Reference To Related Application

This application claims the benefit of U.S. Provisional Application Serial No. 61/108962 filed October 28, 2008.

Field of the Invention

The present invention relates to substituted pyrazoioquinoϊines and derivatives thereof, to the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors for the treatment of PDE10-modulated disorders, to pharmaceutical compositions comprising the compounds, and to the use of additional substituted pyrazoloquinolines and derivatives thereof for the treatment of PDE10-modu!ated diseases.

Background of the Invention

Schizophrenia, a debilitating psychiatric illness affecting 1% of the world's population, is thought to be at least partly due to excessive nigral dopaminergic and insufficient corticostriatal glutamatergic input to the striatum. These neurochemical abnormalities lead to reduced striatal output to other areas of the brain, resulting in inappropriate behavioral activation. The efficacy of existing antipsychotics is largely due to antagonism of D2 dopamine receptors in the striatal medium spiny neurons (MSNs) that project to the globus pallidus (also known as the striatopailidal indirect output pathway). D2 dopamine receptor antagonism increases striatal output via the indirect striatopalϋdal pathway, which improves some of the aspects of schizophrenia, but does not affect striatal output via the direct striatonigral output pathway.

PDE 10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehier et ai, "The potential therapeutic use of phosphodiesterase 10 inhibitors' ^' , Expert Opin. Ther. Patents (2007) 17(2):147-158.

PDE10 is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery. By increasing cAMP and cGJviP levels in ai! striatal MSNs, PDE10 inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopaliidai output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striata! output that characterizes schizophrenia. By increasing corticostriatal transmission, PDE10 inhibition should improve the cognitive dysfunction that characterizes schizophrenia. Furthermore, the discrete localization of PDE 10 should lead to an improved side effect profile: typical side effects inciude extrapyramidal syndrome, diabetes, weight gain, hyperproiactinemia, sedation and QT _C prolongation.

PDE10 inhibitors have also been reported to be useful in treating in other CNS disorders such as psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome.

Papaverine has been identified as a PDE10 inhibitor, and has been shown to be effective in animal models of schizophrenia.

Heteroaromatic quinoline compounds useful as PDE 10 inhibitors are disclosed in VVO 2006/072828, and pyrrolodihydroisoquinoline PDE 10 inhibitors are disclosed in WO 2006/089815.

Antiviral and/or antitumor pyrazoloquinolines are disclosed in US 5,459,146, US 5,506,236 and US 5,608,067, and by Crenshaw et al, J. Med. Chem., 19(2), 262-275 (1976). Pyrazoloquinolines useful as activators of caspases and inducers of apoptosis are disclosed in US 2007/0253957 A1.

Summary of the Invention

In its several embodiments, the present invention provides a novel class of substituted pyrazoloquinoline PDE 10 inhibitor compounds and derivatives thereof represented by Formula I, below, pharmaceutical compositions comprising one or more of said compounds, and methods of treating PDE10 inhibitor mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds or pharmaceutical compositions. The invention also provides for methods of treatment of PDE10 inhibitor- mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome, using a class of substituted pyrazoϊoquinoiiπe PDE10 inhibitor compounds and derivatives thereof represented by Formula II,

Novel compounds of the invention have the structural Formula I:

Formula or a pharmaceutically acceptable salt thereof, wherein all substituents are independently selected; and the carbon atoms to which it is attached form a phenyl ring, a heteroaryl ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R ² is absent;

R ¹ is H, alkyl, alkoxy, aikoxyalkoxy, OH ₁ hydroxyalkyl, -CF ₃ , -OCF ₃ , halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO ₂ H, -C(O)N(R ^6A ) _2! -N(R ^6β ) ₂ , -alkySN(R ^6B ) _2l -NR ⁶ -C(O)N(R ^6A ) ₂ , -N(R ⁶ )C(O)Oalky(, -N(R ⁶ )SO ₂ -alkyl, phenyl, CN,

-SO ₂ R ⁵ , -SR ^fa , trimethylsilyl-, -SF _5s -OSF ₅ , ^{" ■ / r} , or

-(CH ₂ ) _n -X~(CH ₂ )m-R ¹⁸ , wherein X is -0-, -S-, or -NR ⁶ -, n is O, 1 or 2, m is 1 , 2 or 3 and R ¹⁸ is selected from the group consisting of

R ² is H ₁ aikyl, alkoxy, alkoxyalkoxy, OH ₅ hydroxyalkyl, -CF ₃ , -OCF ₃ , halo, -O-cycloalkyl, benzyloxy, -C(O)Oaiky!, -O-alkyl-CO ₂ H, -C{O)N(R ^δA ) _2[ -N(R ^6B ) _2i -aikylN(R ^6B ) ₂ , -NR ⁶ ~C(O)N(R ^6A ) ₂ , -N(R ⁶ )C(O)Oatkyl, -N(R ⁶ )SO ₂ -alkyi, phenyl or CN; or R ¹ and R ² on adjacent ring carbon atoms together form -O-CH ₂ -O- or ~O-(CH ₂ ) ₂ -O-;

R ³ is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyaikyl, cycloalkyi, ~N(R ^6B ) ₂ , -OCF ₃ , -CF ₃ , -SF ₅ , -OSF ₅ or -CN;

R ⁴ is H, alkyi, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -aikyi-OC(O)-alkyi, -SO ₂ -alkyl, -C(O)N(R ^δA ) ₂ or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;

R ⁵ is alkyl, -CN, -C{O)OR ^6A , -C(O)N<R ^6A ) ₂ , aryI-{(R ^17a , R ^17b )-alkylene)-, heteroary!~((R ^17a , R ^17b )-alkylene)-, heterocycϊoa!kyl-((R ^17a , R ^17b )-aikylene)-, hydroxyalkenyl, heteroarylalkenyl-, arylalkynyi- ₅ heteroaryiaikynyh bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, -alkyl-O-heteroaryl, -atkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -a!kyl-N(R ⁶ )~aryl, -atkyi-N(R ⁶ )-heteroary[ ₁ -aikyl-N(R ^β )-cycioalkyl, -aIkyl-N(R ^e )-heterocycloalkyl, ~a!kyl-heterocycioalkyl, heterocycloalkenyl, heteroaryl, heterocycloaikyl-heteroaryl-aikylene-, cycloalkyl (e.g., cyctopropyl),

b is 1 , 2 or 3; r is 1 or 2; t is O ₁ 1 or 2; each R ⁶ is independently selected from H and alky!; each R ^6A is independently selected from the group consisting of H, alkyl, aryi, heteroaryi, cycloalkyl, arylaJkyl- and heteroaryiaikyl-; or two R ^6A groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R ^6A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morphoiinyi, homomorpholinyi, thiomorphoJinyi or homothiomorpholinyf ring; each R ^6B is independently selected from the group consisting of H, aikyl, aryl, heteroaryi, cycloalkyl, arylalkyh heteroarylalky!-, -SO ₂ alky!, ~SO ₂ -aryi, -SOa-heteroaryS, -C(O)a!kyi _s -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl. -C(O)O-heteroaryi, -C(O)N(R ⁶ J ₂ , -C(O)N R ⁶ -aryϊ, and -C(O)NR ⁶ ~heteroaryI; or two R ^6B groups are afky! and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R ^6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morphoiinyl, homomorphoiinyl, thiomorphofinyl or hornothiomorpholiπyl ring; R ⁹ is H, aikyi, or two hydrogen atoms on a carbon ring member are replaced by =O;

R ¹¹ is alkyl, phenyl or two hydrogen atoms on a single carbon ring member are replaced by a spirocyclic group is formed by replacing two hydrogen atoms on a singte carbon ring member with -(CH ₂ ) ₂ _ ₆ - or ~O~(CH ₂ ) ₂ -O-;

R ¹² is 1 or 2 substituents independently selected from the group consisting of aikyi, hydroxyalkyl and fluoroalkyl;

R ¹³ is hydroxyaikyl, cycloalkyl, -C(O)-cycloaIkyi, -C(O)-a!kyl-cycloaikyi, aryi, aiyialkyh -C(O)alkyl, -C(O)Oatkyl, -C(O)aryl, -C(O)-alkylaryl, -C(O)O-ary1, -C(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryi, -C(O)N(R ^6A ) ₂ , -C(O)-alky!-NR ⁶ -C(O)-ary! _! -C{O)-alky!-NR ⁶ -C(O)O-a!kyi, -C(O)-alkyϊ-NR ⁶ -C(O)O- bertzyl, ~SO ₂ alkyl, -SO ₂ -aryl, -SO ₂ -alkylaryl, -SO ₂ -heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with haio;

R ¹⁴ is H, alky!, hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalky ^j -, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-a!kylaryl, -C(O)O-aryl, -C(O)O-alkylaryl, heteroaryl, heteroaryiaikyh -C(O)-heteroaryl, -C(O)N(R ^6A ) ₂ , -C(O)-alkyi-NR ⁶ -C(O)-aryi, -C(O)-alkyl-NR ⁶ -C(O)O~ alkyl, -C(O)-alkyl-NR ⁶ -C(O)O-benzyI, -S0 ₂ aSkyl, -SO ₂ -aryl, -SO ₂ -alkylaryl, -SO ₂ - heteroaryl or diphenylmethyl, optionally substituted on a phenyl ring with halo;

R ¹⁵ is 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, OH, hydroxyaikyl, halo, -CF ₃ , -C(O)Oalkyi, -C(O)N(R ^6A ) _2t aminoalkyh -N(R ^6B ) ₂ , -NR ⁶ -C(O)N(R ^6A ) ₂ , -NR ⁶ ~C(O)-aikyi, -NR ⁶ -C(O)OaJkyl, -NR ⁶ -SO ₂ -alkyl, -alkyl-imidazolyl, wherein the imidazolyl is optionally substituted with alky!, and phenyl, or two hydrogen atoms on a carbon ring member are replaced by -(CH ₂ J ₂ -S- or -O- (CH ₂ ) ₂ ~O-; and

R ^17a is H or alkyl and R ^17b is H _} alkyl, OH, F, -N(R ^6B ) _2! -NOR ⁶ , aSkoxy, CN, -CH ₂ OH ₁ -CH ₂ -O-alkyl, -CON(R ^βa ) ₂ , -CH ₂ N(R ⁶ ) ₂ Or -CO ₂ R ⁶ ; or R ^17a and R ^17b are each F; or R ^17a and R ^17b are on the same carbon atom and together are =0, =NOR ^δ or

-iCH2)2-% ^' , provided that when R ⁵ is heterocycloa!kyl-((R ^17a , R ^m )~Eϊlkyϊene)- and the heterocycloalkyl ring is joined to the alkyiene group by a ring nitrogen, the R ^17b substituent on the α-carbon is H, alkyl, CN, -CH ₂ OH ₅ -CH ₂ -O-alkyf, ~CON(R ^6a ) ₂ , ~CH ₂ N(R ^δ ) ₂ or -CO ₂ R ⁶ . in one example, R ³ for Formula i is H, alkyl, halo, fluoroaikyl, aikoxyalkyl, hydroxyaikyl, cycloaikyi, -N(R ^6B ) ₂ , -OCF ₃ , -SF ₅ , -OSF ₅ or -CN,

In one example R ⁵ for Formula I is alkyl, -CN, -C(O)OR ^6A , -C<O)N(R ^6A ) ₂ , aryi-«R ^17a , R ^17b )-alkylene)-, heteroaryI-((R ^17a , R ^17b )-alkylene)-, heterocycloalkyKfR ¹⁷⁸ , R ^17b )-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, aryialkynyl- heteroarylaikynyh bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl - alkyl-O-heteroaryi, -alkyi-O-cycloalkyl, -alkyi-O-heterocycloalkyl, ~alkyl-N(R ⁶ )-aryl, -alkyl-N(R ⁶ )-heteroaryl, -alkyl-N(R ⁶ )-cycioalkyl, -alkyi-N(R ⁶ )-heterocyc!oalkyl, -alkyl-heterocycϊoalkyl, heterocycloalkenyl, heteroaryi,

The present invention further includes the compound of formula i in all its isolated forms.

The present invention also relates to a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a method of treating PDE 10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering a therapeutically effective amount of at least one compound of Formuia I or a pharmaceuticaϊly acceptable salt thereof to a mammal in need of such treatment. In another embodiment, the invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceuticaliy acceptable carrier.

In another embodiment, the present invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of structural Formula il:

Formula Il or a pharmaceutically acceptable saft thereof, wherein all substrtutents are independently selected;

⁽ S < ^■" and the carbon atoms to which it is attached form a phenyl ring, a heteroaryi ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R ² is absent;

R ¹ is H, aikyi alkoxy, alkoxyalkoxy, OH, hydroxyaikyl, -CF ₃ , -OCF ₃ , halo, -O-cycløalky!, benzyloxy, -C(O)OaikyL -O-aIkyl~CO ₂ H, -C(O)N(R ^6A ) ₂₎ -N(R ^6B ) ₂ , -afkyiN(R ^6B ) ₂ , -NR ⁶ -C(O)N(R ^6A ) _2s -N(R ⁶ )C{O)Oalkyl. -N(R ⁶ )SO ₂ ~aIkyf, phenyl, CN,

-SO ₂ R ⁶ , -SR ⁶ , trimethylsiiyh ~SF _5s -OSF _5i -C(=NOR ⁶ )-R ⁶ <λ ^~ or

-(CH ₂ )π-X-(CH ₂ }m-R )18 , wherein X is -0-, -S-, or -NR -, n is O, 1 or 2, m is 1 , 2 or 3, and

R ,18 is selected from the group consisting of

R ² is H, aikyi, alkoxy, aikoxyaikoxy, OH, hydroxyafkyi, -CF ₃ , -OCF ₃ , halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-aϊkyl-CO ₂ H, -C(O}N(R ^6A ) ₂ , -N(R ^6B ) ₂ , -aikylN(R ^6B ) ₂ , -NR ⁶ -C(O)N(R ^6A ) ₂ , -N(R ⁶ )C(O)Oalky[ _! -N(R ⁶ )SO ₂ -alkyi, phenyl or CN; or R ¹ and R ² on adjacent ring carbon atoms together form -0-CH ₂ -O- or -O-(CH ₂ ) ₂ -O-; r is 1 or 2;

R ³ is H, aikyi, halo, fluoroalkyi, aikoxyalkyl, hydroxyaikyl, cycioalkyl, -N(R ^6B ) ₂ , -OCF ₃₁ -SF ₅ , -OSF ₅ or -CN;

R ⁴ is H, alky!, alkoxyaikyk benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl~OC(O)-alky!, - SO ₂ -alkyt, ~C(0)N(R ^8A ) ₂ or -C(O}O-benzyl, wherein benzyf is optionally substituted by halo or alkoxy;

R ^SA is H, halo, OH, alkoxy, -O-alkyl-N(alkyl) _2t -O-heterocycloalkyl, -O-alkyl-heterocycloafkyf, aryloxy-, arylalkoxy-, heteroaryloxy-. -N(R ^SA ) _2l -NR ⁶ -a!ky!-N(alkyl) _2> -NR ⁶ -atky^O-alkyi-OH, ~NR ⁶ -hydroxyaikyi, -S-alkyi, -S-hydroxyalkyl, -S-aryL -S-alkylaryi, -S-heteroaryi, -S-alkyi-heterσaryl, -S-heterocycloalkenyl, -SC(O)-alkyl, -SO ₂ -aϊkyI, -S-alkyI~C(O)OH, -5-aIkyI-N{aikyI) ₂ ,

— N N-a!kyl

-S-alkyl-NHC(O)H, -S-alkyl-C(O)NH-alkyl-pyrrolidinone, ^r

each R ⁶ is independently H or alkyi; each R ^6A is independently selected from the group consisting of H ₅ alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl- and heteroarylalkyl-; or two R ^6A groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R ^6A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homornorpholinyl, thiomorpholinyl or homothiomoφholϊnyl ring; and each R ^6B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl-, heteroarylalkyl-, -SC^alkyl, -SCVaryi, -SO ₂ -heteroaryi _! -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -C(0)0-heteroaryi, -C(O)N(R ⁶ ) ₂ , -C(O)NR ⁶ -aryl, and -C(O)N R ⁶ -heteroaryl; or two R ^6B groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R ^6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorphoitnyl or homothiomorphoiinyi ring. in another embodiment, the invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula Il or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Detailed Description

In one embodiment of Formula i, ⁽ S <■ forms a phenyl ring,

In some embodiments of Formula I ₁ R ¹ and R ² are independently selected from the group consisting of R ¹ is H, alkyl, alkoxy, alkoxyalkoxy, -CF ₃ , -OCF ₃ and halo.

In other embodiments of Formula I:

R ¹ is alkyl, preferably methyl, and R ² is alkoxy, preferably methoxy; or R ¹ is alkyl, preferably methyl, and R ² is -OCF ₃ ; or

R ¹ is alkyl, preferably methyl, and R ² is H, OH, haio or alkoxyalkoxy (preferably methoxyethoxy); or

R ¹ is alkoxy, preferably methoxy, and R ² is alkoxy, preferably methoxy, or H; or R ¹ is alkoxyalkoxy (preferably methoxyethoxy) and R ² is H; or R ¹ is halo and R ² is H; or R ¹ is haio and R ² is -OCF ₃ ; or R ¹ and R ² together are methylenedioxy,

In another embodiment of Formula I ₁ R ³ is alkyl, preferably methyl, or H.

In another embodiment of Formula I, R ³ is -CF ₃ .

In another embodiment of Formula I, R ⁴ is H, -C(O)O-alkyl, wherein alkyl is preferably t-butyl, or -SOaalkyl, preferably -SO ₂ CH ₃ .

In another embodiment of Formula I, b is 1.

In another embodiment of Formula I, R ⁵ is selected from the group consisting of -CN, -C(O)N(R ^6A ) ₂ , aryK(R ^17a , R ^17b )-alkylene)-, heteroaryl-((R ^17a , R ^17b )-alkylene)-, heterocycloalkyi-((R ^17a , R ^17b )-alkylene)~, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyf, heteroary! (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), , wherein b, r, R ⁶ , R ^6A _S R ⁹ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ R ¹⁵ , R ^17a and R ^17b are as defined above.

In other embodiments of Formula I ₁ R ⁵ is -CN; -C(O)NH-alkyl-pyridyi; -CH(OH)-pheny); -alkylene-phenyl; -aikylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyI;

-CH(OH)-pyridyl; -CH=CH-(CH _Ξ ) ₃ -OH;

^{' 14} wherein R ¹⁴ is H, alkyi (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);

wherein R ¹⁴ is H or atkyl; or In another embodiment of Formula I ₁ when R ⁵ is heterocycloa!kyl-((R ^17a , R ^17b )~ aikylene)-, (R ^17a , R ^17b )-aikylene- is preferably -C(OH)-, and R ⁵ is a group such as

In another embodiment of Formula I, R ⁵ is heterocycloalkyl-((R ^17a , R ^17b )- alkylene)-, wherein R ^17a and R ^17b are independently H or aikyl, R ⁵ being preferably

wherein b is 1 , 2 or 3; r is 1 or 2;

R ⁷ is H, a!kyl or -SO ₂ -aiky!;

R ⁸ is 1 or 2 substituents independently selected from the group consisting of H, aikyl, OH ₁ hydroxyalkyf, halo, and -CF ₃ ;

R ⁹ is H, alky!, or two hydrogen atoms on a carbon ring member are replaced by =0; and

R ¹⁰ is H, aikyl or hydroxyalkyl.

Additional embodiments of compounds of Formula I wherein R ⁵ is

.0

-CH ₂ -N NH -CH ₂ -N NH heterocycloalkyl-((R > 1 ¹ 7 ^/ a ^a , R ^{1 /D} )-aikylene)~ are

-CH ₂ -N' "NSO ₂ CH ₃

optionally substituted by m ethyl or hydroxymethyl, optionally

-CH ₂ -N / substituted by OH, F or CF ₃ , and V—- ¹ optionally substituted by methyl or OH. Sn another embodiment of Formula I ₁ R ⁵ is , r is 1 , R ⁹ is H or aikyi,

and R ¹³ is -SO ₂ alkyl, -CONH ₂ , -C(O)heteroary! _f for example

C(0)cycloalkyl, for example ; more preferably, R ¹³ is -SO ₂ aikyl or

N _NR 13

-CONH ₂ . In another embodiment, R ⁵ is ^{W r} r is 2, R ⁹ is H and R ¹³ is

~SO ₂ alky! or -CONH ₂ .

In another embodiment of Formula I, R ⁵ is _r j _s 2, and R ¹⁵ is alky! (preferably methyl), allkoxy (preferably methoxy), -CF ₃ , OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH ₂ , -C(O)NH ₂ , -CH ₂ NH ₂ , -C(O)0-alkyl, -NHSO ₂ alkyl Or -NHC(O)NH ₂ , where R ¹⁵ is preferably in the

4-position. In another embodiment, R ⁵ is M _r js _{s 2} 2,, and R ¹⁵ is hydroxyalkyl, preferably hydroxymethyl, in the 3-position.

In another embodiment of Formula 1, R ⁶ is r is 1. and R ¹⁵ is OH or hydroxyalkyl (preferably hydroxymethyl).

Exampies of the heterocycfoaikyl-heteroaryl-alkytene- R ⁶ group for Formula I include, but are not limited to:

Thus, in one example the heterocycloalkyl-heteroaryl-alkylene- R ⁵ group for Formula I is:

In another example the heterocycloalkyf-heteroaryl-aikyiene- R ⁵ group for Formula I is

In another example the heterocycloalkyf-heteroaryf-aikylene- R ⁵ group for Formula I is

in one example the R ⁵ cycJoalkyl group is cyclopropyl In another embodiment of the compounds of Formula I:

R ¹ and R ² are independently selected from the group consisting of H, aikyf, afkoxy, alkoxyaikoxy, -CF ₃ , -OCF ₃ and halo.

R ³ is H or alky!;

R ⁴ is H ₁ -C(O)O-aikyl or -S0 ₂ alkyl; and

R ⁵ is selected from the group consisting of -CN ₁ -C(O)N{R ^6A ) ₂₍ aryi-((R ^17a , R ^17b )- alkylene)-, heteroaryl-((R ^17a , R ^17b )-alkyϊene)~, heterocycloalkyK{R ^17a _s R ^17b )-alkylene)-, hydroxyalkenyl, heteroarylalkenyh heteroarylalkynyl-, heterocycloalkenyi, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen),

, wherein b, r, R ⁶ , R ^6A R ^s , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ _S R ^17a and R ^17b are as defined above. in yet another embodiment of the compounds of Formula !:

R ¹ is alky!, preferably methyi _s and R ² is alkoxy, preferably methoxy; or

R ¹ is alkyj, preferably methyl, and R ² is -OCF ₃ ; or

R ¹ is alky!, preferably methyl and R ² is H, OH, haio or alkoxyaikoxy (preferably methoxyethoxy); or

R ¹ is aikoxy, preferably methoxy, and R ² is alkoxy, preferably methoxy, or H; or

R ¹ is alkoxyaikoxy (preferably methoxyethoxy) and R ² is H; or

R ¹ is halo and R ² is H; or

R ¹ is halo and R ² is -OCF ₃ ; or R ¹ and R ² together are methyleneciioxy; R ³ is alkyl; R ⁴ Is H; and

R ⁵ is -CN; -C(O)N H-alkyf-pyridyϊ; ~CH(OH)~phenyi; -alkylene-phenyl; -aϊkylene-pyridyl, -C(O)-pyridyi, -CH(F)-pyπdyl; -CH(OH)-pyridy);

^■ (CH ₂ ) _b -NR , ⁶ — < O — ¹⁴ wherein R ¹⁴ is H, alky!

(preferably methyl) or hydroxyalkyi (preferably hydroxyethyl);

~NR ⁶ -(CH ₂ } _b — / ) -NR ⁶ -(CH ₂ ) _b — / NR ¹⁴

N ' ; > ' wherein R is preferably H or alkyl; heterocycloalkyl-((R ^17a , R ^17b )-alkylene)-, wherein (R ^17a , R ^17b )-alkylene is heterocycϊoatkyl-((R ^17a , R' ^7b )-aikyiene)~, wherein R ^17a and R ^17b are independently H or alky!, preferably

, wherein b is 1 , 2 or 3; r is 1 or 2; R ⁷ is H, alky! or -SO ₂ -aikyI; R ⁸ is 1 or 2 substituenfs independently selected from the group consisting of H, alkyi, OH, hydroxyalkyS, halo, and -CF ₃ ; R ⁹ is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0: and R ¹⁰ is H, alkyl or hydroxyalkyf;

— N NR ¹³ w ^r , wherein r is 1 , R ⁹ is H or a!kyi _s and R ¹³ is -S0 ₂ alkyl, -CONH ₂ , -C(0}heteroaryi, for example ^OH , or -C(0)cycloalkyi, for example

; more preferably R ¹³ is -S0 ₂ alky! or -CONH ₂ ;

herein r is 2, R ⁹ is H and R ¹³ is -S0 ₂ alkyl or -CONH ₂ ; wherein r is 2, and R ¹⁵ is alkyl (preferably methyl), alikoxy (preferably methoxy), -CF ₃ , OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH ₂ , -C(O)NH ₂ , -CH ₂ NH ₂ , -C(O)O-alkyl, -NHSO ₂ alkyl or -NHC(O)NHa, where R ¹⁵ is preferably in the 4-position; wherein r is 2, and R ¹⁵ is hydroxyaikyl, preferably hydroxymethyi, in the 3-positioπ; or wherein r is 1 , and R » 15 ; i,s OH or hydroxyaikyl (preferably hydroxymethyl). Preferred compounds of Formula I are those in Examples 3E, 3F, 3S, 3V, 3BB, _4i 4A _t 4B, 4F, 4H _t 41, 4K, 4L 5, 5F, 5G, 5K ₁ 5M, 50, 5Q, 5R, 5S ₁ 6H, 7A, 7B ₅ 7E, 8, 8A, 8B, 8C, 9, 1OA, 10C ₁ 1OD, 1OE, 10F, 10G ₁ 1OH, 13, 13-1 , 13A, 13B, 13C ₁ 13D, 13F, 13G ₁ 13I ₁ 13J, 13K ₁ 13L, 13N, 130, 13P, 13Q ₁ 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 23, 24, 26 _S 27, 27A, 27B, 27C, 28, 29A ₁ 29B, 29D, 29E, 29F, 32B, 33, 34A ₁ 34B, 35, 36C, 36E ₁ 36F ₁ and 36G2.

More preferred compounds of Formula I are Examples 3E ₁ 3F, 3S ₁ 3V _S 4, 4B ₁ 4F, 4H, 4I ₁ 4K, 5, 5F, 5K ₁ 5M, 50, 5G, 5R, 5S ₁ 6H, 7E ₁ 8B, 8C, 9, 1OA, 1OC, 1OD, 1OE, 10F ₁ 10G ₁ 1OH, 13, 13A ₁ 13C, 13F ₁ 13G, 131, 13J, 13K ₁ 13L, 13N ₁ 130, 13P, 13Q, 13R ₁ 13S, 13V, 14, 15, 16, 17, 18, 21 B ₁ 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B, 29F, 32B, 34B, 35, 36C, 36E ₁ 36F, and 36G2. in one embodiment the compound of Formula i is 3E. In another embodiment the compound of Formula ! is 3F. In another embodiment the compound of Formula i is 3S. in another embodiment the compound of Formula I is 3V. In another embodiment the compound of Formula I is 3BB. in another embodiment the compound of Formula 1 is 4. In another embodiment the compound of Formula I is 4A. In another embodiment the compound of Formula I is 4B. In another embodiment the compound of Formula I is 4F, In another embodiment the compound of Formula i is 4H. In another embodiment the compound of Formula I is 41. In another embodiment the compound of Formula I is 4K. In another embodiment the compound of Formula I is 4L, In another embodiment the compound of Formula I is 5. In another embodiment the compound of Formula I is 5F. In another embodiment the compound of Formula I is 5G. In another embodiment the compound of Formula f is 5K. In another embodiment the compound of Formula 1 is 5M. In another embodiment the compound of Formula I is 50. In another embodiment the compound of Formula ! is 5Q. In another embodiment the compound of Formula I is 5R. In another embodiment the compound of Formula S is 5S. In another embodiment the compound of Formufa I is 6H. in another embodiment the compound of Formula I is 7A. fn another embodiment the compound of Formula I is 7B. in another embodiment the compound of Formula I is 7E. In another embodiment the compound of Formula I is 8. In another embodiment the compound of Formula I is 8A. In another embodiment the compound of Formula I is 8B. In another embodiment the compound of Formula 1 is 8C. In another embodiment the compound of Formula I is 9. In another embodiment the compound of Formula I is 1OA. fn another embodiment the compound of Formula I is 1OC. In another embodiment the compound of Formula ! is 1OD. In another embodiment the compound of Formula I is 1OE. In another embodiment the compound of Formula I is 1OF. In another embodiment the compound of Formula I is 10G. In another embodiment the compound of Formula I is 10H. In another embodiment the compound of Formula I is 13. In another embodiment the compound of Formula I is 13- 1. In another embodiment the compound of Formula I is 13A. In another embodiment the compound of Formula I is 13B. In another embodiment the compound of Formula I is 13C. In another embodiment the compound of Formula i is 13D. In another embodiment the compound of Formula ! is 13F. In another embodiment the compound of Formula I is 13G. In another embodiment the compound of Formula I is 131. In another embodiment the compound of Formula I is 13J. In another embodiment the compound of Formula I is 13K. In another embodiment the compound of Formula I is 13L. In another embodiment the compound of Formula I is 13N. In another embodiment the compound of Formula I is 130. In another embodiment the compound of Formula I is 13P. In another embodiment the compound of Formuia I is 13Q. In another embodiment the compound of Formuia I is 13R. In another embodiment the compound of Formula I is 13S. In another embodiment the compound of Formula I is 13T. In another embodiment the compound of Formula I is 13V. In another embodiment the compound of Formula I is 14. In another embodiment the compound of Formula I is 15. In another embodiment the compound of Formula Ms 16. In another embodiment the compound of Formula ! is 17. In another embodiment the compound of Formuia I is 18. In another embodiment the compound of Formuia I is 21 B. Sn another embodiment the compound of Formula I is 21 D. In another embodiment the compound of Formula ! is 21 F. In another embodiment the compound of Formuia f is 22. In another embodiment the compound of Formula I is 23. In another embodiment the compound of Formula I is 24. in another embodiment the compound of Formula ! is 26. In another embodiment the compound of Formula ! is 27. In another embodiment the compound of Formula I is 27A. In another embodiment the compound of Formula I is 278, In another embodiment the compound of Formula I is 27C. tn another embodiment the compound of Formula ! is 28, In another embodiment the compound of Formula I Is 29A. In another embodiment the compound of Formula I is 298, In another embodiment the compound of Formula i is 29D. in another embodiment the compound of Formula i is 29E. In another embodiment the compound of Formula I is 29F. In another embodiment the compound of Formula I is 32B. In another embodiment the compound of Formula I is 33. In another embodiment the compound of Formula I is 34A. in another embodiment the compound of Formula I is 34B. In another embodiment the compound of Formula I is 35. In another embodiment the compound of Formula I is 36C. In another embodiment the compound of Formula I is 36E. in another embodiment the compound of Formula I is 36F. in another embodiment the compound of Formula I is 36G2.

in one embodiment of the compound of Formula Il forms a phenyl ring.

In some embodiments of Formula II, R ¹ and R ² are independently selected from the group consisting of R ¹ is H, alkyl, aikoxy, alkoxyaikoxy, -CF ₃ , -OCF ₃ and halo.

In other embodiments of Formula II:

R ¹ is aikyl, preferably methyl, and R ² is alkoxy, preferably methoxy; or R ¹ is alkyl, preferably methyl, and R ² is -OCF ₃ ; or

R ¹ is alkyl, preferably methyl, and R ² is H, OH, halo or alkoxyaikoxy (preferably methoxyethoxy); or

R ¹ is alkoxy, preferably methoxy, and R ² is alkoxy, preferably methoxy, or H; or R ¹ is aikoxyalkoxy (preferably methoxyethoxy)and R ² is H; or R ¹ is halo and R ² is H; or R ¹ is halo and R ² is -OCF ₃ ; or R ¹ and R ² together are methyienedioxy.

In another embodiment of Formula II, R ³ is alkyl, preferably methyl _s or H, In another embodiment of Formula II, R ⁴ is H. in another embodiment of Formula Ii ₁ b is 1 ,

In another embodiment of Formula IL R ^5A is H, halo, -O-alkyi-N(aikyl)2, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, -N(R ^6A ) ₂ , -NR ⁶ -alkyl-O~alky1-OH, -NR ⁶ -hydroxyalkyi _s -S-hydroxyalkyl, -SO ₂ -alkyl, 0r -S-alky!-NHC(O)H.

In other embodiments of Formula II, R ^5A is H, Cl, -O-(CH ₂ ) ₂ -N(CH ₃ ) ₂ , , -N(CHs) ₂ , -NH(CHa) ₃ CH ₃ , -NH-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -OH,

~NH-(CH ₂ ) ₂ -OH, -NH-CH ₂ -CH(OH)-CH ₃₅ -NH-alkyi-morpholinyl, -S-CH ₂ CH(OH)-CH ₂ OH, or -SO ₂ CH ₃ -

In another embodiment, when R ^5A is -N(R ^6A ) ₂ , R ^5A is -N(R ^6A )-(cycioalkyl), wherein R ^6A is H or alkyl, and wherein cycioalkyl is cyclobutyl, cyciopentyl, cyclohexyi or cycloheptyl, and wherein the cycloalkyl potion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably 1 or 2 substituents independently selected from the group consisting of alkyl, OH ₁ hydroxyalkyl, halo, and -CF ₃ .

In another embodiment, when R ^5A is -N(R ^6A ) _2l R ^5A is -N(R ^6A )-(heterocycloalkyl), wherein R ^6A is H or alkyl, and wherein heterocycloalkyl is or wherein R ¹⁹ is H, alkyl or -SO ₂ alkyl. In another embodiment, when R ^5A is -N(R ^6A ) ₂ , R ^5A is -NR ⁶ -alkyl~aryi, wherein R ^6A is H or alkyl, and wherein aryl is preferably phenyl, and further wherein the phenyl portion is optionally substituted by 1 or 2 ring system substituents, wherein the optional sobstituents are preferably 1 or 2 substituents independently selected from the group consisting of OH, alkoxy or -OCF ₃ , or two hydrogen atoms on adjacent carbon ring members are replaced by -0-(CH ₂ J ₂ -O-. In another embodiment, when R ^5A is ~N(R ^6A ) ₂₎ R ^5A is -NR ^6A -afkyi-heteroalky! wherein R ^6A is H or alkyi, and wherein the heteroary! portion is preferably pyridyϊ, e.g.

In another embodiment, when R ^5A is -N(R ^6A ) ₂ , the two R ^6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of

wherein q is 1 or 2, s is 2 or 3, and R ⁶ is as defined above. tn another embodiment of the compounds of Formula II:

R ¹ and R ² are independently selected from the group consisting of H, alkyi, alkoxy, alkoxyaikoxy, -CF ₃ , -OC F ₃ and halo.

R ³ is H or aikyl;

R ⁴ is H ₁ -C(O)O-alky) or -SO ₂ alkyl; and

R ^5A is selected from the group consisting of H, halo, -O-alkyl-N(alkyl)2, -O-heterocycloaikyl, -O-alkyϊ-heterocycloaikyi, -N(R ^6A ) ₂ , -NR ⁶ -alkyf-O-alkyl-OH, -NR ⁶ -hydroxyalkyl, -S-hydroxyalkyl, -SO ₂ -alkyl and ~S-a!kyϊ-NHC(O)H,

In yet another embodiment of the compounds of Formula II:

R ¹ is alkyi, preferably methyl, and R ² is alkoxy, preferably methoxy; or

R ¹ is alkyi, preferably methyl, and R ² is -OCF ₃ ; or

R ¹ is alkyi, preferably methyl, and R ² is H, OH, halo or alkoxyaikoxy (preferably methoxyethoxy); or

R ¹ is alkoxy, preferably methoxy, and R ² is alkoxy, preferably methoxy, or H; or

R ¹ is alkoxyaikoxy (preferably methoxyethoxy} and R ² is H; or

R ¹ is halo and R ² is H; or

R ¹ is halo and R ² is -OCF ₃ ; or

R ¹ and R ² together are methylenedioxy;

R ³ is alkyi;

R ⁴ is H; and R ^5A is H; Cl; -O-(CH ₂ ) ₂ -N(CH ₃ ) ₂ ; -N(CHa) ₂ ;

-NH(CH ₂ ) ₃ CH ₃ ; -NH-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -OH; -NH-(CH ₂ ) ₂ -OH; -NH-CH ₂ -CH(OH)-CH ₃ ; -NH-alky!-morpholinyl; -S-CH ₂ CH(OH)-CH ₂ OH; -SO ₂ CH ₃ ; or

-N(R ^βA ) ₂ selected from the group consisting of:

-N(R ^6A )-(cycloaikyl), wherein cycioaikyl is cyciobutyl, cyciopentyl, cyclohexyl or cycϊoheptyl, and wherein the cycioaikyl potion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably 1 or 2 substituents independently selected from the group consisting of alkyl, OH ₁ hydroxyalkyl, fluoro, and -CF ₃ ;

-N(R ^6A )-(heterocycloaikyl), wherein heterocycloalkyl is or , wherein R ¹⁹ is H, alky! or -S0 ₂ a!kyl; -NR ^6A -alkyl-aryl, preferably -NR ^6A -alkylphenyl, wherein the phenyl portion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably independently selected from the group consisting of OH, alkoxy or -OCF ₃ , or two hydrogen atoms on adjacent carbon ring members are replaced by -O-(CH ₂ ) ₂ ~O-;

-NR ^6A -alkyl-heteroaIkyi wherein the heteroaryl portion is preferably pyridyl; and -N(R ^6A )2 wherein the two R ^6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of

wherein q is 1 or 2, s is 2 or 3, and R ⁶ is as defined above, and wherein the R ^DA in "N(R ^6A )-(cycfoalkyl) ₅ -N(R ^6A )-(heterocycloalkyl), -NR ^ΘA -alkylaryl and -NR ^6A -aIkyi~ heteroaryl is preferably H or aikyl. Preferred compounds of Formula Il are those in Examples 3, 3D, 3G, 3I ₁ 3M, 3N, 30, 3R, 3T ₁ 3W ₁ 3Y ₁ 3AA, 3CC, 4C, 40, 4P, 4Q ₁ 4R ₁ 4S, 4U ₁ 4V, 5A ₁ 5C, 5D ₁ 5E, 5H ₁ 5J _r 5L ₁ 5P ₁ 5T. 5V _S 5W ₁ 5X ₁ 5Y, 6, 6A, 6D, 61, 6K ₁ 6L ₅ 6M ₅ 6N, 60, 6P ₁ 7, 7D ₁ 12, 13U, 2OA, 2OC, 21 C ₅ and 21 E.

More preferred compounds of Formula II are those in Examples 3, 3D, 3G, 3I, 30, 3R, 3T ₁ 3W ₁ 3Y ₁ 3AA, 3CC ₅ 4C ₁ 40, 4P, 4Q, 4R, 4S, 4W, 5H _; 5P, 5T ₁ 5V ₁ 5W ₁ 5Y _S 6, 6A ₁ 61, 6K ₁ 6L, 6M, 6N, 6P _! 7, 7D _S and 12.

In one embodiment the compound of Formula INs 3. In another embodiment the compound of Formula Il is 3D. In another embodiment the compound of Formula Il is 3G. In another embodiment the compound of Formula Il is 31. In another embodiment the compound of Formula Il is 3M. In another embodiment the compound of Formula Il is 3N. in another embodiment the compound of Formula I! is 30. In another embodiment the compound of Formula Il is 3R. In another embodiment the compound of Formula Il is 3T. In another embodiment the compound of Formula Il is 3W. In another embodiment the compound of Formula Il is 3Y. In another embodiment the compound of Formula Il is 3AA. In another embodiment the compound of Formula Il is 3CC. In another embodiment the compound of Formula Il is 4C. In another embodiment the compound of Formula Il is 40. in another embodiment the compound of Formula Il is 4P. In another embodiment the compound of Formula Il is 4Q. In another embodiment the compound of Formula Il is 4R. In another embodiment the compound of Formula Il is 4S. in another embodiment the compound of Formula Il is 4U. In another embodiment the compound of Formula Il is 4V, In another embodiment the compound of Formula Il is 5A. In another embodiment the compound of Formula Il is 5C. In another embodiment the compound of Formula H is 5D. In another embodiment the compound of Formula Ii is 5E. Sn another embodiment the compound of Formula Il is 5H. in another embodiment the compound of Formula I! is 5J. ϊn another embodiment the compound of Formula Il is 5L. In another embodiment the compound of Formula Il is 5P. In another embodiment the compound of Formula Ii is 5T. Jn another embodiment the compound of Formula Ii is 5V. In another embodiment the compound of Formula H is 5W. In another embodiment the compound of Formula Ii is 5X. In another embodiment the compound of Formula Il is 5Y. In another embodiment the compound of Formula il is 6. In another embodiment the compound of Formula Il is 6A. In another embodiment the compound of Formula il is 6D, In another embodiment the compound of Formula Il is 61. In another embodiment the compound of Formula Il is 6K. In another embodiment the compound of Formula II is 6L. In another embodiment the compound of Formula Il is 6M. In another embodiment the compound of Formula Il is 6N. In another embodiment the compound of Formula Il is 6O. In another embodiment the compound of Formula Il is 6P. In another embodiment the compound of Formula I! is 7. In another embodiment the compound of Formula Il is 7D. In another embodiment the compound of Formula Il is 12. In another embodiment the compound of Formula Il is 13U. in another embodiment the compound of Formula II is 2OA. In another embodiment the compound of Formula Il is 2OC. In another embodiment the compound of Formula Ii is 21 C. In another embodiment the compound of Formula Il is 21 E.

As used herein, the following terms are as defined below unless otherwise indicated;

Mammal means humans and other mammalian animals.

The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alky)" as well as the "alkyl" portions of "hydroxyalkyl", "haioalkyl", "alkoxy", etc.

Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyi groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyf groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more tower alky! groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.

AIkylene means a difunctional alkyl group obtained by removal of a hydrogen atom from a C1-C3 alkyl group as defined above. Non-limiting examples of aikyiene include methylene, ethylene and propylene {i.e., -CH ₂ -, -(CH ₂ J ₂ --, -(CH ₂ ) _S -). When substituted, the R ^17a and R ^17b groups can be on the same or different carbon atoms. The proviso that when R ⁵ is heterocycioaikyi-((R ^17a , R ^17b )-alky1ene)- and the heterocycloalkyt ring is joined to the alkylene group by a ring nitrogen, the R ^17b substttuent on the α-carbon is H ₅ alkyi, CN, -CH ₂ OH, -CH ₂ ~O-alkyi, -CON(R ^aa ) ₂ , -CH ₂ N(R ⁶ J ₂ Or -CO ₂ R ⁶ is intended to eliminate unstable compounds, e.g., compounds wherein the α-carbon (herein meaning the carbon adjacent to the ring nitrogen) is substituted by OH.

Hydroxyalkyl represents an alkyt group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alky! group.

Alkoxy means an alkyl-O- group in which the aikyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

Aminoalkyl means an amino-alkyl group in which the a!ky! group is as previously described. The bond to the parent moiety is through the alkyi.

Halogen represents fluoro, chloro, bromo and iodo.

"Hydroxyalky!" means a HO-aikyi- group in which alkyi is as previously defined. Preferred hydroxyalkyls contain lower alkyi. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Alkenyi" means means a straight or branced aliphatic hydrocarbon group containing at least one carbon-carbon double bond and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkeny! groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain, "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyj, propenyf, n-butenyi, 3-methy!but-2~enyf n-pentenyl, octenyi and decenyl.

"Hydroxyalkenyl refers to an aikenyl group substituted by one or more hydroxy! groups, preferably 1 or 2 hydroxy groups, provided that a hydroxy! group is not present on a carbon that is part of a double bond. "Alkynyr means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyi groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyi chain. "Lower aikynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyi groups include ethynyl, propynyl, 2-butyny! and 3-rnethylbutynyl.

"Aryi" means an aromatic monocyclic or multicyclic ring system comprising about 8 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryi group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryi groups include phenyl and naphthyl.

Ηeteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryis contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryis include pyridyl, pyrazinyl, furanyl, thienyL pyrimidinyi, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyi, thiazolyl, pyrazolyl, furazanyl, pyrroiyl, pyrazolyi, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxaiinyl, phthalazinyl, oxindoly!, imidazo[1 ,2-a]pyridinyI, imsdazo[2,1~blthiazoiyf, benzofurazanyl, indoiyl, azaϊπdolyl, benzimidazolyl, benzothienyl, quinoiinyl, imidazolyl, thϊenopyridyf, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyi, benzothiazoiyi and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl. tetrahydroquinolyl and the ⁽ ike.

"Aralky!" or "arylafky!" means an aryl-alkyl- group in which the aryi and alkyi are as previously described. Preferred araikyls comprise a lower alky! group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

"Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aikenyl, alkynyl, aryi, heteroaryl, aralkyi, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyiheteroaryl, -CH(Yi)(Y ₂ ), -O-Y1, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxy, -C(O)Y ₁ , halo, nitro, cyano, -C(O) ₂ -Yi, -S(O) ₂ -Yi, -S-Y ₁ , cycloalkyi, cycloalkylaikyi, heterocycloalkylalkyi, cycloalkenyl, -Cf=N-CN)-NH ₂ , -C(=NH)~NH ₂ , -C(=NH)-NH(alkyi), -NYiY ₂ , -alkyl-N YiY ₂ , -C(O)NYiY ₂ , and -SO ₂ NY ₁ Y ₂ , wherein Y ₁ , Y ₂ and Y ₃ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryi, heteroaryl, cycloalkyi, heterocycioalkyl, aralkyi and heteroarylaikyl. "Ring system substituents" on aromatic rings can also be selected from the group consisting Of -SF ₅ , -OSF ₆ , -Si(Y ₄ J ₃ , -S(O)N(YO(Y ₂ ), -Ct=NOY ₁ )Y ₂ , -P(O)(OY ₁ )(OY ₂ ), -N(Yi)C(O)Y ₂ , -CH ₂ -N(Yi)C(O)Y ₂ , -CH ₂ -N(Y ₁ )C(O)N(Yi)(Y ₃ ), -N(Yi)S(O)Y ₂ , -N(Yi)S(O) ₂ Y ₂ , -CH ₂ -N(Y ₁ )S(O) ₂ Y ₂ , -N(Y ₁ )S(O) ₂ N(Y ₂ )(Y ₃ ), -N(Yi)S(O)N(Y ₂ )(Y ₃ ), -N(Y ₁ )C(O)N(Y ₂ )(Y ₃ ), -CH ₂ -N(Y ₁ )C(O)N(Y ₂ )(Y ₃ ), -N(Y ₁ )C(O) ₂ (Y ₂ ), -CH ₂ -N(Yi)C(O) ₂ (Y ₂ ), -S(O)Y ₁ , =NOY ₁ , and -N ₃ , wherein Yi, Y ₂ and Y ₃ are as defined above and each Y ₄ is independently selected from alkyl, aryi, heteroaryl, cyciσalkyl, heterocycioalkyl, aralky! and heteroarylalkyl. Furthermore, the alkyl, cyciøafkyl, aryS, heteroaryl and heterocycioalkyl portions of Yi, Y ₂ or Y ₃ can be optionally substituted with 1 or 2 substttuents independently selected from the group consisting of halo, OH, -CF ₃ , CN, aikoxy, -NH ₂ , -NH-aikyl, -N(aikyl) ₂ and Si(alkyl) ₃ . "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CHa^- and the like which form moieties such as, for example:

Similarly, a single divalent moiety such as a divalent alkyi chain or a -O-(CH ₂ ) ₂ -O~ group can simultaneously replace two available hydrogen atoms on one carbon atoms on a ring system. An example of such spiro moieties is:

" -Heterocyciyl" means a non-aromatic saturated monocyclic or multicyclϊc ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyi root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyi ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyi can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyi can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyi rings include piperidyf, pyrrolidinyl, piperazinyi, morpholinyl, thiomorpholinyl, thiazoϋdiπyl, 1.4-dioxanyL tetrahydrofuranyf, tetrahydrothϊophenyi, lactam, lactone, and the like.

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxy! groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention,

"Heteroarylalkyl" means a heteroaryt-aikyl- group in which the heteroaryl and alky! are as previously described. Preferred heteroaralkyls contain a lower alky! group. Non-limiting examples of suitable heteroaralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

Similarly, cycloalkylalkyl and heterocycloalkylalkyl mean cycloaikyl-alkyl and heterocycloaikyl-alkyl groups wherein cycloalkyl, heterocycloalkyl and alky! are as previously described, wherein the alky! portion is preferably lower alkyl. The bond to the parent moiety is through the alkyl portion.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a usefui degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof, The term "purified" or 'in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

When phenyl, Formula I or Il has the structure

When ^" 2 C I i?s heteroaryl, heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, pyrrolyl, thiazoiyl, imidazolyl and furanyl. Examples of such groups are shown in the following partial structures:

One skilled in the art will recognize that when er £ I is a five membered ring containing two heteroatoms, there is only one substitutabte carbon, hence R ² is absent. "Cycloaikyl" means a non-aromatic mono- or multϊcyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms. The cycfoaikyi can be optionally substituted with one or more "ring system subststuents" which may be the same or different, and are as defined above. Non-limiting examples of suitabfe monocyclic cydoalkyis include cyclopropyi cyclopenty), cyclohexyi, cycloheptyl and the like. Non-iimiting examples of suitable multicyclic cydoalkyis include 1- decalinyl, norbornyl, adamantly and the like. "Cycloalkenyl" means partially saturated species such as, for example, cyclopentene, cyclohexene, indanyl, tetrahydronaphthy! and the like.

As used herein, the term "bridged heterocycfoaϊkyt" means a piperidinyl, ptperazinyl, rnorpholinyl, tetrahydropyranyl or tetrahydrofuranyl ring wherein a carbon on one side of the ring is joined by a C1-C3 alkyl group, or a hydroxy substituted C1-C3 alkyl group, to a carbon on the opposite side of the ring, provide that when the bridge is a C1 bridge both carbon atoms to which the bridge is bound to are not adjacent to the same heteroatom, Non-limiting examples include:

— N O? /— OH and \2J

As used herein, the term "fused ring heterocycioalkyl" means a 5 or six- membered heterocycioalkyl ring joined to a cycloalky! or heterocycloalky! ring through two adjacent shared carbon ring members. Non-limiting examples include

Haloalkyl represents an afkyl group as defined substituted by one or more halo atoms. Examples wherein haio is fluoro are -CH ₂ F, -CHF ₂ . -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ and the like. ft should afso be noted that any carbon as we!! as heteroatom with unsatisfied valences in the text, schemes, examples and Tabtes herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene ef al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any variable (e.g., alkyl, halo, etc.) occurs more than one time in any constituent or in Formula I or II, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs, solvates and co-crystais of the compounds of the invention are also contemplated herein.

The term "prodrug", as employed herein, means a compound that is transformed in vivo to yield a compound of Formula (I) (or Formuia II) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference thereto.

For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-CsJalkyt (C ₂ -Ci ₂ )a!kanoyloxymethyf, 1-{alkanoyioxy)ethy! having from 4 to 9 carbon atoms, 1-methyi-1~(aikanoy!oxy)-ethy: having from 5 to 10 carbon atoms, alkoxycarbonyioxymethy! having from 3 to 6 carbon atoms, 1-(a!koxycarbonyioxy)ethyi having from 4 to 7 carbon atoms, 1-methyi-1- (alkoxycarbonyioxy)ethyl having from 5 to 8 carbon atoms, N- (aikoxycarboπyl)amiπomethy! having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyi)amino)ethyl having from 4 to 10 carbon atoms, 3-phthaϋdyl, 4- crotonolactonyi, gamma-butyrolacton-4-yl, di-N,N-(CrC ₂ )alkylam!no(C ₂ -C ₃ )alkyt (such as β-dimethyiaminoethyi), carbamoyl-(C ₁ -C ₂ )aiky!, N,N-di (Ci-C ₂ )alkylcarbarnoy)-(C1- C2)afkyl and piperidino-, pyrrolidine- or morpholino(C2-C ₃ )alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-pCeJaikanoyloxymethyl, 1-((Ci- C ₆ )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C ₆ )alkanoyfoxy)ethyl, (Cr Ce)alkoxycarbony!oxymethyi, N-(Ci -C ₆ )a!koxycarbonylaminomethyl, succinoyf, (Ci- C ₆ )alkanoy!, α-amino(Ci-C ₄ )a!kanyl, arylacyi and α-aminoacyl, or α-aminoacyi-α- arninoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O(CrC ₆ )alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂ O.

A co-crystal is a crystalline superstructure formed by combining an active pharmaceutical intermediate with an inert molecule that produces crystallimty to the combined form, Co-crystais are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I of this invention in different proportions depending on the nature of the co-crystal. (Rmenar, J. F. et. al. J Am. Chem, Soc. 2003, 125, 8456). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective as PDE 10 inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula i or El can form salts which are also within the scope of this invention. Reference to a compound of Formula I or M herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)'\ as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as we!! as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I or Il contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesujfonat.es, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesuSfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toiuenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stah! et al, Camille G, (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiiey-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1- 19; P, Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, atkafi metal salts such as sodium, lithium, and potassium salts, aikaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, f-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialky! sulfates (e.g. dimethyl, diethyl, and dibutyi sulfates), long chain haiides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Compounds of Formula I or II, and salts, solvates, co-crystais and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, co-crystals and prodrugs of the compounds as well as the salts and solvates, co-crystals of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents. including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemptated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with ail other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "satt" , "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautorners, positional isomers, racemates or prodrugs of the inventive compounds. Isomers can be prepared using conventional techniques, either by reacting optically pure or opticaliy enriched starting materials or by separating isomers of a compound of Formula I. isomers may aiso include geometric isomers, e.g., when a double bond is present

Those skilled in the art will appreciate that for some of the compounds of Formula I or II, one isomer will show greater pharmacological activity than other isomers.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as ² H, ³ H ₁ ¹¹ C, ¹³ C, ¹⁴ C ₅ ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P. ³⁵ S, ¹⁸ F, ³⁶ CI and ¹²³ I ₅ respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like ¹¹ C or ¹⁸ F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like ¹²³ I can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., ^H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo haif-iife or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. lsotopicaily labeled compounds of Formula fl), in particular those containing isotopes with longer half lives (T1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopicaiiy labeled reagent for a non-isotopically labeled reagent.

Polymorphic forms of the compounds of Formula i or H ₁ and of the salts, solvates, co-crystals and prodrugs of the compounds of Formula I or II, are intended to be included in the present invention.

In this specification, the term "at least one compound of Formula I (or Formula II)" means that one to three different compounds of Formula ! or Il may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I or il is used.

Compounds of Formula I are prepared by methods known in the art. A typical reaction scheme for preparing the compounds of Formula I is shown in Scheme 1.

SCHEME 1

NHNH,

An amino-substituted ary! or heteroaryl, 1 , in absolute ethanol is treated with ammonium hydroxide and then carbon disulfide, followed by chloroacetic acid and then hydrazine to give compound 2, which is purified by column chromatograpy on silica gel. Compound 2 in ethanol is treated with ethyl 2-chIoroacetoacetate to give ester compound 3. Ester 3 in absolute ethanol is treated with KOH in water. The resulting mixture is heated at reflux and then cooled. On acidification, the acid 4 is isolated. The actd 4 is treated with POCI ₃ under reflux, followed by cooling and adjusting the pH with 20% NaOH to give the chϊoro compound 5. Chloro compounds 5 can be converted to the R ⁵ -susbtituted compounds of formula 6 using methods known in the art and described in the examples below. Compounds of Formula Il can be prepared by methods similar to those described for compounds of Formula I, and by methods known in the art, for example the procedures described in US 5,459,146, US 5,506,236, US 5,608,067, and US 2007/0253957, all incorporated herein by reference, and by Crenshaw et al, J, Med. Chem., 19(2), 262-275 (1976).

In the scheme above and in the following preparative examples, the following abbreviations are used: RT - room temperature; Ac - acetyl; Me - methyl; Et - ethyl; Ph - phenyl; iPr - isopropyl; t-Bu - t-butyl ; tBOC - N-tert-butoxycarbonyi; DCM - dichloromethane; DMSO - dimethylsulfoxide; DlBAL - diisobutyia!uminum hydride; DCE - dichloroethane; DMF - dimethylformamide; THF - tetrahydrofuran; SEM-CI - 2-(tπmethylsilyl)ethoxymethy! chloride; DAST - (diethylamino)suffur trifluoride; TBAF - tetrabutylammonium fluoride; sat. (or sat) is saturated; IBX - iodoxybenzoic acid; TFA - trifluoroacetic acid.

Where LC/MS data are presented, analyses were performed using an Applied Biosystems APi-150 mass spectrometer and Shimadzu SCL-10A LC system. Column: Phenomenex Gemini C18, 5 micron, 50 mm x 4.6 mm ID; Gradient: From 90% water, 10% CH ₃ CN and 0.05%TFA, 5 min to 5% water, 95% CH ₃ CN, 0.05% TFA in 5 minutes. MS data were obtained using Agilent Technologies LC/MSD SL or 1100 series LC/MSD mass spectrometer. Retention times refer to Total Ion Current (TIC) unless uv is indicated.

Following are examples of the preparation of intermediates and compounds of Formula I and II.

Example 1

CS ₂ (4.5 mL) was added to a mixture of 4-methoxy-2-methyIaniiine (9.0 g), absolute EtOH (25 mL) and NH ₄ OH (6 mL). After 1 hr _; chioroacetic acid (7.0 g), NaHCO ₃ (4.5 g) and water (20 mL) were added. After an additional hour, H ₂ NNH ₂ monohydrate (7.5 mL) was added dropwise to the black mixture. The resulting mixture was refrigerated overnight. The mixture was filtered and washed with cold EtOH. The purple solid was dried in a vacuum oven at 50 ^D C to give a purple-white solid (11.52 g). This material was purified with a silica gel normal phase column (330 g) eluting with CH ₂ CI;? with a slow ramp to 10%, then 50% MeOH over 60 min. The fractions containing compound JU2 were concentrated in vacuo to give compound 1^2 (10.71 g) as an orange-white solid. LCMS: M is 211. Found: M+1 is 212 at 2.27 min. Step 2:

Compound 1^2 (8.33 g) and absolute EtOH (50 mL) were stirred at RT for 10 min. Ethyl 2-chloroacetoacetate (6.7 mL) in absolute EtOH (5 mL) was added dropwise. After 2 hr., the mixture was refrigerated for 1 hr. The mixture was filtered to give a yellow solid that was washed with cold EtOH ₁ and dried in a vacuum oven at 50 ⁰ C.

The filtrate was evaporated to about 10 mL, refrigerated overnight and filtered. The precipitates were combined to give compound I^ as a yellow soSid (7.30 g). LCMS: M is 289. Found, M+1 is 290 at 3.88 min.

KOH (13.7 g) in water (80 mL) was slowly added to a mixture of compound 1N3 (7.63 g) and absolute EtOH (40 mL) over 4 min. The resulting mixture was heated under reflux for 5 hr, then cooled in an ice bath and water (50 mL) was added. Cone. HCI (-18 mL) was added until the pH was ~3 to give a yeiiow solid. The solid was washed with water and dried in vacuum oven at 50 ⁰ C to give compound %A as a fluffy tan solid (4.59 g) that was used in the next step without purification. Step 4:

A mixture of compound I^ (4.50 g) and POCI ₃ (5 mL) was purged with nitrogen and heated under reflux for 1 hr. The mixture was cooled to 70 ⁰ C and concentrated in vacuo (bath at 70 ⁰ C). The mixture was cooled to 0 ⁰ C, the pH was adjusted to -8 with 20% NaOH, and water was added to give a brown solid. The mixture was filtered, washed with water, and dried at 50 ⁰ C to give compound I^ as a brown solid (3.90 g) which was used in Example 3 without purification.

The following compounds were prepared in a similar manner.

Example 2

Alternate Synthesis of Analogs of 1-2

Hydrazine monohydrate (2 g) was added to a solution of isothiocyanate ΪM (10 g) in DCM slowly. The mixture was stirred at RT for 3 hr and the resulting mixture was filtered. The precipitate was washed with DCM to yield 7Λ (10,54 g). LCMS: M is 235. Found: m/z 236 (MH ⁺ ).

The following compounds were similarly prepared.

microwave

Compound JM5 (0.825 g), piperazine (2.0 g), trifluoromethyltoluene (3.5 mL) and dioxane (3.5 mL) were added to a microwave vial. The mixture was purged with nitrogen, sealed and placed in a microwave reactor. The mixture was heated at 165 ⁰ C for 2 hr. The reaction mixture was diluted with EtOAc ₅ DCM, and MeOH, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was dried (K ₂ CO ₃ ) and concentrated in vacuo to give a residue (0.51 g). The residue was purified on silica gel piates (6, 1000 μ) eluting with DCM:MeOH (9:1) to give the title compound 3 as a yeliow solid (0.23 g). LCMS: M is 311. Found M+1 is 312 at 1.66 min.

The following compounds were prepared in a similar manner:



50

51

Example 4

microwave

A microwave vial charged with I^ (0.100 g), NaH (0.030 g), KI (0.060 g), and 4- methylpiperidine (0.44 mL) was purged with nitrogen, sealed and heated in a microwave reactor at high setting for 1 hr. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue (0.066 g). This residue was purified on silica gel plates (6, 1000 μ) eiuting with acetone:DCM (2.8) to give the compound 4 (0.012 g). LCMS: M is 324. Found M+1 is 325. Retention time: 2.84 min

The following compounds were prepared in a similar manner:

53

54

* Compound 4C is a byproduct of the genera! reaction of Example 4. The following compounds were prepared in a similar manner, using dioxane as the solvent and heating the reaction mixture at 160 ⁰ C overnight:

The following compounds were prepared in a similar manner, using dioxane as the solvent, without Kl, and heating the reaction mixture at 160 ⁰ C overnight: 

The following compound was prepared in a similar manner, using dioxane as the solvent without Kl:

Example 5

H ₂ N /-Λ neat

±£ y ⁰ 125 ⁰ C

A mixture of compound VS (41 mg) and 4-amiπomethyltetrahydropyran (400 mg) was stirred at 125 ⁰ C overnight. The reaction mixture was cooled to room temperature and water was added. The mixture was filtered and the precipitate was purified by silica gel column chromatography (hexane-EtOAc) to give compound 5 (16 mg). The mono

HCi salt was prepared by adding -1 equivalent of HCI/ether to a solution of compound 5 in ether and then evaporating to dryness. LCMS: M is 340. m/z 341 [M+Hf. R _t is 2.23 min.

The following compounds were obtained in a similar manner:



60

61

Example 6

A mixture of compound 1^5 (50 mg), homαmorpholine hydrochloride (200 mg), iriethyiamine (-200 mg) in DMSO (1 mL) was stirred at 125 ⁰ C for two days The reaction mixture was cooled to room temperature and water was added. The mixture was filtered. The precipitate was purified on silica gel plates eluting with 2% DCM- MeOH to give the compound 6 (5 mg) The mono HCf salt was prepared by adding ~1 equivalent of HCI/ether to a solution of compound 6 in ether and then evaporating to dryness after 1 hr LCMS M is 326 Found m/z 327 (MH) ⁺ R ₁ is 2 4 mm

The following compounds were prepared in a similar manner

64

The following compound was prepared in a similar manner, using NMP as the

The following compounds were prepared in a similar manner, using NMP as the solvent and (1-Pr) ₂ NEt as the base

Example 7

A mixture of compound JM (92 mg), homomorphøline hydrochloride (74 mg), K ₂ CO ₃ (72 mg) and phenol (1 g) was heated at 120 ^* C for 4 h. The mixture was cooled to RT and 1M NaOH (50 ml_) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gef chromatography, efuting with a gradient of 0 to 100% EtOAc in hexanes to afford 10 mg of compound 7 as yellow oil. LCMS: M is 342. Found: M+1 is 343.

The following compounds were obtained in a similar manner: 

Example 3

CH _1J SO ₂ Ci pyridine

CH ₂ CI ₂

S

A mixture of compound 3 (0.15 g) and DCM (10 mL) was treated with pyridine (50 μL) and then CH ₃ SO ₂ CI (50 μL). After 24 hr, additional pyridine (25 μL) and CH ₃ SOaCi (25 μL} were added. After 2 hr, the reaction mixture was concentrated and purified on silica gel plates (2, 1000 μL) eluting with DCM:MeOH (9:1) to give a yellow solid. This yellow solid was suspended in DCM and filtered to give compound 8 as a yellow solid (0.050 g). The filtrate was placed on silica gel plates (2, 1000 μ) and eiuted as above to give additional compound 8 as a yeilow solid (0.028 g). LCMS: M is 389, Found M+1 is 390 at 0.79, 2.04 min.

acid (0.33 ml). After 1.5 hr, the reaction mixture was concentrated in vacuo. DCM was added and concentrated in vacuo (twice), The residue was partitioned between DCM and 2.5N K ₂ COa solution. The organic layer was dried (K ₂ CO ₃ ), concentrated in vacuo, and the residue was purified on silica gel plates (2, 1000 μ) eluting with DCM:MeOH:NH ₄ OH (180:20:2) to give compound 9 as a yellow solid (0.039 g). LCMS: M is 325. Found: M+1 is 326 at 0.68, 1.53 (uv) min.

Example 10

Trimethylsilyl isocyanate (55 μl) was added to compound 9 (121 mg) in dry dioxane (15 mL) at 60 ⁰ C, The mixture was heated for 70 mirs. The reaction mixture was cooled to RT, MeOH (5 mL) was added, and the mixture was concentrated in vacuo to give a yellow solid (142 mg). This solid was purified on silica gel plates (4, 1000 μ) eluting with DCM:MeOH (9:1) to give a yellow foam (92 mg). This foam was purified on a reverse phase HPLC column (10 μ; 30 x 100 mm) eluting with 0.1% HCO ₂ H in CH ₃ CN / 0.1% HCO ₂ H in water (10% to 95% over 20 min) (2 runs) to give W ₂ A as an orange solid (63 mg) and 10-B as a yellow solid (22 mg). LCMS for ICkA: M is 368. Found: M+1 is 369 at 2.26 min (uv). LCMS for 10-B: M is 411. Found: M+1 is 412 at 0.82, 1.87 min (uv).

The following compounds were prepared in a similar manner:

Example 11

Compound ^S was treated with N-Boc-pϊperazine in a similar manner as described in Example 3 to give compound 11-1 as a brown solid {104 mg), which was used in the next step without purification. LCMS: M is 411. Found: M+1 is 412 at 2.88 min.

Under a nitrogen atmosphere, a soiution of 11-1 (100 mg) in CH ₃ CN (3 mL) was treated with freshly ground K ₂ CO ₃ (168 mg) and then CH ₃ ! (90 μl_). After 1 hr, additional CH ₃ I (100 mL) and CH ₃ CN (1.5 mL) were added. After 2.5 hr., additional CH ₃ I (100 μl_) was added. The mixture was heated at 60 ⁰ C for 18 h. The reaction mixture was purified on silica gel plates (4, 1000 μ) eluting with DCM: MeOH 9:1 to give an amber oil (70 mg). This oil was purified on silica gel plates (2, 1000 μ) eluting with DCM:MeOH (9:1) to give an amber film (39 mg). This amber film was placed on silica gel plates and eluted with EtOAc:hexane (1 :3) to give the title compound 11-2 as a yellow foam (21 mg) which was used in the next step. LCMS: M is 425. Found: 426 at 4.56 min. Step 3:

A mixture of compound 11-2 (19 mg) in dry DCM (750 μL) was treated with trifluoroacetic acid (250 μL). After 35 min, the reaction mixture was concentrated in vacuo. DCM was added and the mixture was concentrated in vacuo two times. The residue was partitioned between DCM and 2.5N K ₂ CO ₃ . The organic layer was dried (K ₂ CO ₃ ) and concentrated in vacuo. The residue was purified on a silica gel plate (1000 μ) eluting with DCM:MeOH:NH ₄ OH (90:10:1) to give compound H as a yellow solid (12 mg). LCfVIS: M is 325. Found: M+ 1 is 326 at 2.37 mϊn (uv).

The foilowing compounds were prepared in a similar manner:

12-1 Compound JMS (1 ,0 g) was treated with 48% HBr in water. The resulting mixture was heated at 110 °C for 18 hr. The reaction mixture was cooled and filtered to give compound 12-1 as a dark green sofid which was used in the next step without purification. LCIVtS: M is 229. Found: M+1 is 230 at 1.96 min. Step 2:

A mixture of compound 12-1 (1.10 g) in acetic anhydride (40 mL) was treated with p-toluenesulfonic acid (40 mg). The resulting mixture was heated at 125 ⁰ C for 2 hr. The reaction mixture was cooled and filtered to give the title compound 12-2 (0.22 g) as a white solid. The filtrate was concentrated in vacuo to ~5 mL and filtered to give additional title compound (0.31 g). LCMS: M is 313. Found: M+1 is 314 at 3.51 min. Step 3:

A mixture of compound 12-2 (0.52 g) in DCM (30 mL) was treated with oxalyl chloride (2.4 mL) and stirred at RT for 4 hr. The reaction mixture was concentrated in vacuo to give a light tan residue. This residue was triturated with diethyl ether, then filtered to yield compound 12-3 (0.46 g) as an off white solid. LCMS: M is 331. M+1 is

332 at 4.41 min. Step 4:

dioxarte A microwave vial was charged with compound 12 _. -3 (0.20 g), trifϊuoromethylfoluene (2 mL), dioxane (2 mL), and /V-methyihomopiperazine (0.6 mL). The vial was purged with nitrogen, sealed, and heated at 165 ^C C in a microwave reactor. The reaction mixture was purified on silica gel plates (4, 1000 μ) eluting with DCM:MeOH (9:1) to give a yellow solid (0.27 g). This residue was purified on silica gel plates (2, 1000 μ) using DCM;MeOH:NH ₄ OH (90:10:1) as the solvent to give a yellow solid. The chromatography was repeated using silica gel plates (4. 1000 μ) to yield compound 12 (0.76 g) as a yellow solid. LCMS: IvI is 325. Found: M+1 is 326 at 0.91: 1.43 min.

13-1

A solution of compound U> (4.6 g) and KCN (12 g) in DMSO (120 mL) was stirred at 110 ⁰ C overnight. The reaction mixture was cooled, diluted with water and filtered. The precipitate was washed with water, ether and DCM to yield compound 13; i (-3 g). LCMS: M is 252. Found: m/z 253 (MH) ⁺ .

33a. DiBAL (42 mL, 1M in hexane) was slowly added to a solution of compound 13-1 (3 g) in toluene (150 mL) at -78 ⁰ C. The mixture was warmed to RT and stirred overnight. The mixture was quenched at -78 ⁰ C with MeOH (19 mL), and then saturated aqueous NH ₄ CI (27 mL). The reaction mixture was warmed to RT and partitioned between 1 N NaOH and a large amount of ether. The organic layer was dried (Na ₂ SO ₄ ) and evaporated to dryness to yield compound 13-2 (1.2 g), which was used in the next step without purification. LCMS: M is 326, m/z 256 [M+H] ⁺ . Step 3:

13-2 °w ^NH

12

NaBH(OAc) ₃ CH ₂ Cl ₂

NaBH(OAc) ₃ (820 mg) was added to a mixture of aldehyde 13-2 (410 mg) and morpholine (820 mg) in anhydrous DCM. The mixture was stirred at RT overnight, then partitioned between 1 N NaOH and DCM. The organic layer was dried (MgSO ₄ ) and evaporated to dryness. The crude material was purified by HPLC (CH ₃ CN-H ₂ O, 0.1% formic acid) to yield compound 13. (110 mg). The mono HCI salt was prepared by adding -1 equivalent of HCI/ether to an ether solution of compound 13 and then evaporating to dryness after 1 hr. LCMS: M is 326. Found: m/z 327 (MH ⁺ ). R ₁ is 2.20 min.

The following compounds were prep _ared in a sim _ila ^r m^anner:





80

Example 14

A mixture OfAICI ₃ (1.02 g) and DCE (30 mL) was cooled to 0 °C EtSH (760 μL) was added dropwise. The resulting solution was stirred at 0 °C for 10 min. then a mixture of 13S (351 mg) and DCE (30 mL) was added. The solution was warmed to RT and stirred 3 h, H ₂ O (150 mL) and sat NaHCO ₃ (150 mL) were added. The mixture was extracted with EtOAc (3 x 200 mi_). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give compound 14, which was used without further purification.

Example 15

A mixture of 14 (32 mg), K ₂ CO ₃ (31 mg), 2-bromoethyI methyl ether (10 μL) and DMF (2 rtiL) was heated at 80 ⁰ C for 3 h. H ₂ O (15 mL) was added and the mixture extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by reverse phase HPLC, eluting with 0.1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 1 mg of compound IjS as a yellow oil. LCMS: M is 384. Found: M-M is 385, Rt = 2.07 min.

A mixture of I ₁ S (5.45 g), 1M HCl (40 mL), and MeOH (180 mL) was heated at 90 "C for 18 h. The mixture was allowed to cool to RT and the MeOH was removed in vacuo. H ₂ O (200 mL) was added. The mixture was cooled to 0 ^" C and filtered. The precipitate was dried at 50 °C in a vacuum oven and used without further purification. A mixture of the crude 16-1. POBr ₃ (4.13 g) and DMF (20 mL) was heated at 90 ^° C for 2 h. The mixture was allowed to coof to RT and sat, NaHCO ₃ (50 mL) was added slowly. H ₂ O (200 mL) was added and the mixture was filtered. The filtrate was dried at 50 ⁰ C in a vacuum oven, affording 3.98 g of compound 16-2 as a brown solid, which was used without further purification.

NaH (393 mg, 60% dispersion in mineral oil, 9.83 mmol) was added to a mixture of 16-2 (2.65 g) and THF (50 mL). The resulting mixture was stirred at RT for 1 h. SEM-CI (2.3 mL) was added. The solution was stirred at RT for 2 h, whereupon sat NaHCO ₃ (50 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column silica gel chromatography to afford 1.36 g (36 %) of 16-3 as a yellow oil. A solution of 16-3 (685 mg) in THF (20 mL) was cooled to -78 °C. n-BuLi (1.7 mL, 1.04M in hexanes) was added dropwise. The resulting solution was stirred at - 78 ^" C for 20 rnin. 4-Pyridinecarboxaldehyde (220 μL) was added dropwise. The solution was stirred at -78 ^° C for 45 min, then allowed to slowly warm to RT over 1 h. The solution was stirred at RT for 12 h, whereupon H ₂ O (20 mL) was added. The mixture was extracted with EtOAc (2 x 3OmL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give 748 mg of compound 16-4 as a yellow oil, which was used without further purification. Step 3:

A mixture of compound 16-4 (263 mg), HCi (2 ml), H ₂ O (4 mL), and EtOH (4 mL) was stirred at RT for 24 h. Sat. NaHCO ₃ was added until the pH was 7. The mixture was diluted with H ₂ O (50 mL), cooled to 0 "C, and filtered. The precipitate was purified by reverse phase HPLC, eluting with 0.1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were combined, neutralized with sat NaHCO ₃ , and extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 30 mg of compound 16 as a yellow solid, LCMS: M is 334. Found: M+1 is 335, R _t = 1.95 min.

IM

A solution of 16-4 (22 mg) and IBX (29 mg) in DMSO (2 mL) was stirred at RT for 30 min. EtOAc (20 mL) was added and the solution washed with H ₂ O (3 x 10 mL). The organic phase was dried (MgSO ₄ ) and concentrated in vacuo to give 17-1 The residue was used without further purification. A mixture of 17-1, HCI (250 μL). H ₂ O (500 μl_), and EtOH (500 μL) was stirred at RT for 1 h. The solution was then heated at 75 ^° C for 45 min. The solution was cooled to RT and sat. NaHCO ₃ (2 mL) and H ₂ O (10 mL) were added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by reverse phase HPLC ₅ elutϊng with 0,1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 5 mg of compound 17 as a yellow solid. LCMS: M is 332. Found: M+1 is 333, R ₁ - 3.57 min.

DAST (5 drops) was added via syringe to a solution of 16-4 (12 mg) in CH ₂ CI ₂ (2 mL). The resulting solution was stirred at RT for 5 min, then sat. NaHCO ₃ (2 mL) and H ₂ O (10 mL) were added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give 18-1. The residue was used without further purification. A solution of 18-1, HCI (250 μL), H ₂ O (500 μL), and EtOH (500 μL) was stirred at RT for 2 h, then at 75 "C for 30 min. Sat NaHCOs (2 mL) and H ₂ O (10 mL) were added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by reverse phase HPLC ₁ eluting with 0.1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCOs and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 1 mg of compound 18 as a yellow oil. LCMS: M is 336, Found: M+1 is 337, R _t - 2.68 min. The following compounds were prepared in a similar manner _^

A mixture of compound 13-1 (7 mg) in cone H ₂ SO ₄ (-400 μl_) was heated at 60 C for 3 days The mixture was cooled and added to ice water The resulting solution was neutralized with 15% NaOH solution and filtered. The precipitate was washed with DCM and then recrystatized from MeOH to afford compound IJt (1 mg).

Example 20

20-1 20-2 20-3

A mixture of 1-iodo-3-methylbenzoic acid, 20-1 , (5 g), 1-benzyl-3~methyl-1 H- pyrazof-5-amine, 20-2, (3.93 g), K ₂ CO ₃ (2.64 g) and copper powder (0,61 g) in water (20 mL) was heated at reflux overnight. The resulting mixture was cooled to RT. The pH was adjusted to 14 with 1N aqueous NaOH and the mixture was extracted with CH ₂ CI ₂ . Concentrated HCI was added to the aqueous solution to adjust the pH to 3 and the mixture was filtered. The white solid was dried in a vacuum oven at 50 ⁰ C to give 20-3 (3.05 g). LCMS: M is 321. Found: MH ⁺ is 322. The solid was used without further purification. The following compound was prepared in a similar manner.

Step 2:

A mixture of 20-3 (3.05 g) and POCl ₃ (5 mL) in a 50 mi round bottom flask was purged with nitrogen and heated at 100 ⁰ C for 2 h. The mixture was concentrated in vacuo at 70 ⁰ C . ice was added to the mixture and the pH was adjusted to ~8 with 20% NaOH. The mixture was extracted with CH ₂ CI2, dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ , eluting with a gradient of 0 to 10% EtOAc in hexanes to afford 184 mg of 20-4. LCMS: MW is 321. Found: MH ⁺ is 322,

The following compound was prepared in a similar manner.

Step 3:

A mixture of compound 20-4 {184 mg) and 4-amiπotetrahyd ropy ran (462 mg) was heated at 150 ⁰ C overnight. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with CH ₂ CS ₂ , dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ , eluting with a gradient of 0 to 3% MeOH in CH ₂ CI ₂ to afford 216 mg of 20-5. LCMS: M is 386. Found: MH ⁺ is 387.

The following compound was prepared in a similar manner.

: M is ^N 4 ^H 32. Found: M+1 is 433. Retention time: 2.74 min. Step 4:

A mixture of compound 20-5 (216 mg), Pd/C (82 mg) and formic acid (96%, 3 mL) was heated at 150 ⁰ C overnight. The mixture was cooled to RT, additional Pd/C (200 mg) and formic acid (3 mL) were added and the mixture was stirred at 150 ⁰ C for 36 h. The mixture was filtered and concentrated in vacuo. Aqueous NaHCOa solution was added to the residue. The resulting mixture was extracted with 10% MeOH in CH ₂ CI ₂ , dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ , eluting with a gradient of 0 to 5% MeOH in CH ₂ CI ₂ to afford 18 mg of Example 20-A (LCMS: M is 296. Found: M+1 is 297) and 68 mg of Example 20- B (LCMS: M is 213. Found: M+1 is 214, Retention time: 2.29 min).

The following compound was prepared in a similar manner:

LCMS: M is 342, Found: MH ⁺ is 343. Retention time: 2.03 min. Example 21

Step 1:

Compound 21-3 was prepared using procedures simitar to those described in earlier examples.

/T-BuLi (0.31 mL, 1.6 M in hexane) was added to a solution of 21-3 (199 mg) at - 78 ⁰ C, The mixture was stirred at -78 ⁰ C for 1 hr. DMF (0.32 mL) was added. The mixture was sfowfy warmed to RT over a 2~hr period. Additional DMF (1 mL) was added to the mixture at RT and the resulting mixture was stirred for 1 hr. The reaction was quenched with water, extracted with EtOAc, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂₅ eiuting with a gradient of 0 to 10% hexane in EtOAc to afford 2.4 mg of 21 -A (LCMS: M is 351 Found: MH ⁺ is 352) and 78 mg of a mixture of 21 -A and 21-4 (LCMS: M is 379. Found: MH ⁺ is 380) with a ratio of 1 :2.

Step 2:

A mixture of 21-4 (500 mg), 2-methy!morphoIine (266 mg) _r Et ₃ N (0.74 mL) and NaBH(0Ac) ₃ in CH ₂ Cb (30 mL) was stirred at RT overnight. The reaction was quenched with 1N NaOH, extracted with EtOAc, dried (MgSO ₄ ) and concentrated in vacuo. The residue was treated with TFA (13 mL) and the resulting mixture was heated at 73 ⁰ C for 40 h. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 extracted with CH ₂ CI ₂ , dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ . eluting with a gradient of 0 to 2% MeOH in CH ₂ Cl ₂ followed by HPLC to afford 129 mg of 21B. LCMS: M is 344. Found: MH* is 345, Retention time: 2.87 min.

The following compounds were prepared in a similar manner:

Example 22

Cyclopropyi magnesium b THF) was added to a suspension of 2Λ-A (93 mg) in THF at -40 ⁰ C and stirred for 1 hr The mixture was warmed to RT, treated with saturated aqueous NaHCO ₃ solution, extracted with EtOAc ₅ dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on SiO ₂ , eluting with a gradient of 0 to 55% EtOAc in hexane. The purified compound (76 mg) was treated with TFA (20 mL) and heated at 80 ⁰ C overnight. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO ₃ , extracted with CH ₂ Ci ₂ , dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by HPLC to afford 10 mg of 22. LCMS: M is 301 , Found MH ⁺ is 302, Retention time: 3.43 min. Example 23

LAH (0.46 mL, 2M in THF) was added to a solution of 7F (117 mg) in dioxane (1 mL) at 0 ⁰ C dropwise. The reaction mixture was warmed to RT, stirred for 10 min, and heated at 100 ⁰ C for 3.5 hr. The mixture was cooled to RT, and treated with H ₂ O (0,02 mL), 10% NaOH (0.03 mL), and H ₂ O (0.02 mL). The resulting mixture was diluted with CH ₂ Cb, stirred for 90 min, filtered and concentrated. The residue was purified by column chromatography on SiO ₂ , eiuting with a gradient of 0 % to 10% MeOH in CH ₂ CI ₂ to afford 9.5 mg of 23. LCMS: MW is 359. Found: MH ⁺ is 360. Retention time: 1.97 min.

Example 24

TEA (0.23 mL), DMAP (27 mg), and Boc ₂ O (0.36 mg) were added to 16^2 in THF (20 mL) and stirred at RT overnight. The reaction was quenched with 10% aqueous Na2COa solution, extracted with EtOAc, washed with 10% aqueous NH ₄ CI solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on SiCb eluting with a gradient of 0 to 30% EtOAc in hexane to give 24-1.

Compound 24 was prepared from 24-1 according the procedure for the synthesis of 16-4 using π-BuLi (0.51 ml, 1.6 M ), and tetrahydro-2H-pyran~4~carba!dehyde (93 mg) in THF (8 mL). LCMS: MW is 441. Found: MH ⁺ : 442. Retention time: 4.65 min.

Example 25

A mixture of compound 24 (28 mg) and TFA (1 mL) was stirred at RT for 2 hr. The mixture was concentrated in vacuo, and partitioned between CH ₂ CI ₂ and aqueous NaHCOs. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified on silica gel plates to yield 25. LCMS: M is 341. Found: M+1 is 342 _S retention time: 2.92 min.

Example 26

Step 1:

rt-8uLi in hexane (1 ml, 1.6 M) was added to a solution of 16-2 (50 mg) in anhydrous THF at -78 ⁰ C dropwise. After stirring for 1 h _s a solution of 26-1 (175 mg) in THF was added to the mixture slowly. The solution was stirred at -78 ⁰ C for at least 1 h, slowly warmed to RT and stirred overnight. The reaction was cooled to -78 ⁰ C and quenched with H ₂ O. The solution was warmed to RT, extracted with EtOAc, dried (Na ₂ SO^, and concentrated. The residue was purified by silica gel chromatography eluttng with EtOAc-Hexane (0-100%) to afford 26^2 (17 mg). LCMS: M is 440. Found: M+1 is 441, retention time: 3.78 min. Step 2:

A mixture of 26-2 (15 mg) and 20% TFA in CH ₂ CI ₂ (1 mL) was stirred at RT for 1 h. The mixture was concentrated and partitioned between EtOAc and aq. sat. NaHCO ₃ . The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was washed with ether, and recrystalized from CH ₂ CI ₂ to afford 26 (7.5 mg). LCMS: IV! is 340. Found: M-M is 341 , retention time: 2.12 min.

Example 27

/7-BuLi in hexane (2 mL, 1.6 M) was added to a mixture of 16-2 (200 mg) in anhydrous THF at -78 ⁰ C dropwise. After stirring for -40 rnin, p-fluorobenzylaldehyde (200 mg) was added slowly. The mixture was stirred at -78 ⁰ C for ~1 h, slowly warmed to RT (~1 hr) and stirred at RT for 1 hr. The reaction was cooled to -78 ⁰ C. quenched with H ₂ O, warmed to RT, and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography elυting with EtOAc-Hexane (0-100%) to afford 27 (18 mg). LCMS: M is 351 Found: M+1 is 352, retention time: 3.66 min.

The following compounds were prepared in a similar manner:

97

A mixture of 27A (12.7 m inane (19.4 mg) in CH ₂ Cl ₂ was stirred at RT for 2 h. The mixture was treated with saturated aqueous NaHCOs. The organic layer was dried over MgSO ₄ and evaporated to dryness. The residue was purified using preparative TLC eluting with 40% EtOAc-hexane to yield 28. LCMS: M is 331. Found: M+1 is 332, retention time: 4.58 min.

The following compound was prepared in a similar manner:

28A

Example 29

Step i:

A mixture of 16-2 (100 mg), 2-ethynyipyridine (41 mg), PdCI ₂ (PPh ₃ ) ₂ (19.4 mg), CuI (5.3 mg), diisopropylamine (1.5 ml_) in toluene (-3 mL) was degassed and charged with N ₂ . The mixture was heated at ~9G ⁰ C overnight. The resulting mixture was cooled and filtered. The precipitate was washed with CH ₂ CI ₂ , and MeOH to yield 29A as a yellow solid (35 mg). LCMS: M is 328. Found: M+1 is 329, retention time: 4.17 min. Step 2:

A mixture of 29A (31 mg) and 10% Pd/C (15 mg) in EtOH was stirred under H ₂ (1 atm) at RT for 2 days. The mixture was filtered and washed with CH ₂ CI ₂ . The filtrate was concentrated. The residue was purified by HPLC (CH ₃ CN-H ₂ O, 0.01 % HCOOH, 10% to 100% gradient) to yield 29B (9 mg), LCMS: M is 332, Found. M+1 is 333, retention time: 2.25 min.

The following compounds were prepared in a simiiar manner:

Ex. No. Structure i ftΛW ! ES-MS ! R _t 100

101

To a mixture of 16-2 {500 mg) in anhydrous THF (10 mL) in a microwave vial was sequentially added 4-(aminomethy[)pyridine (540 mg), DBU (760 mg), Herrmann's catalyst (40 mg), f-Bu ₃ P'HBF ₄ (30 mg), and Mo(CO) ₆ (440 mg). The mixture was sealed, purged with N ₂ , and placed in a microwave reactor. The mixture was heated at 150 ⁰ C (high absorption) for 40 min. Additional three batches were carried out using the same conditions. After cooling, the reaction mixtures were combined and evaporated to dryness. The residue was purified by silica gel chromatography eluting with CH ₂ CI ₂ - MeOH, and followed by HPLC (CH ₃ CN-H ₂ O, 0.1 % HCO ₂ H) to yield 30 (206 mg). LCMS; M is 361. Found: M-M is 362, retention time: 2.14 min.

The following compound was prepared in a similar manner:

Example 31

To a solution of 4-hydroxy-tetrahydropyran (~5 mL) in Λ/~methyl-2~pyrroiidinone (-5 mL) was added NaH (764 mg of 60% in oil) at 0 ⁰ C. After stirring for 0.5 h, compound JUS (500 mg) was added to the reaction mixture. The mixture was heated at 1 10 ⁰ C overnight. The mixture was cooled and quenched with ice water, and filtered. The residue was purified by silica gel column chromatography eluting with DCM-MeOH to afford compound 3J. (-76 mg). LCMS: M is 327. Found: m/z 328 (MH ⁺ ), retention time: 2.79 min.

Example 32

Step 1 :

To a solution of KI (60 mg) in Λ/-methyl-2-pyrroitdinone (-1 mL) in a microwave vial was added NaH (60 mg of 60% in oil) and then compound jM5 (100 mg). The mixture was sealed, purged with N ₂ , and placed in a microwave reactor. The mixture was heated at 150 ⁰ C (high absorption) for 1 hr. The reaction mixture was cooled, treated with ice water and filtered. The precipitate was washed with ether to yield 32A (-50 mg). LCMS: M is 324. Found: m/z 325 (MH ⁺ ), retention time: 2.47 min Step 2:

To a solution of compound 32A (35 mg) in THF at -78 ⁰ C was added DIBAL (323 uL, 1M in hexane). The mixture was warmed to RT and stirred for 2 h. The mixture was cooled -78 ⁰ C, treated with IVIeOH (140 uL), sat, NH ₄ Cl (200 uL). The mixture was warmed to RT and partitioned between 1 N NaOH and EtOAc. The organic layer was dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by silica gel column chromatography to yield compound 32B (-1 mg). LCMS: M is 308. Found: m/z 309 (IvIH ⁺ ), retention time: 2,22 min. A mixture of 16-2 (133 m d (80 mg), Pd(PPh ₃ ) ₄ (96 mg),

Na ₂ CO ₃ (40 mg), toluene (8 mL), EtOH (2 mL), and H ₂ O (2 mL) was heated in a microwave reactor at 120 ⁰ C for 1 h. Sat. NaHCO ₃ (15 mL) was added and the mixture extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica get chromatography, eluting with a gradient of 0 to 70% EtOAc in hexanes. The resultant residue was further purified by reverse phase HPLC ₁ equipped with a silica gel column 6 μm; 25 x 100 mm eluting with 0.1% HCOOH in CH ₃ CN / 0.1 % HCOOH in water (10% to 95% over 20 mm). Fractions possessing the product were neutralized with sat. NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 37 mg of 33 as a yellow solid, LCIVIS: M is 304. Found: M+1 is 305, R _t = 2.46 min.

Example 34

Preparation of 34A:

A mixture of 1^2 (124 mg), 4-vinyipyrfdine (110 μL), Pd(OAc) ₂ (20 mg), P(o-tol) ₃ (20 mg), TEA (1 mL) and DMF (1 mL) was heated for 30 min at 120 ⁶ C in the microwave. Saturated NaHCO ₃ (10 mL), brine (20 mL), and EtOAc (30 mL) were added. The phases were separated and the organic layer washed with H ₂ O (2 x 20 rnL). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0 to 100% EtOAc in hexanes. The residue so obtained was further purified by reverse phase HPLC, eluting with 0.1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 6 mg of 34A as a yellow oil. LCMS: M is 330. Found: M+1 is 331 , R _t = 2.43 min. Preparation of 34B:

Compound 16*2 (315 mg) was subjected to the Heck conditions as described above. Following flash column chromatography, the residue was dissolved in EtOH (8 rnL) and HOAc (2 mL). Pd/C (10%, 20 mg) was added and the mixture placed under a balloon atmosphere of H ₂ . The mixture was stirred for 24 h at RT. The mixture was filtered and the solvent removed in vacuo. The residue was purified by reverse phase HPLC ₁ eiuting with 0.1% HCOOH in CH ₃ CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 11 mg of 34B as a yellow oil. LCMS: M is 332. Found: M+1 is 333, R _t = 2.17 min.

A solution of 35-1 (TIPS is triisopropylsilyl) (1.35 g) in THF (25 mL) was cooled to -78 "C. /1-BuLi (2.30 mL, 1.04 M in hexanes) was added dropwise. The resulting solution was stirred at -78 °C for 20 min, whereupon B(OMe) ₃ (500 μL) was added. The mixture was stirred at -78 "C for 1 h, whereupon a 1 :1 solution of MeOH and H ₂ O (4 mL) was added. The mixture was warmed to RT and H ₂ O (20 mL) was added. The mixture was extracted with Et ₂ © (3 x 40 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to obtain 35-2. Step 2:

35-3

A mixture of 16-2 (300 mg), the crude 35-2, Pd(PPh ₃ J ₄ (96 mg), Na ₂ CO ₃ (40 mg), toluene (8 mL), EtOH (2 mL), and HaO (2 mL) was heated in a microwave reactor at 120 ⁶ C for 1 h. Sat. NaHCO ₃ (15 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0 to 25% EtOAc in hexanes to give 35-3. Step 3:

Compound 35-3 (167 mg) was dissolved in THF (10 mL) and TBAF (1 M solution in THF, 450 μL _s 0.45 rnmol) was added. The mixture was stirred at RT for 30 min. H ₂ O (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gef chromatography, eluting with a gradient of 0 to 35% EtOAc ϊn hexanes. The residue was purified by reverse phase HPLC, efuting with 0.1% HCOOH in CH ₃ CN / 0.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO ₃ and the product extracted with EtOAc. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 14 mg of 35 as a yellow solid. LCMS: M is 292. Found: M+1 is 293, R _t - 2.89 min.

To a cold (0 ⁰ C), stirred solution of dtisopropyl amine (135 mg) in anhydrous THF (5 rnL) was added /i-BuLi (0.81 mL of 1.6 M solution in hexane) dropwise via syringe. After being stirred at 0 ⁰ C for 20 min, the solution was cooled to -78 ⁰ C and 4- methylpyrimidine (118 mg) was added dropwise via syringe. The resulting solution was stirred at -78 ⁰ C for 1 h. in a separate flask, 3.6-1 (150 mg) (prepared in a manner similar to compound 16-2) was dissolved in anhydrous THF (5 mL). To this solution was added NaH (33 mg of 60% in oil) in portions at RT. The resulting mixture was stirred at RT for 1 h before being added dropwise via syringe at -78 ⁰ C to the (pyrimidinylmethyl)lithium solution prepared above. The resulting mixture was slowly warmed to RT and stirred overnight. The reaction was quenched with a saturated aqueous solution of NH ₄ CI (10 mL) followed by dilution with H ₂ O (20 mL), The resulting layer was extracted with CH ₂ Cb (3 x 20 mL). The combined organic iayer was dried over MgSO ₄ , filtered and concentrated to give a residue which was purified by column chromatography on silica eluting with 30: 1 CH ₂ CI ₂ :Me0H to afford 36 (118 mg) as a light yellow solid. LCMS: M is 373. Found M+1 is 374. Retention time: 3.75 min.

The following compounds were prepared in a similar manner: 108

109

The amount and frequency of administration of the active compound employed and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient. A typical recommended dosage regimen can range from about 10 mg/dose to about 100 mg/dose, preferably about 10 to about 50 mg/dose, and more preferably about 20 to about 25 mg/dose.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A Genπaro (ed.), The Science and Practice of Pharmacy, 20 ^th Edition, (2000), Lippincott Williams & Wiikins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral Injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered In portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.

The activity of the compounds of Formula I or I! can be determined by the following procedures. In Vitro PPE10 assay

PDE10A1 activity was measured in white opaque 384-weil Opti-Piates (Perkin Elmer Life Sciences) using a scintillation proximity assay (GE Healthcare). Human recombinant PDE10A1 was purchased from BPS Bioscience, Inc. The reaction mixture contained PDE10A1 ( 0.02 nM), 10 nM [ ³ H]cAMP ((5\8- ³ H]Adenosine 3\5"-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in 50 mM Tris-HCI, pH 7.5 _S 8.3 mM MgCI ₂ , 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 μl. The assay was initiated with the addition of substrate and was allowed to proceed for 30 minutes at room temperature before being stopped by the addition of 300 μg yttrium SPA PDE beads. The reaction mixtures were thoroughly mixed, and the beads were allowed to settle for 30 minutes. The plates were then counted in a TopCount scintillation counter. Under these conditions, less than 30% of the substrate was hydroiyzed in the absence of compound. Ki values were determined as described by Cheng and Prusoff (1973).

Using the test procedures described above, the following compounds of Formula I were found to have Ki values of less than 500 nM: Examples 3E, 3F, 3S ₁ 3V, 38B ₁ 4, 4A, 4B, 4F ₁ 4H, 41, 4K ₁ 4L, 5, 5F ₁ 5G, 5K ₁ 5IVI ₅ 50, 5Q, 5R, 5S, 6H, 7A, 7B, 7E, 8, 8A ₁ 8B _S 8C, 9, 10A, 10C, 10D, 10E, 10F ₁ 10G, 10H, 13, 13-1 , 13A, 13B, 13C, 13D, 13F, 13G ₁ 131, 13J. 13K ₅ 13L _S 13N, 130, 13P. 13Q, 13R ₅ 13S ₁ 13T ₁ 13V, 14, 15, 16, 17, 18, 21B, 21 D, 21F, 22 _S 23, 24, 26, 27, 27A, 27B ₁ 27C, 28, 29A, 29B. 29D, 29E, 2SF, 32B. 33, 34A ₅ 348, 35, 36C, 36E, 38F and 38G2. Compounds of Formula I having a Ki of less than 100 nM are Examples 3E, 3F ₁ 3S ₅ 3V ₁ 4, 4B, 4F, 4H, 41, 4K ₁ 5, 5F ₅ 5K, 5M ₁ 5O ₁ 5Q ₁ 5R ₁ 5S, 6H, 7E, 8B, 8C ₁ 9, 10A ₁ 10C, 10D, 10E, 10F, 10G, 10H, 13, 13A ₁ 13C, 13F ₁ 13G ₁ 131, 13J, 13K, 13L ₁ 13N ₁ 13O _r 13P, 13Q, 13R, 13S, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B ₁ 29F, 32B, 34B, 35, 36C, 36E, 36F and 36G2.

Using the test procedures described above, the following compounds of Formula II were found to have Ki values of !ess than 500 nM: Examples 3, 3D, 3G, 31, 3M, 3N, 3O ₁ 3R, 3T ₁ 3W ₁ 3Y, 3AA, 3CC, 4C, 40, 4P ₁ 4Q, 4R, 4S, 4U, 4V, 5A, 5C ₁ 5D, 5E ₁ 5H. 5J, 5L, 5P, 5T, 5V, 5W, 5X, 5Y, 6, 6A ₁ 6D, 61, 6K, 6L, 6M, 6N, 6O _η 6P, 7, 7D, 12, 13U, 2OA, 20C ₅ 21C ₁ and 21 E. Compounds of Formula tl having a Ki of less than 100 nM are those in Exampfes 3, 3D, 3G _S 3I ₁ 3O, 3R, 3T ₁ 3W ₁ 3Y, 3AA _; 3CC ₁ 4C, 40, 4P ₁ 4G, 4R, 4S, 4V, 5H ₁ 5P ₁ 5T _S 5V ₁ 5W, 5Y, 6, 6A ₅ 61, 6K, 6L _S 6M, 6N, 6P, 7, 7D, and 12.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. AN such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.