alcohols. One common procedure is to oxidize the benylic site with selenium dioxide to give the aldehyde, which is subsequently reduced with sodium borohydride. Benzyl halides can be formed by halogenation (see Syn. Comm. 1995, 25 (21) 3427-3434). These analogs can then be coupled to phenol by alkylation or Mitsunobu reaction.

Experimental Procedure General Experiments Unless otherwise specified, organic solvents were dried over magnesium sulfate or sodium sulfate. Room temperature is abbreviated as RT. The HPLC-MS system 1 is a Zorbax Bonus-RP ™ 4.6 × 150 mm column, 1.0 mL / min, solvent A = MeCN, solvent B = 0.1% aqueous formic acid in 10 minutes A: B1: 9 A Hewlett-Packard 1100 HPLC system consisting of a linear gradient from to A: B 95: 5 and equipped with a diode array and mass detector was used. HPLC system 2 used a linear gradient from A: B3: 7 to A: B95: 5 over 15 minutes. Where purification by RP-HPLC is indicated, a Shimadzu preparative HPLC instrument equipped with an X-Terra ™ 50 × 50 mm column, solvent A = acetonitrile, solvent B = water, each 0.1% trifluoroacetic acid ("Acidic conditions") or 0.1% concentrated ammonium hydroxide ("basic conditions"), A: B linear gradient from 25% to 85% in 10 minutes.

(Preparation 1)
4- (Benzyloxy) -2-fluoro-N-methoxy-N-methylbenzamide

４−（ベンジルオキシ）−２−フルオロ安息香酸（３．１５ｇ）のジオキサン（３２ｍＬ）／アセトニトリル（３２ｍＬ）溶液に、カルボニルジイミダゾール（２．６９ｇ）を添加した。窒素雰囲気下で１時間攪拌した後、トリエチルアミン（４．０８ｍＬ）およびＮ−メトキシメタンアミン塩酸塩（１．６１ｇ）を添加した。一晩攪拌した後、反応混合物を濃縮し、１Ｎ ＮａＯＨとクロロホルムに分配し、分離し、有機層を硫酸マグネシウムで乾燥、濾過し、濃縮した。１０〜３０％酢酸エチル／ヘキサンで溶出し、ｂｉｏｔａｇｅ ＭＰＬＣで精製して、表題化合物を得た（３．３３ｇ、９０％）。

Carbonyldiimidazole (2.69 g) was added to a solution of 4- (benzyloxy) -2-fluorobenzoic acid (3.15 g) in dioxane (32 mL) / acetonitrile (32 mL). After stirring for 1 hour under a nitrogen atmosphere, triethylamine (4.08 mL) and N-methoxymethanamine hydrochloride (1.61 g) were added. After stirring overnight, the reaction mixture was concentrated, partitioned between 1N NaOH and chloroform, separated, and the organic layer was dried over magnesium sulfate, filtered and concentrated. Elution with 10-30% ethyl acetate / hexanes and purification by biotage MPLC gave the title compound (3.33 g, 90%).

(Preparation 2)
1- (4- (Benzyloxy) -2-fluorophenyl) -2- (pyridin-4-yl) ethanone

４−ピコリン（３．３５ｍＬ）の溶液をＴＨＦ（３３ｍＬ）に溶解し、１当量のＬＤＡを０℃で添加した。別のフラスコに、４−（ベンジルオキシ）−２−フルオロ−Ｎ−メトキシ−Ｎ−メチルベンズアミド（３．３３ｇ）を添加し、これをＴＨＦ５５ｍＬに溶解し、−７８℃に冷却した。４−（ベンジルオキシ）−２−フルオロ−Ｎ−メトキシ−Ｎ−メチルベンズアミド溶液に、１当量の４−ピコリンアニオン溶液を添加し、反応物を１時間攪拌した。１時間後、さらに１当量の４−ピコリンアニオン溶液を添加した。さらに１時間後、反応混合物を酢酸５ｍＬでクエンチし、反応混合物を室温に温めた。飽和重炭酸塩溶液でｐＨを８に調節し、酢酸エチルで２回抽出し、硫酸マグネシウムで乾燥、濾過し、濃縮して、固体を得た。その固体をエチルエーテルで摩砕し、濾過し、乾燥して、表題化合物２．１９ｇを得た（６２％）。

A solution of 4-picoline (3.35 mL) was dissolved in THF (33 mL) and 1 equivalent of LDA was added at 0 ° C. To another flask was added 4- (benzyloxy) -2-fluoro-N-methoxy-N-methylbenzamide (3.33 g), which was dissolved in 55 mL of THF and cooled to -78 ° C. To 4- (benzyloxy) -2-fluoro-N-methoxy-N-methylbenzamide solution, 1 equivalent of 4-picoline anion solution was added and the reaction was stirred for 1 hour. After 1 hour, another equivalent of 4-picoline anion solution was added. After an additional hour, the reaction mixture was quenched with 5 mL of acetic acid and the reaction mixture was allowed to warm to room temperature. The pH was adjusted to 8 with saturated bicarbonate solution, extracted twice with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give a solid. The solid was triturated with ethyl ether, filtered and dried to give 2.19 g of the title compound (62%).

(Preparation 3)
2- (5- (4- (Benzyloxy) -2-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrazol-1-yl) ethanol

１−（４−（ベンジルオキシ）−２−フルオロフェニル）−２−（ピリジン−４−イル）エタノン（４００ｍｇ）の溶液に、ジエトキシ−Ｎ，Ｎ−ジメチルメタンアミン５ｍＬを添加した。反応物を１１０℃で２時間加熱し、濃縮した。反応混合物にエタノール４ｍＬ、水２ｍＬ、酢酸０．４５ｍＬ、および２−ヒドラジニルエタノール０．１１ｍＬを添加し、反応混合物を９０℃で４時間加熱した。反応混合物を１Ｎ ＮａＯＨに注ぎ入れ、クロロホルムで３回抽出し、硫酸マグネシウムで乾燥、濾過し、濃縮した。メチレン中２〜５％ＭｅＯＨで溶出し、Ｂｉｏｔａｇｅ ＭＰＬＣで精製。

To a solution of 1- (4- (benzyloxy) -2-fluorophenyl) -2- (pyridin-4-yl) ethanone (400 mg) was added 5 mL of diethoxy-N, N-dimethylmethanamine. The reaction was heated at 110 ° C. for 2 hours and concentrated. To the reaction mixture was added 4 mL of ethanol, 2 mL of water, 0.45 mL of acetic acid, and 0.11 mL of 2-hydrazinylethanol, and the reaction mixture was heated at 90 ° C. for 4 hours. The reaction mixture was poured into 1N NaOH, extracted three times with chloroform, dried over magnesium sulfate, filtered and concentrated. Elute with 2-5% MeOH in methylene and purify on Biotage MPLC.

(Preparation 4)
1-Pyridin-4-yl-8- (benzyloxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

２−（５−（４−（ベンジルオキシ）−２−フルオロフェニル）−４−（ピリジン−４−イル）−１Ｈ−ピラゾール−１−イル）エタノール（４８０ｍｇ）の溶液に、ＤＭＦ（８ｍＬ）およびカリウムｔ−ブトキシド（３０１ｍｇ）を添加し、反応混合物を１１５℃で８時間加熱した。反応混合物を１Ｎ ＮａＯＨに注ぎ入れ、クロロホルムで抽出し、硫酸マグネシウムで乾燥、濾過し、濃縮した。０．５〜２％ＭｅＯＨ／塩化メチレンで溶出し、Ｂｉｏｔａｇｅ ＭＰＬＣで精製して、表題化合物を得た（７５ｍｇ）。

To a solution of 2- (5- (4- (benzyloxy) -2-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrazol-1-yl) ethanol (480 mg), DMF (8 mL) and Potassium t-butoxide (301 mg) was added and the reaction mixture was heated at 115 ° C. for 8 hours. The reaction mixture was poured into 1N NaOH, extracted with chloroform, dried over magnesium sulfate, filtered and concentrated. Elution with 0.5-2% MeOH / methylene chloride and purification on Biotage MPLC gave the title compound (75 mg).

(Preparation 5)
1-Pyridin-4-yl-8-hydroxy-4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−（ベンジルオキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン（７５ｍｇ）の溶液に、エタノール１０ｍＬおよび酢酸エチル１０ｍＬ、水酸化パラジウム（７５ｍｇ）を添加し、Ｈ_２ガス３０ｐｓｉ下で４時間、Ｐａｒｒシェーカーに置いた。反応混合物をセライトで濾過し、濃縮した。０．５〜２％ＭｅＯＨ／塩化メチレンで溶出し、ｂｉｏｔａｇｅ ＭＰＬＣで精製して、表題化合物を得た（４５ｍｇ、８０％）。

To a solution of 1-pyridin-4-yl-8- (benzyloxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene (75 mg), 10 mL of ethanol and 10 mL of ethyl acetate, hydroxylated Palladium (75 mg) was added and placed on a Parr shaker under 30 psi of H ₂ gas for 4 hours. The reaction mixture was filtered through celite and concentrated. Elution with 0.5-2% MeOH / methylene chloride and purification by biotage MPLC gave the title compound (45 mg, 80%).

Example 1
1-Pyridin-4-yl-8- (quinolin-2-ylmethoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−ヒドロキシ−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレンのＤＭＦ（１ｍＬ）溶液に、炭酸セシウム（１５７ｍｇ）および２−（クロロメチル）キノリン塩酸塩（４２ｍｇ）を添加し、反応混合物を６０℃で６時間加熱し、１Ｎ ＮａＯＨに注ぎ入れ、エチルエーテルで３回抽出し、硫酸マグネシウムで乾燥、濾過し、濃縮した。０．５〜２％ＭｅＯＨ／０．５％ＮＨ_４ＯＨ／８０％酢酸エチル／ヘキサンで溶出し、Ｂｉｏｔａｇｅ ＭＰＬＣで精製して、表題化合物を得た（２５ｍｇ）。ＩＣ_５０＝０．８ｎＭ。

To a solution of 1-pyridin-4-yl-8-hydroxy-4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene in DMF (1 mL) was added cesium carbonate (157 mg) and 2- (chloromethyl). ) Quinoline hydrochloride (42 mg) was added and the reaction mixture was heated at 60 ° C. for 6 hours, poured into 1N NaOH, extracted three times with ethyl ether, dried over magnesium sulfate, filtered and concentrated. Elution with _{0.5~2% MeOH / 0.5% NH 4} OH / 80% ethyl acetate / hexane and purified by Biotage MPLC, to give the title compound (25 mg). IC ₅₀ = 0.8nM.

The following compounds can be prepared by the schemes and procedures described above.
1-Pyridin-4-yl-8- (quinolin-2-ylmethoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−（（１−メチル−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メタノキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン

1-pyridin-4-yl-8-((1-methyl-1H-benzo [d] imidazol-2-yl) methanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−（（Ｈ−イミダゾ［１，２−ａ］ピリジン−２−イル）メタノキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン

1-Pyridin-4-yl-8-((H-imidazo [1,2-a] pyridin-2-yl) methanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−（［１，２，４］トリアゾロ［１，５−ａ］ピリジン−２−イルメタノキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン

1-Pyridin-4-yl-8-([1,2,4] triazolo [1,5-a] pyridin-2-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo -Azulene

１−ピリジン−４−イル−８−（キナゾリン−２−イルメタノキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン

1-Pyridin-4-yl-8- (quinazolin-2-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene

１−ピリジン−４−イル−８−（イミダゾ［２，１−ｂ］チアゾール−６−イルメタノキシ）−４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ−アズレン、

1-pyridin-4-yl-8- (imidazo [2,1-b] thiazol-6-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene,

および１−ピリジン−４−イル−８−（キノリン−２−イルメトキシ）−４，５，６−ジヒドロ−３，３ａ−ジアザ−ベンゾ−アズレン。

And 1-pyridin-4-yl-8- (quinolin-2-ylmethoxy) -4,5,6-dihydro-3,3a-diaza-benzo-azulene.

Since the specific embodiments disclosed herein are for the purpose of illustrating some aspects of the invention, the invention described and claimed herein is limited to the scope of those embodiments. Is not to be done. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims (14)

A compound of formula I, or a pharmaceutically acceptable salt thereof

[Wherein ring 2 is monocyclic aryl or monocyclic heteroaryl, and said ring 2 may be substituted with at least one R ⁵ ;
HET ³ is an 8, 9, or 10 membered bicyclic heteroaryl, said HET ³ may be substituted with at least one R ⁶ ,
R ¹ is halogen, hydroxyl, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₃ to C, respectively. ₈ cycloalkyl, C ₃ to C ₇ heterocycloalkyl, C ₁ to C ₈ alkylthio, —NR ³ R ³ , C ₁ to C ₈ haloalkyloxy, —S (O) _r —R ³ , —C (O) — Independently selected from the group consisting of NR ³ R ³ , and C ₁ to C ₈ alkyl substituted with a heteroatom, wherein the heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur; From C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, and C ₁ to C ₈ haloalkyl May be further substituted with one or more substituents selected from the group consisting of:
Each R ³ is independently selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ haloalkyl, C ₃ to C ₈ cycloalkyl And
R ⁵ is halogen, hydroxyl, cyano, —NR ⁸ R ⁸ , C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₃ to C _{8, respectively.} Independently selected from the group consisting of cycloalkyl, C ₁ to C ₈ alkylthio, and C ₁ to C ₈ haloalkyl;
B ³ and B ⁴ are adjacent atoms of Het ³ , B ³ is carbon, B ⁴ is nitrogen,
X and X ¹ are each independently selected from the group consisting of oxygen, sulfur, C (R ² ) ₂ , and NR ² , provided that at least one of X or X ¹ is C (R ² ) ₂ ;
A and A ¹ are each independently selected from the group consisting of oxygen, S (O) _r , C (R ⁹ ) ₂ , and NR ⁹ , provided that at least one of A or A ¹ is C (R ⁹ ) ₂
R ² is hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₂ to C ₈ alkynyl, C ₂ to C ₈ alkenyl, C ₁ to C ₈ haloalkyl, respectively. And independently selected from the group consisting of C ₃ to C ₈ cycloalkyl,
R ⁶ is halogen, hydroxyl, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₁ to C, respectively. ₈ alkylthio, C ₃ to C ₈ cycloalkyl, —NR ⁷ R ⁷ , C ₁ to C ₈ haloalkyloxy, —S (O) _r —R ⁷ , —C (O) —NR ⁷ R ⁷ , substituted with heteroatoms is selected from C ₁ that is independently from the group consisting of C ₈ alkyl, heteroatom, nitrogen, is selected from oxygen, and from the group consisting of sulfur, the heteroatom is hydrogen, C ₈ alkyl from C _1, C ₁ further is substituted by _{C 8} cycloalkyl, substituents selected _{C 8} alkenyl _{C 2,} from _{C 2 C 8} alkynyl, and from the group of _{C 1} consisting _{C 8} haloalkyl from Or it may be,
Or two R ⁶ together with the atoms to which they are attached, C ₄ to C ₁₀ cycloalkyl, C ₄ to C ₁₀ cycloalkenyl, (4 to 10 membered) heterocycloalkyl, or (4 to 10 membered) hetero. May form a cycloalkenyl ring,
Each R ⁷ is independently selected from the group consisting of hydrogen and C ₁ to C ₈ alkyl;
Each R ⁸ is independently selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, and C ₂ to C ₈ alkynyl;
R ⁹ is hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₂ to C ₈ alkynyl, C ₂ to C ₈ alkenyl, C ₁ to C ₈ haloalkyl, respectively. And independently selected from the group consisting of C ₃ to C ₈ cycloalkyl,
n = 0 or 1, m = 1 or 2, p = 0, 1, 2, or 3 and r = 0, 1, or 2.] The HET ³ is selected from the group consisting of

Wherein, Y each, CH, are independently selected from the group consisting of CR 6 or ^nitrogen,, Z is oxygen or sulfur, The compound of claim 1. Y are all CH or CR ⁶ independently The compound of claim 2. The HET ³ is selected from the group consisting of:

The compound of claim 1.   The compound of claim 1, wherein Ring 2 is selected from the group consisting of phenyl, 4-pyridyl, 4-pyridazinyl, and isoxazolyl.   2. A compound according to claim 1 wherein ring 2 is 4-pyridyl. The compound of claim 1, wherein X ¹ is C (R ² ) ₂ and X is oxygen.   The compound of claim 1, wherein m and n are both 1. The compound of claim 1, wherein A and A ¹ are oxygen and C (R ⁹ ) ₂ , respectively. The compound is
1-pyridin-4-yl-8- (quinolin-2-ylmethoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene;
1-pyridin-4-yl-8-((1-methyl-1H-benzo [d] imidazol-2-yl) methanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene ;
1-Pyridin-4-yl-8-((H-imidazo [1,2-a] pyridin-2-yl) methanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene ;
1-Pyridin-4-yl-8-([1,2,4] triazolo [1,5-a] pyridin-2-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo -Azulene;
1-pyridin-4-yl-8- (quinazolin-2-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene;
1-pyridin-4-yl-8- (imidazo [2,1-b] thiazol-6-ylmethanoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene;
1-phenyl-4-yl-8- (quinolin-2-ylmethoxy) -4,5-dihydro-6-oxa-3,3a-diaza-benzo-azulene;
1-pyridin-4-yl-8- (quinolin-2-ylmethoxy) -4,5,6-dihydro-3,3a-diaza-benzo-azulene;
And the compound of claim 1 selected from the group consisting of pharmaceutically acceptable salts thereof.   A pharmaceutical composition for treating psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, said disorder or condition being treated A pharmaceutical composition comprising an amount of a compound of formula I according to claim 1 effective to do so.   A method of treating a disorder selected from psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, obesity, and neurodegenerative disorders, effective for treating said disorders Administering a compound of claim 1 in an amount.   The disorder is dementia, Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, cognition associated with Huntington's disease or Parkinson's disease Or AIDS-related dementia; delirium; amnesia disorder; post-traumatic stress disorder; mental retardation; learning disorders such as reading disorders, math disorders, or written expression disorders; attention deficit / hyperactivity disorder; Sexual cognitive decline, mild, moderate, or severe major depression episodes; depression or mixed mood episodes; mild mood episodes; depression episodes with atypical features; depression episodes with melancholic features; Depressive episodes with features; mood episodes with postpartum onset; post-stroke depression; major depressive disorder; mood modulation Harm; Minor depressive disorder; Premenstrual dysphoric disorder; Postpsychotic depressive disorder in schizophrenia; Major depressive disorder associated with psychotic disorder including delusional disorder or schizophrenia; Bipolar I disorder Bipolar type II disorder, bipolar disorder including mood circulation disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related dementia, frontotemporal dementia; Associated neurodegeneration; Neurodegeneration associated with stroke; Neurodegeneration associated with cerebral infarction; Hypoglycemia-induced neurodegeneration; Neurodegeneration associated with epileptic seizures; Neurodegeneration associated with neurotoxin poisoning; Multiple system atrophy, delusions Type, dismantled type, tension type, indistinguishable type, or remnant type; schizophrenia-like disorder; delusional or depressive type schizophrenic disorder; paranoid disorder; substance-induced psychotic disorder, alcohol, ampheta 13. A disease selected from the group consisting of: Cannabis, Cannabis, Cocaine, Hallucinogens, Obesity, Inhalants, Opioids, or Phencyclidine-Induced Psychosis; Delusional Personality Disorder; and Schizophrenic Personality Disorder The method described in 1. A method of treating psychotic disorders, delusional disorders, and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, an amount effective to inhibit PDE10 A method comprising administering a compound according to claim 1.