AU2009320125A1 - Substituted pyrazoloquinolines and derivatives thereof - Google Patents

Description

WO 2010/062559 PCT/US2009/062071 SUBSTITUTED PYRAZOLOQUINOLINES AND DERIVATIVES THEREOF 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 pyrazoloquinolines 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-modulated 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 striatopallidal indirect output pathway). D2 dopamine receptor antagonism increases striatal output via the indirect striatopallidal pathway, which improves some of the aspects of schizophrenia, but does not affect striatal output via the direct striatonigral output pathway. PDE10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehler et al, "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 cGMP levels in all striatal MSNs, PDE10 inhibition WO 2010/062559 PCT/US2009/062071 2 will mimic D2 dopamine receptor antagonism in the indirect striatopallidal output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striatal output that characterizes schizophrenia. By increasing corticostriatal transmission, PDE10 inhibition should improve the cognitive dysfunction that characterizes schizophrenia. Furthermore, the discrete localization of PDE10 should lead to an improved side effect profile: typical side effects include extrapyramidal syndrome, diabetes, weight gain, hyperprolactinemia, sedation and QTc 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 WO 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 Al. Summary of the Invention In its several embodiments, the present invention provides a novel class of substituted pyrazoloquinoline PDE10 inhibitor compounds and derivatives thereof represented by Formula 1, 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.

WO 2010/062559 PCT/US2009/062071 3 The invention also provides for methods of treatment of PDE1 0 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 pyrazoloquinoline PDE1 0 inhibitor compounds and derivatives thereof represented by Formula 11. Novel compounds of the invention have the structural Formula I:

R

4 R 2 N N A N R3

R?

5 Formula I 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 0, provided that when it is a 5 membered heteroaryl containing two heteroatoms, R 2 is absent;

R

1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C0 2 H, -C(O)N(R 6

A)

2 , -N(R 6 5

)

2 , -alkyN(R 8

)

2 , -NR 6

-C(O)N(R

6

A)

2 , -N(R 6 )C(O)Oalkyl, -N(R 6 )S0 2 -alkyl, phenyl, CN, -N N 0 -SO2R6, -SR', trimethylsilyl-, -SF 5 , -OSF, -C(=NOR 6

)-R

6 , r, or

-(CH

2 ),-XjCH 2 )m-R 1 wherein X is -0-, -S-, or -NR6-, n is 0, 1 or 2, m is 1, 2 or 3 and

R

18 is selected from the group consisting of WO 2010/062559 PCT/US2009/062071 4 N N N NC ~N N N N SN and

R

2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C0 2 H, -C(O)N(RA)2, -N(R 6

B)

2 , -alkylN(R 6

B)

2 , -NRe-C(O)N(R 6

A)

2 , -N(R)C(O)Oalkyl, -N(RC)S0 2 -alkyl, phenyl or CN; or R 1 and R 2 on adjacent ring carbon atoms together form -O-CH 2 -O- or -O-(CH2)2-0-;

R

3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl,

-N(R

6

B)

2 , -OCF 3 , -CF 3 , -SF 5 , -OSF 5 or -CN;

R

4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, -S0 2 -alkyl, -C(O)N(RA) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;

R

5 is alkyl, -CN, -C(O)OR6A, -C(O)N(R 6

A)

2 , aryl-((R 17 a R17b)-alkylene)-, heteroaryl-((R 1 7a, R 7 b)-alkylene)-, heterocycloalkyl-((R 17a, R 17 b)-alkylene)-, hydroxyalkenyl, heteroarylaikenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, -alkyl-O-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R-aryl, -alkyl-N(R 6 )-heteroaryl, -alkyl-N(R 6 )-cycloalkyl, -alkyl-N(R6)-heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocycloalkyl-heteroary-alkylene-, cycloalkyl (e.g., cyclopropyl), WO 2010/062559 PCT/US2009/062071 5 0 Re -CH 2

)-NR

6 0 -- (CH 2 )bNR 6

NR

14 N H -N 0 N -N NNR 6 10H 2 )b r-r r R14,

-NR

6

-(CH

2 )b 1NR 6

-(CH

2 )b NR 4 0 or N-R 1 4 bis 1,2or3; r is 1 or 2; t is0, 1 or 2; each Rr is independently selected from H and alkyl; each R 6A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two RBA groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R6A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring; each Re is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-, -SO 2 alkyl, -S0 2 -aryl,

-SQ

2 -heteroaryL -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(0)0-alkyl, -C(0)0-aryl, -C(O)O-heteroaryl, -C(O)N(R 6

)

2 , -C(O)NRr-aryl, and -C(O)NR6-heteroaryl; or two R6B groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or hornothiomorpholinyl ring; WO 2010/062559 PCT/US2009/062071 6

R

9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0; R" 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 single carbon ring member with -(CH 2

)

2

-

6 - or -0-(CH 2

)

2 -0-;

R

12 is 1 or 2 substituents independently selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl; R3 is hydroxyalkyl, cycloalkyl, -C(0)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalkyl-, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-alkylaryl, -C(0)0-aryl, -C(0)0-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R 6

A)

2 , -C(O)-alkyl-NR 6 -C(O)-aryl, -C(0)-alkyl-NR 6 -C(0)O-alkyl, -C(O)-alkyl-NR 6 -C(O)0 benzyl, -SO 2 alkyl, -S02-aryl, -S0 2 -alkylaryl, -S0 2 -heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with halo; R1 4 is H, alkyl, hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalkyl-, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-alkylaryl, -C(0)0-aryl, -C(0)0-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R 6

A)

2 , -C(O)-alkyl-NR 6 -C(O)-aryl, -C(O)-alkyl-NR 6 -C(0)O alkyl, -C(O)-alkyl-NR 6 -C(O)O-benzyl, -SO 2 alkyl, -S02-aryl, -S0 2 -alkylaryl, -S02 heteroaryi or diphenylmethyl, optionally substituted on a phenyl ring with halo;

R'

5 is 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, OH, hydroxyalkyl, halo, -CF 3 , -C(O)Oalkyl, -C(O)N(RA) 2 , aminoalkyl-,

-N(R

6 B)2, -NR6-C(O)N(R 6

A)

2 , -NR 6 -C(O)-alkyl, -NR 6 -C(O)Oalkyl, -NR 6 -S0 2 -alkyl, -alkyl-imidazolyl, wherein the imidazolyl is optionally substituted with alkyl, and phenyl, or two hydrogen atoms on a carbon ring member are replaced by -(CH 2

)

2 -r.- or -O

(CH

2

)

2 -0-; and

R

17 2 is H or alkyl and R'7b is H, alkyl, OH, F, -N(R6B)2, -NOR6, alkoxy, CN.

-CH

2 OH, -CH 2 -O-alkyl, -CON(R 6 a) 2 , -CH 2

N(R%)

2 or -CO2R6; or R 17 and R'i7 are each F; or R 17 ' and R7b are on the same carbon atom and together are =0, =NOR6 or

-(CH

2

)

2

.;

WO 2010/062559 PCT/US2009/062071 7 provided that when R 5 is heterocycloalkyl-((Ra, R17)-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the R 17 b substituent on the a-carbon is H, alkyl, CN, -CH 2 OH, -CH 2 -0-alkyl, -CON(Ra,)2

-CH

2 N(R)2 or -C0 2

R

6 . In one example, R 3 for Formula I is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(RB) 2 , -OCF 3 , -SF 5 , -OSF 5 or -CN. In one example R 5 for Formula I is alkyl, -CN, -C(O)ORA, -C(O)N(R6A)2, aryl-((R1 7 a, R17b)-alkylene)-, heteroaryl-((R1 7 a, R17)-alkylene)-, heterocycloalky-((R1a, R 7 b)-alkylene), hydroxyalkenyl, heteroarylalkenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, alkyl-0-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R%-aryl, -alkyl-N(R 6 )-heteroaryl, -alkyl-N(R)-cycloalkyl, -aikyl-N(R)-heterocycloalkyl, -alkyl-heterocycloalky, heterocycloalkenyl, heteroaryl, 0 r -(CH 2 )bNR 6 O (CH 2 )b-NR 6

NR

4 -N NH R12 R9>

NR

6

-(CH

2 )b0S -N 0RN N R -- N -- R5 - (H -Nr \Ar N R4 -NRe-(CH2)b 0NR-(CH2)b

NR

1 4 0 HO HO tor 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.

WO 2010/062559 PCT/US2009/062071 8 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 a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically 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 pharmaceutically 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 II:

R

1 N R 2 NM1 3 R5A Formula 1l or a pharmaceutically acceptable salt thereof, wherein all substitutents 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 WO 2010/062559 PCT/US2009/062071 9 heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and 0, provided that when it is a 5 membered heteroaryl containing two heteroatoms, R 2 is absent; R' is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C0 2 H, -C(O)N(R6A) 2 , -N(R6B)2, -alkylN(R 68

)

2 , -NRe-C(O)N(RA) 2 , -N(R 6 )C(O)Oalkyl, -N(R 5 )S0 2 -alkyl, phenyl, CN, 6-N -- N O

-SO

2

R

6 , -SR , trimethylsilyl-, -SF 5 , -OSF , -C(=NOR 6

)-R

6 , Ir r, or

-(CH

2 )n-X-(CH 2 )m-R 8 , wherein X is -0-, -S-, or -NR 6 -, n is 0, 1 or 2, m is 1, 2 or 3, and

R

1 8 is selected from the group consisting of N N N N N N N N andNN

R

2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF3, halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C0 2 H, -C(O)N(R6A) 2 , -N(R6B) 2 , -alkylN(R6B) 2 , -NRsC(O)N(RA) 2 , -N(R )C(O)Oalkyl, -N(R)S0 2 -alkyl, phenyl or CN; or R 1 and R 2 on adjacent ring carbon atoms together form -O-CH 2 -O- or -O-(CH2)rO0-; r is 1 or 2;

R

3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl,

-N(R

8

)

2 , -OCF 3 , -SF 5 , -OSF or -CN;

R

4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, S0 2 -alkyL, -C(O)N(R6A) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy; RA is H, halo, OH, alkoxy, -O-alkyl-N(alky) 2 , -0-heterocycloalkyl, -O-alkyl-heterocycloalkyl, aryloxy-, arylalkoxy-, heteroaryloxy-,

-N(RA)

2 ,

-NR

6 -alkyl-N(alkyl)2, -NR 6 -alkyl-O-alkyl-OH, -NR-hydroxyalkyl, -S-alkyl, WO 2010/062559 PCT/US2009/062071 10 -S-hydroxyalkyl, -S-aryl, -S-alkylaryl, -S-heteroaryl, -S-alkyl-heteroaryl, -S-heterocycloalkenyl, -SC(O)-alkyl, -SO2-alkyl, -S-alkyl-C(O)OH, -S-alkyl-N(alkyl) 2 , -N N-alkyl -S-alkyl-NHC(O)H, -S-alkyl-C(O)NH-alkyl-pyrrolidinone, r -N -N NR 6 r or XIr each R 6 is independently H or alkyl; each RA is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two R 6 A groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 6 A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring; and each R 6 B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-,

-SO

2 alkyl, -S02-aryl, -S02-heteroaryl, -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(0)0-alkyl, -C(O)O-aryl, -C(O)O-heteroaryl, -C(O)N(R 6

)

2 , -C(O)NR 6 -aryl, and -C(O)NR 6 -heteroaryl; or two R 6 B groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 68 3 groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring. In another embodiment, the 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 to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

WO 2010/062559 PCT/US2009/062071 11 Detailed Description In one embodiment of Formula 1, forms a phenyl ring. In some embodiments of Formula 1, R' and R 2 are independently selected from the group consisting of R' is H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo. In other embodiments of Formula I: R' is alkyl, preferably methyl, and R 2 is alkoxy, preferably methoxy; or R' is alkyl, preferably methyl, and R 2 is -OCF 3 ; or R' is alkyl, preferably methyl, and R 2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R' is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or R1 is alkoxyalkoxy (preferably methoxyethoxy) and R 2 is H; or R' is halo and R 2 is H; or R' is halo and R 2 is -OCF 3 ; or R' and R 2 together are methylenedioxy. In another embodiment of Formula 1, R 3 is alkyl, preferably methyl, or H. In another embodiment of Formula 1, R 3 is -CF 3 . In another embodiment of Formula 1, R 4 is H, -C(0)0-alkyl, wherein alkyl is preferably t-butyl, or -SO 2 alkyl, preferably -SO 2

CH

3 . In another embodiment of Formula I, b is 1. In another embodiment of Formula 1, R 5 is selected from the group consisting of -CN, -C(O)N(R 6

A)

2 , aryl-((R1 7 a, RI 7 b)-alkylene)-, heteroaryl-((Rl 7 a, Rl1b)-alkylene)-, heterocycloalkyl-((R" 7a, R'7b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), WO 2010/062559 PCT/US2009/062071 12 R"i R12 R9

-(CH

2 )b-NR 6 0 -N NH N N R13 N R1 0 -N R 6

-(CH

2 )b 0 N R14

-NR

6

-(CH

2 )b

,NR

6 -(CH2)b

NR

14 , and

-NR

6 -(CH2)b r wherein b, r, R, RGA, R 9 , R, R', R3, R 4 , R 1 5 , Rla and Rl 7 b ae as defined above. In other embodiments of Formula I, R 5 is -CN; -C(O)NH-alkyl-pyridyl; -CH(OH)-phenyl; -alkylene-phenyl; -alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl; / N R' -CH(OH)-pyridyl;- CH=CH-(CH 2

)

3 -OH; -CH=CH-pyridyl; -C=C-pyridyl;

OH

3 /NR N (CH 2 )b-NR 6 O -N NH -N NH CH2OH CH3 _-N CH3 -NR 6

-(CH

2 )b 0- -- N O0 t t.J CH 3 ; R 14 wherein R 14 is H, alkyl (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);

NR

6

-(CH

2 )b -NR 6

-(CH

2 )b NR 1 4 - - wherein R 14 is H or aikyl; or

-NR

6 ~0CH2)b WO 2010/062559 PCT/US2009/062071 13 In another embodiment of Formula 1, when R 5 is heterocycloalkyl-((Ri1@, Ri11)1 alkylene)-, (R 17 a, R1 7 b)-alkylene- is preferably -C(OH)-, and R 5 is a group such as O H /-\OH -C NH -C H and O In another embodiment of Formula 1, R 5 is heterocycloalkyl-((R1 7 a, Rl17b)_ alkylene)-, wherein R 1 a and R 1 7 b are independently H or alkyl, R 5 being preferably -(CH2)b-N NR' - -N -R8 r R9 2W -R 8 CH2)b-N r or -- RO, wherein b is 1, 2 or 3; r is 1 or 2;

R

7 is H, alkyl or -SO 2 -alkyl; R3 is I or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, 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 hydroxyalkyl. Additional embodiments of compounds of Formula I wherein R 5 is 0 -CH2-N NH -CH 2 -N NH heterocycloalkyl-((R7a, Ri b)-alkylene)- are \--- ,

CH

3 -CH2-N

NSO

2

CH

3

-CH

2 -N 0 CH -cH 2 -N 0 optionaHy substituted by methyl or hydroxymethyl, \__/ optionally substituted by OH, F or CF 3 , and optionally substituted by methyl or OH.

WO 2010/062559 PCT/US2009/062071 14

R

9 -N NR 13 In another embodiment of Formula I, R 5 is )r r is 1, R 9 is H or alkyl, and R 13 is -SO 2 alkyl, -CONH 2 , -C(O)heteroaryl, for example OH , or 0 -C C(O)cycloalkyl, for example CH3; more preferably, R 1 3 is -SO 2 alkyl or RS -N NR 1

-CONH

2 . In another embodiment, R 5 is r r is 2, R 9 is H and R 13 is

-SO

2 alkyl or -CONH 2 . -N ~~- R15 In another embodiment of Formula 1, R 5 is \ r r is 2, and R 15 is alkyl (preferably methyl), alikoxy (preferably methoxy), -CF 3 , OH, hydroxyalkyl, preferably hydroxymethyl, halo (preferably F), -NH 2 , -C(O)NH 2 , -CH 2

NH

2 , -C(0)0-alkyl, -NHSO 2 alkyl or -NHC(O)NH 2 , where R 15 is preferably in the -N -R 15 4-position. In another embodiment, R 5 is r is 2, and R 15 is hydroxyalkyl, preferably hydroxymethyl, in the 3-position. N -- R 5 In another embodiment of Formula 1, R 5 is r r is 1. and R- is OH or hydroxyalkyl (preferably hydroxymethy). Examples of the heterocycloalkyl-heteroaryi-alkylene-

R

5 group for Formula I include, but are not limited to: WO 2010/062559 PCT/US2009/062071 15 N- N N N N Nand Oo o 0 Thus, in one example the heterocycloalkyl-heteroaryl-alkylene-

R

5 group for Formula I is: N N (N 0 In another example the heterocycloalkyl-heteroaryl-alkylene-

R

5 group for Formula I is: N N 0 In another example the heterocycloalkyl-heteroaryl-alkylene-

R

5 group for Formula I is: N N In one example the FR 5 cycloalkyl group is cyclopropyl.

WO 2010/062559 PCT/US2009/062071 16 In another embodiment of the compounds of Formula I:

R

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

R

3 is H or alkyl;

R

4 is H, -C(0)0-akyl or -SO 2 alkyl; and

R

5 is selected from the group consisting of -CN, -C(O)N(R6A) 2 , aryl-((Rl 7 a, R7b) alkylene)-, heteroaryl-((R 1 7a, R 1 7 b)-alkylene)-, heterocycloalkyl-((R" 7a", R 17 b )-alkylene), hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), R11 R12R /~~x' 1 -r -N NR -- N -- (CH2)b-NRs0 -N NH -N 0 \

-NR

6

-(CH

2 )b 0

-NR

6 -- (CH 2 )b -NR 6

-(CH

2 )b NR 1 4 R 14 A -0 -Cand -NRS-(CH2)b r , wherein b, r, R 6 , R A, R 9 , R 1 1 , R 1 2 , R 1 3 , R 14 , R 1 5 , R 1 7 a and R 1 7 b are as defined above. In yet another embodiment of the compounds of Formula 1:

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, halo or alkoxyalkoxy (preferably methoxyethoxy); or R' is aikoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H; or R1 is alkoxyalkoxy (preferably methoxyethoxy) and R 2 is H; or R' is halo and R 2 is H; or

R

1 is halo and R 2 is -OCF 3 ; or WO 2010/062559 PCT/US2009/062071 17

R

1 and R 2 together are methylenedioxy;

R

3 is alkyl;

R

4 is H; and

R

5 is -CN: -C(O)NH-alkyl-pyridyl; -CH(OH)-phenyl; -alkylene-pheny; -alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl; -CH(OH)-pyridyl;

/NR

6 1 iNR 6 N -CH=CH-(CH2)r-OH; -CH=CH-pyridyl;, -C=C-pyridyl ;

CH

3

CH

2 OH

-(CH

2 )b-NR 6 O -N NH -N NH -N 0

CH

3 N OCH3

-NR

6

-(CH

2 )b -N O N\

CH

3 ; R 14 wherein R 14 is H, alkyl (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl); 0

-NR

6

-(CH

2 )b -NR 6

-(CH

2 )b NR 14 wherein R 1 4 is preferably H or alkyl; ~N

R

6 -(CH2)b O heterocycloalkyl-((Rl 7 a, Rl 7 b)-alkylene)-, wherein (R1 7 ,, R 7 b )-alkylene is OH OH -C NH -C o -C(OH)-, such as H and H heterocycloalkyl-((Ra, R )-alkylene)-, wherein R ' and R 17 b are independently H or alkyl, preferably

-(CH

2 )b-N NR 7 -R R (CH 2 )b-N R (CH2)b-N ro WO 2010/062559 PCT/US2009/062071 18 b is 1, 2 or 3; r is 1 or 2; R 7 is H, alkyl or -S0 2 -alkyl; R 8 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, 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 hydroxyalkyl; R9S -N NR 1 3 r , wherein r is 1, R 9 is H or alkyl, and R' 3 is -SO 2 alkyl, -CONH 2 , if NZ4 -C(O)heteroaryl, for example OH , or -C(O)cycloalkyl, for example 0 -- C

CH

3 ; more preferably R1 3 is -SO2alkyl or -CONH 2 ; R R9 N NR1 3 T1r wherein r is 2, R 9 is H and R' 3 is -SO2alkyl or -CONH 2 ; N R r wherein r is 2, and R' 5 is alkyl (preferably methyl), allkoxy (preferably methoxy), -CF 3 , OH, hydroxyalkyl, preferably hydroxymethyl, halo (preferably F), -NH 2 , -C(O)NH 2 , -CH 2

NH

2 , -C(0)0-alkyl, -NHSO 2 alkyl or

-NHC(O)NH

2 , where R' 5 is preferably in the 4-position; N R 5 r wherein r is 2, and R 15 is hydroxyalky, preferably hydroxymethyl, in the 3-position; or r- wherein r is 1, and R' 5 is OH or hydroxyalkyl (preferably hydroxymethyl) WO 2010/062559 PCT/US2009/062071 19 Preferred compounds of Formula I are those in Examples 3E, 3F, 3S, 3V, 388, 4, 4A, 48, 4F, 4H, 41, 4K, 4L, 5, 5F, 5G, 5K, 5M, 50, 5Q, 5R, 5S, 6H, 7A, 7B, 7E, 8, 8A, 8B, 8C, 9, 10A, 10C, 10D, 10E, 10F, 10G, 10H, 13, 13-1, 13A, 138, 13C, 13D, 13F, 13G, 131, 13J, 13K, 13L, 13N., 130, 13P, 13Q, 13R, 13S, 13T, 13V, 14,15,16, 17, 18, 218, 21D, 21F, 22, 23, 24, 26, 27, 27A, 27B, 27C, 28, 29A, 29B, 29D, 29E, 29F, 328, 33, 34A, 34B, 35, 36C, 36E, 36F, and 36G2. More preferred compounds of Formula I are Examples 3E, 3F, 3S, 3V, 4, 4B, 4F, 4H, 41, 4K, 5, 5F, 5K, 5M, 50, 5Q, 5R, 58, 6H, 7E, 88, 8C, 9, 10A, 10C, 10D, 10E, 1OF, 10G, 10H, 13, 13A, 13C, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 130. 13R, 13S, 13V, 14, 15, 16, 17, 18, 21B, 21D, 21F, 22, 26, 27, 27A, 27B, 27C, 29B, 29F, 32B, 348, 35, 36C, 36E, 36F, and 36G2. In one embodiment the compound of Formula I is 3E. In another embodiment the compound of Formula I 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 I 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 I is 5K. In another embodiment the compound of Formula I is 5M. In another embodiment the compound of Formula I is 50. In another embodiment the compound of Formula I is 5Q. In another embodiment the compound of Formula I is 5R. In another embodiment the compound of Formula I is 5$. In another embodiment the compound of Formula I is 6H. In another embodiment the compound of Formula I is 7A. In 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 WO 2010/062559 PCT/US2009/062071 20 the compound of Formula I is 8B. In another embodiment the compound of Formula I is 8C. In another embodiment the compound of Formula I is 9. In another embodiment the compound of Formula I is 10A. In another embodiment the compound of Formula I is lOC. In another embodiment the compound of Formula I is 10D. In another embodiment the compound of Formula I is 10E. 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 I 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 Formula I is 13Q. In another embodiment the compound of Formula 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 I is 16. In another embodiment the compound of Formula I is 17. In another embodiment the compound of Formula I is 18. In another embodiment the compound of Formula I is 21B. In another embodiment the compound of Formula I is 21 D. In another embodiment the compound of Formula I is 21F. In another embodiment the compound of Formula I 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 I is 26. In another embodiment the compound of Formula I is 27. In another embodiment WO 2010/062559 PCT/US2009/062071 21 the compound of Formula I is 27A. In another embodiment the compound of Formula I is 27B. In another embodiment the compound of Formula I is 27C. In another embodiment the compound of Formula I is 28. In another embodiment the compound of Formula I is 29A. In another embodiment the compound of Formula I is 29B. 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 11 forms a phenyl ring. In some embodiments of Formula 11, R' and R 2 are independently selected from the group consisting of R' is H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo. In other embodiments of Formula 11: R' is alkyl, preferably methyl, and R 2 is alkoxy, preferably methoxy; or R' is alkyl, preferably methyl, and R 2 is -OCF 3 ; or R' is alkyl, preferably methyl, and R 2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R' is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or R' is alkoxyalkoxy (preferably methoxyethoxy)and R 2 is H; or R' is halo and R2 is H; or

R

1 is halo and R 2 is -OCF 3 ; or R' and R 2 together are methylenedioxy. In another embodiment of Formula I, R3 is alkyl, preferably methyl, or H.

WO 2010/062559 PCT/US2009/062071 22 In another embodiment of Formula 11, R 4 is H. In another embodiment of Formula 11, b is 1. In another embodiment of Formula 11, RSA is H, halo, -O-alkyl-N(alkyl) 2 , -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl, -N(R 6

A)

2 , -NR 6 -alkyl-0-alkyl-OH,

-NR

6 -hydroxyalkyl, -S-hydroxyalkyl, -S0 2 -alkyl, or -S-alkyl-NHC(O)H. In other embodiments of Formula 1I, R 5 A is H, Cl, -O-(CH 2

)

2

-N(CH

3

)

2 , -o 0 -OCH 2 0

-N(CH

3

)

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-alkyl-morpholinyl,

-S-CH

2

CH(OH)-CH

2 OH, or -SO 2

CH

3 . In another embodiment, when RSA is -N(R 6

A)

2 , R 5 A is -N(RSA)-(cycloalkyl), wherein R 6 A is H or alkyl, and wherein cycloalkyl is cyclobutyl, cyclopentyl, cyclohexyl 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, hydroxyalkyl, halo, and

-CF

3 . In another embodiment, when R 5 A is -N(R 6

A)

2 , R 5 A is -N(R 6 A)-(heterocycloalkyl), O wherein R6A is H or alkyl, and wherein heterocycloalkyl is or N -R 19 , wherein R 9 is H, alkyl or -SO 2 alkyl. In another embodiment, when R5A is -N(R6A) 2 , R5A is -NR 6 -alkyl-aryl, wherein RGA 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 substituents 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

)

2

-O-.

WO 2010/062559 PCT/US2009/062071 23 In another embodiment, when R5A is -N(R 6

A)

2 , R 5 A is -NR 6 A alkyl-heteroalkyl wherein Rf^ is H or alkyl, and wherein the heteroaryl portion is preferably pyridyl, e.g., - NH--(CH 2 )1 2 N In another embodiment, when R 5 A is -N(R6A) 2 , the two RA groups and the nitrogen to which they are attached form a ring selected from the group consisting of -N / -N q% S-N \4NR6 -- N S q \ , and wherein q is 1 or 2, s is 2 or 3, and R 6 is as defined above. In another embodiment of the compounds of Formula II: R' and R 2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo.

R

3 is H or alkyl;

R

4 is H, -C(0)0-alkyl or -SO 2 alkyl; and RSA is selected from the group consisting of H, halo, -O-alkyl-N(alkyl) 2 , -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl,

-N(R

6

A)

2 , -NR 6 -alkyl-O-alkyl-OH,

-NR

6 -hydroxyalkyl, -S-hydroxyalkyl, -S0 2 -alkyl and -S-alkyl-NHC(O)H, In yet another embodiment of the compounds of Formula 11: R' is alkyl, preferably methyl, and R 2 is alkoxy, preferably methoxy; or R' is alkyl, preferably methyl, and R 2 is -OCF 3 ; or R' is alkyl, preferably methyl, and R 2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R1 is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or R' is alkoxyalkoxy (preferably methoxyethoxy) and R 2 is H; or R1 is halo and R 2 is H; or R' is halo and R 2 is -OCF 3 ; or R' and R 2 together are methylenedioxy;

R

3 is alkyl;

R

4 is H; and WO 2010/062559 PCT/US2009/062071 24 -0 -o

-CH

2 O

R

5 A is H; Cl; -O-(CH 2

)

2

-N(CH

3

)

2 ; ; ; -N(CH 3

)

2 ;

-NH(CH

2

)

3 CH3; -NH-(CH 2

)

2

-O-(CH

2

)

2 -OH; -NH-(CH 2

)

2 -OH; -NH-CH 2

-CH(OH)-CH

3 ; -NH-alkyl-morpholinyl; -S-CH 2

CH(OH)-CH

2 OH; -S0 2

CH

3 ; or

-N(RA)

2 selected from the group consisting of:

-N(R

6 A)-(cycloalkyl), wherein cycloalkyl is cyclobutyl, cyclopentyl, cyclohexyl 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, hydroxyalkyl, fluoro, and -CF3; -N(RA)-(heterocycloalkyl), wherein heterocycloalkyl is - or N -R 19 , wherein R 1 9 is H, alkyl or -SO 2 alkyl; -NR6A-alkyl-aryl, preferably -NR 6 A-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

6 A-alkyl-heteroalkyl wherein the heteroaryl portion is preferably pyridyl; and

-N(R

6

A)

2 wherein the two R 6 A groups and the nitrogen to which they are attached form a ring selected from the group consisting of -N -Nq ) -N O N-R6' -- N S q, \__/ s 6 and N ; wherein q is I or 2, s is 2 or 3, and R 6 is as defined above, and wherein the RA in -N(RA)-(cycloalkyl), -N(R 6 A)-(heterocycloalkyl), -N RSA-alkylaryl and -NR 6 A-alkyl heteroaryl is preferably H or alkyl.

WO 2010/062559 PCT/US2009/062071 25 Preferred compounds of Formula I are those in Examples 3, 3D, 3G, 31, 3M, 3N, 30, 3R, 3T, 3W, 3Y, 3AA, 3CC, 4C, 40, 4P, 4Q, 4R, 4S, 4U, 4V, 5A, 5C, 5D, SE, 5H, 5J, 5L, SP, 5T, 5V. SW, 5X, 5Y, 6, 6A, 6D, 61, 6K, 6L, 6M, 6N, 60, 6P. 7, 7D, 12, 13U, 20A, 20C, 21C, and 21E. More preferred compounds of Formula 11 are those in Examples 3, 3D, 3G, 31, 30, 3R, 3T, 3W, 3Y, 3AA, 3CC, 4C, 40, 4P, 4Q, 4R, 4S, 4W, 5H, 5P, ST, 5V, 5W, 5Y, 6, 6A, 61, 6K, 6L, 6M, 6N, 6P, 7, 7D, and 12. In one embodiment the compound of Formula Il is 3. In another embodiment the compound of Formula 11 is 3D. In another embodiment the compound of Formula 11 is 3G. In another embodiment the compound of Formula II is 31. In another embodiment the compound of Formula I is 3M. In another embodiment the compound of Formula II is 3N. In another embodiment the compound of Formula il is 30. In another embodiment the compound of Formula 11 is 3R. In another embodiment the compound of Formula 11 is 3T. In another embodiment the compound of Formula If is 3W. In another embodiment the compound of Formula I is 3Y. In another embodiment the compound of Formula II is 3AA. In another embodiment the compound of Formula 11 is 3CC. In another embodiment the compound of Formula I is 4C. In another embodiment the compound of Formula 11 is 40. In another embodiment the compound of Formula 11 is 4P. In another embodiment the compound of Formula 11 is 4Q. In another embodiment the compound of Formula l is 4R. In another embodiment the compound of Formula Il is 4S. In another embodiment the compound of Formula I is 4U. In another embodiment the compound of Formula 11 is 4V. In another embodiment the compound of Formula 11 is 5A. In another embodiment the compound of Formula 11 is 5C. In another embodiment the compound of Formula Il is 5D. In another embodiment the compound of Formula il is 5E. In another embodiment the compound of Formula Il is 5H. In another embodiment the compound of Formula Il is 5J. In another embodiment the compound of Formula Il is 5L. in another embodiment the compound of Formula I is 5P. In another embodiment the compound of Formula 1l is 5T. In another embodiment the compound of Formula Il is 5V. In another embodiment the compound of Formula Il is 5W. in another embodiment the compound of Formula i1 WO 2010/062559 PCT/US2009/062071 26 is 5X. In another embodiment the compound of Formula Il is 5Y. In another embodiment the compound of Formula 11 is 6. In another embodiment the compound of Formula 11 is 6A. In another embodiment the compound of Formula If is 6D. In another embodiment the compound of Formula 11 is 61. In another embodiment the compound of Formula i is 6K. In another embodiment the compound of Formula il is 6L. In another embodiment the compound of Formula 11 is 6M. In another embodiment the compound of Formula 11 is 6N. In another embodiment the compound of Formula II is 60. In another embodiment the compound of Formula II is 6P. In another embodiment the compound of Formula 11 is 7. In another embodiment the compound of Formula If is 7D. In another embodiment the compound of Formula 11 is 12, In another embodiment the compound of Formula 11 is 13U. In another embodiment the compound of Formula 11 is 20A. In another embodiment the compound of Formula Il is 20C. In another embodiment the compound of Formula 11 is 21C. In another embodiment the compound of Formula 11 is 21E. 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 "alkyl" as well as the "alkyl" portions of "hydroxyalkyl", "haloalkyl", "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 alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about I to about 6 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 alkyl chain. Alkylene 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 alkylene include methylene, ethylene and propylene (i.e., -CH2-, -(CH 2

)

2 , -(CH 2

)

3 -). When WO 2010/062559 PCT/US2009/062071 27 substituted, the R17a and R 1 7b groups can be on the same or different carbon atoms. The proviso that when R 5 is heterocycloalkyl-((R1 7 a, R 1 7)-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the R1 7 b substituent on the a-carbon is H, alkyl, CN, -CH 2 OH, -CH 2 -0-alkyl, -CON(R 6 a) 2 ,

-CH

2 N(R ) 2 or -C0 2

R

6 is intended to eliminate unstable compounds, e.g., compounds wherein the a-carbon (herein meaning the carbon adjacent to the ring nitrogen) is substituted by OH. Hydroxyalkyl represents an alkyl group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alkyl group. Alkoxy means an alkyl-O- group in which the alkyl 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 alkyl group is as previously described. The bond to the parent moiety is through the alkyl. Halogen represents fluoro, chloro, bromo and iodo. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Alkenyl" 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 alkenyl 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 ethenyl, propenyl, n-butenyi, 3-methylbut-2-enyl, n-pentenyi, octenyl and decenyl. "Hydroxyalkenyl refers to an alkenyl group substituted by one or more hydroxyl groups, preferably 1 or 2 hydroxy groups, provided that a hydroxyl group is not present on a carbon that is part of a double bond.

WO 2010/062559 PCT/US2009/062071 28 "Alkynyl" 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 alkynyl 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 alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl 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 aryl groups include phenyl and naphthyl. "Heteroaryl" 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 heteroaryls 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 heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyi, imidazo[2,1-bIthiazoyl, benzofurazanyl, indolyl, azaindolyl, benzimidazoly, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also WO 2010/062559 PCT/US2009/062071 29 refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like, "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl 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, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralky, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, -CH(Y 1

)(Y

2 ), -O-Y 1 , hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxy, -C(O)Y1, halo, nitro, cyano, -C(O)rY, -S(Q) 2

-Y

1 , -S-Y1, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkenyl, -C(=N-CN)-NH 2 , -C(=NH)-NH 2 , -C(=NH)-NH(alkyl),

-NY

1

Y

2 , -alkyl-N Y 1

Y

2 , -C(O)NY 1

Y

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, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl and heteroarylalkyl. "Ring system substituents" on aromatic rings can also be selected from the group consisting of -SF 5 , -OSF 5 , -Si(Y4) 3 , -S(O)N(Y1)(Y 2 ),

-C(=NOY

1

)Y

2 , -P(O)(OY 1

)(OY

2 ), -N(Y1)C(O)Y 2 , -CH 2

-N(Y

1

)C(O)Y

2 ,

-CH

2

-N(Y

1

)C(O)N(Y

1

)(Y

3 ), -N(Y 1

)S(O)Y

2 , -N(Y1)S(0) 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(Y 1

)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(Y

1

)C(O)

2

(Y

2 ), -S(O)Y, =NOY, and -N3, wherein Y 1 , Y 2 and Y 3 are as defined above and each Y 4 is independently selected from alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl and heteroarylakyl. Furthermore, the alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl portions of Y, Y 2 or Y 3 can be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, OH, -CF 3 , CN, alkoxy, -NH 2 , -NH-alkyl, -N(alkyl) 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 WO 2010/062559 PCT/US2009/062071 30 on each carbon) on a ring system. Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CH 3

)

2 - and the like which form moieties such as, for example: 0 0 o and Similarly, a single divalent moiety such as a divalent alkyl 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: -N OD 0 "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic 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 heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl 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 heterocyclyl 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 heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydroth iophenyl, lactam, lactone, and the like. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there WO 2010/062559 PCT/US2009/062071 31 are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: 4 5I H 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: N N 0 Ca H and N OH are considered equivalent in certain embodiments of this invention. "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl 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 cycloalkyl-alkyl and heterocycloalkyl-alkyl groups wherein cycloalkyl, heterocycloalkyl and alkyl are as previously described, wherein the alkyl 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 useful 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 WO 2010/062559 PCT/US2009/062071 32 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. A, When is phenyl, Formula I or 11 has the structure R 4 > N N\ R lzX /NI RR R5 or R 5 A A, When is heteroaryl, heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, pyrrolyl, thiazolyl, imidazolyl and furanyl. Examples of such groups are shown in the following partial structures:

R

1 R R2 R 2 R2K R 2

NN

WO 2010/062559 PCT/US2009/062071 33 N1S N> RN R R SR2

R

2 N1RR S N RN$ Ny R' 1 R RN NN R R R RN/ N% N0 0~ Nj~~ NjR~ N N N. N ~ R\ R of </ N N yN A One skilled in the art will recognize that when is a five membered ring containing two heteroatoms, there is only one substitutable carbon, hence R 2 is absent. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms, The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 decalinyl, norbornyl, adamantly and the like. "Cycloalkenyl" means partially saturated WO 2010/062559 PCT/US2009/062071 34 species such as, for example, cyclopentene, cyclohexene, indanyl, tetrahydronaphthyl and the like. As used herein, the term "bridged heterocycloalkyl" means a piperidinyl, piperazinyl, morpholinyl, 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§NH -Na NH -NQO -N O -N N O NQ -NjO -- N2O and As used herein, the term "fused ring heterocycloalkyl" means a 5 or six membered heterocycloalkyl ring joined to a cycloalkyl or heterocycloalkyl ring through two adjacent shared carbon ring members. Non-limiting examples include (C H 2

)

3 6 -N NH -N 0--N N 1-3 1-3 1-3 1-3 Haloalkyl represents an alkyl group as defined substituted by one or more halo atoms. Examples wherein halo is fluoro are -CH 2 F, -CHF 2 , -CF 3 , -CH 2

CF

3 , -CF 2

CF

3 and the like. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables 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 WO 2010/062559 PCT/US2009/062071 35 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 et at, 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-crystals 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 (1) (or Formula 1l) 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 (1) 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, (C 1 -Cs)alkyl, (02-C2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1 (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N (alkoxycarbony[)aminomethyl having from 3 to 9 carbon atoms, 1-(N- WO 2010/062559 PCT/US2009/062071 36 (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4 crotonolactonyl, gamma-butyrolacton-4-y, di-N,N-(C iC 2 )alkylamino(C 2

-C

3 )alkyI (such as P-dimethylaminoethyl), carbamoyl-(C-C 2 )alkyl, N,N-di (C 1

-C

2 )alkylcarbamoyl-(C1 C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2

-C

3 )alky, and the like. Similarly, if a compound of Formula (1) 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-C)alkanoyloxymethyl, 1-((Cl

C

6 )alkanoyloxy)ethyl, 1-methyl-1-((CC)alkanoyloxy)ethyl, (C Ce)alkoxycarbonyloxymethyl, N-(C-C6)alkoxycarbonylaminomethyl, succinoyl, (C C 6 )alkanoyl, a-amino(Cj-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C-C 6 )akyl) 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 0. A co-crystal is a crystalline superstructure formed by combining an active pharmaceutical intermediate with an inert molecule that produces crystallinity to the combined form, Co-crystals 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).

WO 2010/062559 PCT/US2009/062071 37 "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective as PDE10 inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect. The compounds of Formula I or Il can form salts which are also within the scope of this invention. Reference to a compound of Formula I or 11 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 well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I or |1 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, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (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. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) q(j1 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 WO 2010/062559 PCT/US2009/062071 38 Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-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), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (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-crystals 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 contemplated 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 all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the [UPAC 1974 Recommendations. The use of the terms "salt, solvatee" "prodrug'" and the WO 2010/062559 PCT/US2009/062071 39 like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racernates or prodrugs of the inventive compounds. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of Formula 1. Isomers may also 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, 11c, 13, 14C, 1 5 N, 180, 170, 3 1P, 32 p. 35 S, C 8 FI 36C1 and 1231, respectively. Certain isotopically-labelled compounds of Formula (1) (e.g., those labeled with 3 H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (1) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like 11C or "F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 1231 can be useful for application in Single photon emission computed tomography (SPECT). 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. 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 halflife or reduced dosage requirements) and hence WO 2010/062559 PCT/US2009/062071 40 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. Isotopically labeled compounds of Formula (I), 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 isotopically labeled reagent for a non-isotopically labeled reagent. Polymorphic forms of the compounds of Formula I or II, 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 Il)" means that one to three different compounds of Formula I or 11 may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I or 11 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.

WO 2010/062559 PCT/US2009/062071 41 SCHEME I H 1. EtOH, NH 4 OH, CS 2 R1 N NHNH 2

NH

2 2. CICH 2

CO

2 H, Na 2

CO

3 GA Y A3. NH 2 NH,2 R2 0A NIIR2 2 1 OEt N OEt 3 H H KOH, EtOH, A R1 N N R 2 a o:I OH 4 H N 5 ci R1 N N Al / N R2 6 Fl RR2 An amino-substituted aryl 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-chloroacetoacetate 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 acid 4 is treated with POC under reflux, followed by cooling and adjusting the pH with 20% NaOH to give the chloro 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.

WO 2010/062559 PCT/US2009/062071 42 Compounds of Formula I can be prepared by methods similar to those described for compounds of Formula 1, 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-butoxycarbonyl: DCM dichloromethane; DMSO - dimethylsulfoxide; DIBAL - diisobutylaluminum hydride; DCE - dichloroethane; DMF - dimethylformamide; THF - tetrahydrofuran; SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride; DAST - (diethylamino)sulfur 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-1OA 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 11. Example I cH3 H H bCN N H~'0 ci CH3 1-5 WO 2010/062559 PCT/US2009/062071 43 Step 1: cH 3 1. EtOH, NH40H, CS 2 CH3 H

NH

2 2. CICH 2

CO

2 H, Na 2

CO

3 2NNHNH2

CH

3

H

3 C s 1-2

CS

2 (4.5 mL) was added to a mixture of 4-methoxy-2-methylaniline (9.0 g), absolute EtOH (25 mL) and NH 4 0H (6 mL). After 1 hr, chloroacetic 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 0 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

C

2 with a slow ramp to 10%, then 50% MeOH over 60 min. The fractions containing compound 1-2 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: H o O CH3H H bNc'r NHNH2 'K OEt H3C N tEtOH 1-2 1-3 OUt 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, and dried in a vacuum oven at 50 OC. The filtrate was evaporated to about 10 mL, refrigerated overnight and filtered, The precipitates were combined to give compound 1-3 as a yellow solid (7.30 g). LCMS: M is 289. Found, M+1 is 290 at 3.88 min.

WO 2010/062559 PCT/US2009/062071 44 Step 3:

CH

3

CH

3 HfCO N KOH, EtOH, A H O &N OEt OH KOH (13.7 g) in water (80 mL) was slowly added to a mixture of compound 1-3 (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. Conc. HCI (-18 mL) was added until the pH was -3 to give a yellow solid. The solid was washed with water and dried in vacuum oven at 50 *C to give compound 1-4 as a fluffy tan solid (4.59 g) that was used in the next step without purification. Step 4:

CH

3

CH

3 CHH H CHs N POC13 H3, N N A NA N, Hf... 0:

H

3 c' 0 OH cl 1-4 1 A mixture of compound 1-4 (4.50 g) and POC 3 (5 mL) was purged with nitrogen and heated under reflux for 1 hr. The mixture was cooled to 70 C and concentrated in vacuo (bath at 70 SC). The mixture was cooled to 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 'C to give compound 1-5 as a brown solid (3.90 g) which was used in Example 3 without purification. The following compounds were prepared in a similar manner.

WO 2010/062559 PCT/US2009/062071 45 H N N H N MeN N N N N N N MeO CI F ci ci cl C1 N Nz N Example 2 Alternate Synthesis of Analogs of 1-2 H N C s NH 2

NH

2 N H2 >s ;01

NHNH

2

F

3 C RT F 3 C 2-.. 12-2 Hydrazine monohydrate (2 g) was added to a solution of isothiocyanate 2-1 (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 2-2 (10.54 g). LCMS: M is 235. Found: m/z 236 (MH t ). The following compounds were similarly prepared. OCF3 H OMe H H Nc, S N , ps H3C N c ,S

NHNH

2 NHNH2 NHNH2 Br MeO F H F H Et H i-Pr H C S'C' SN'U N~ 'S H3C XHNH2 F NHNH2 N HNH2 NHNH2 H CH 3 Br H BrH -Pr1NH 2

NHNH

2

NHNH

2 H NHNH 2

CI

WO 2010/062559 PCT/US2009/062071 46 Example 3 C H 3 N N

H

3 C' O N N H 3 H H_ _ 3

C

6

H

5

CF

3 dioxane microwave Compound 1-5 (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 'C for 2 hr. The reaction mixture was diluted with EtOAc, 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 plates (6, 1000 P) eluding with DCM:MeOH (9:1) to give the title compound 3 as a yellow 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: Ex. No. Structure MW LCMSR M + I N H N I N' N 3A HCO 296 297 242 N CHa WO 20 10/062559 PCT/US2009/062071 47

H

3 CO I071 3B IN CH3 297 298 13 _ _ _(C ) 132_ _ _ _ CH N N N I N C ~ N . OH 3 12 C H 3 N N OH ) HF N N N 3D H3OO 325 311 02796 N OH 3 i1.6(v

OH

3 N N ~N 303CO 32531 16 (uv) Pd OH -N 0.79 3F H3CO325 32 C N_ CH3 0.6 (u _______________N '*CH3___.~--~_______________________________ - - - .F WO 20 10/062559 PCT/US2009/062071 48 3HH 3 CO C 3 31$20,93, 3H 3~1131 N CH 3 3215 H H3CO 0.94, N CH, 8 82 F 14 N N IC H3 N NN 3L C 281 282 .3 N CH3 I CH H N * NH F I N N CH __ _ ~H N_ __ _ WO 20 10/062559 PCT/US2009/062071 49

CH

3 - _ _ _ _ _ _ _ N N N N 3N ci 1316 317 2.35 NL CH3 011 N N N 30 130 O 3 325 326 1.60 (uv) N CH3 N H 3P30 325 326 1.84(kuvj N H 3 KNIOI

OH

3 H N NF 3Q N 425 426 2.73 (uv) 0113 1~___ ~ ONH 013 H SR cl 329 330 F 1 96 (uv) __£ ___N t_ __ WO 2010/062559 PCT/US2009/062071 50

CH

3 H N N 38 O 3 329 330 1.94 (uv) N CH 3 N 'C H, H

CH

3 H N N N Cl 3T N H 3 343 344 1 185 (uv) N CH3

CH

3 H N N N cl~0.92, 3U cC 329 330 N CH3 195 N CH H

CH

3 H N N N H3CO 0.80 3V CHI 339 340 1 08 1.76 ND CH3 CH3 N N NN H3CO 3W 08 368 369 248 0 0 WO 20 10/062559 PCT/US2009/062071 51 I CH3N 3X H0' N296 297 2.48 N H Cl- 3 I EI

CH

3 SN N r Io 3 ____ ___OH

CH

3 ____ N N,*~

CH

3 o N r/ 38B H 3 00 1. N 3CC 8 3 C0 1 NHS CH34 41 22 _____ _____ ______ ______ ______ ____ __0__ WO 2010/062559 PCT/US2009/062071 52 Example 4

CH

3

H

3 C.O N' N cN H3I0

CC

3

CH

3 4 ,KI, NaH microwave A microwave vial charged with 1-5 (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 P) eluting 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: LCMS Ex. No. Structure MW M+ R CHM NN H N

H

3 CO 4A N CH 3 382 383 2,68 WO 20 10/062559 PCT/US2009/062071 53 Cl-ti , N N N

JM

3 CO ~ 3 N H NN

M

3 COI 4D OH 38 39 125 NN F 1 N N

IH

3 00 4D N CM 3 F 6 6 125 I N HN 4E O 3286 329 2402 _____ I _____ WO 2010/062559 PCT/US2009/062071 54

CH

3 H N N N 4G H 3 CO 326 327 202 N CH3 _____ ____OH __ ___ _ _

CH

3 H N N N 4H H 3 CO 326 327 2 36 N H CH3 (%N H O CH3 CH3 N N N 41 H 3 CO 340 341 2.38 CH CH3 Ca H N N N 43 H3CON Ca 4JO N CH 3 340 341 2.16 CH OH H N N N 4K H7C N7C 3 78

CF

3 WO 2010/062559 PCT/US2009/062071 55

CH

3 H N N N 4L H 3 Co 326 327 1.90 N CH3 CH3 N N 4M H3CO 378 379 2.85 N CH 3 CF *Compound 4C is a byproduct of the general 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 OC overnight: CHH 4N N H N

H

3 CO32 N H 3 F 40NH 31

OH

3 N H

H

3 00 N N NF 4NN 40NH-3 6 363 2.74

OH

3 3 The following compounds were prepared in a similar manner using dioxane as the solvent, without KI, and heating the reaction mixture at 160 *C overnight: WO 20 10/062559 PCT/US2009/062071 56 Exc. No. Structure MW LCS F

CH

3 HCM ___________~ GiNO _ _ _ _ _ _ _ _____ _ _ _ _ N N H N N H CO 4R NH CH 3 ~ 6 _ _ _ _ _ _ _ _ _ _ C H 3 _ _ I H N NN

H

3 CON 4R NH CH 3 3762 363 0266 N H N N ___NKJ CH 3 4S___ 376_____ 377____ 2.82_ ___________ ~______ ___ ____ WO 2010/062559 PCT/US2009/062071 57 CH3 N H N NN 4U H 3 CO 348 349 2.76 NH

CH

3 H3cO The following compound was prepared in a similar manner, using dioxane as the solvent without KI: Ex. No. Structure MW [L 1 R

CH

3 H NIN

H

3 CO 4V CH 325 326 2.47 c Example 5

CH

3 H N N, C~a, N CH3% 0 1A / NH CH 3 5 5

H

2 N neat S~ 125 'C A rmxture of compound 1-5 (41 mg) and 4-aminomethyltetrahydropyran (400 mg) was stirred at 125 OC 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 WO 2010/062559 PCT/US2009/062071 58 in ether and then evaporating to dryness. LCMS: M is 340. m/z 341 [M+H)*. Rt is 2.23 min. The following compounds were obtained in a similar manner: LOMS Ex. No. Structure 1 MW Rt

CM

3 N N N 5A F 300 301 f 32 N CH 3

CH

3 N N N 5B CH 3 296 297 2.28 N CH 3 C CH3 NH N N 5C HCO 324 325 1 2,71 NH CH 3

CH

3 NN 5D H 3 CO NN310 3126 SE H 3 CO 338 339 2.88 NH CH 3 _ _ _ _ WO 2010/062559 PCT/US2009/062071 59 CH3 N N *HN 5F H 3 CO 326 327 2.31 NH C H 3

CH

3 N N N 5G H 3 Co 354 355 2.43 NH CH3

CH

3 N_ 5H H 3 CO 326 327 2.21 NH CH3

CH

3 H N N N 51 H 3 CO 324 325 2.82 N CH C.H CHN CN N N N K N 5J H 3 CO 339 340 1.59 NH CH 3 Na

CH

3 N H HC N N 32 5K H 3 ON O 3 326 327 209

CHI

WO 2010/062559 PCT/US2009/062071 60

CH

3 H NN 5L H3CO 328 329 249 N C H 3 s

CH

3 H N 5M H0o N N 32[ 1 N CH 3

CH

3 p N N 5N H3Co 296 297 214 N CH3 H0 CHH N 50 H3CON N CH3 HO

CH

3 N N 50 H3o NH 340 341 2.1 NH CH HO CH3 HsC N 5Q N C3 33 340 1342.5

H

2

N

WO 20 10/062559 PCT/US2009/062071 61

OH

3 H N

N

4 H-CO N SRNH CH 3 341 342 1 181

CH

3

OH

3 O N r..H CH N H N N. N N H N%

H

3 00 N 5V ~NH33342 WO 2010/062559 PCT/US2009/062071 62

CH

3 H N N N N

H

3 CO 5W NH CH 3 333 334 204 N CH3 H N N N 5X H 3 CO 347 348 2.13 NH CH 3

OH

3 3 CH H N NN N 5Y H CO 347 348 1.86 N H CH3 Example 6 CH O H /N, N, H3CON N CH3 0 6 N HCNEt 3 , DMSO O 1254C A mixture of compound 1-S (50 mg), homomorpholine hydrochloride (200 mg), triethylamine (-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 HCI salt was prepared by adding -1 WO 2010/062559 PCT/US2009/062071 63 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: rnlz 327 (MH)*-. Rt is 2.4 min. The following compounds were prepared in a similar manner: Ex. No. Structure MW LCMSR

CH

3 i N t N GA F 314 315 2,47 (N CH 3 F NH 4 N NN 6B H 3 C 314 315 2.20 N C N 6C F H N N N GC F 6D 318 319 2.91 - N CH3 Pr N 6D 310 311 233 CH - +4 N N N AN 6E iPcH324 325 2.60 AN C3 WO 2010/062559 PCT/US2009/062071 64 CH H N N N 6F 330 331 2.33 Cl N CH3

CH

3 N N N 6G H 3 CO 346 347 2,74 N CH3 F F CH3 H N N N

H

3 CO 6H CH3353 354 2,00 0 NH2 CH3 H N N 61 H 3 CO 340 341 2.19 N CH 3 3

CH

3 aC H N N N 6J Br45350 351 2.55 N CH OCF 6BrI445 445,447 2,53 ( N H 3

,

WO 2010/062559 PCT/US2009/062071 65 N H N 6KA 326 327 2.08 ____ NCHZ 2.08_ ______ The following compound was prepared in a similar manner, using NMP as the solvent: Ex. No. Structure MW LCMS Br 1 H N 6L 361,363 j 2.43 N CH 3 The following compounds were prepared in a similar manner, using NMP as the solvent and (i-Pr) 2 NEt as the base: Ex. No. Structure MW R

CH

3 MI N H N3 NN 6M cl 330 331 2.52 CHCH ONH CH cHH N N N 6N c 330 331 2,31 N cH

LO

WO 2010/062559 PCT/US2009/062071 66 Br T H N H &N N 60 N, 60 ~N361 361,363 2 O NH CH Br N O N 6P H 3 C 375 375,377 2.77 N C H 3 Example 7

OCH

3 N H N

H

3 CO N CH 3 0 7 H N OMe N HCI N HN MeO K 2

CO

3 Cl

CH

3 phenol ZAA z:1 A mixture of compound 7-1 (92 mg), homomorpholine hydrochloride (74 mg),

K

2 00 3 (72 mg) and phenol (1 g) was heated at 120 'C for 4 h. The mixture was cooled to RT and 1 M NaOH (50 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting 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: WO 20 10/062559 PCT/US2009/062071 67 MW I M1---- Ex. No. STRUCTURE 1 LCM Rt, H N N

H

3 00 N 7A JNH O 3 355 356 1.84 Cit N N4 7B NH H 3 385 386 1.62 NH3 C H.N 7C310 311 2.05 ______OK NH OH 3 Oa11 - N N4 NN 7D HO 312 313 1.98

OH

3 N 7EH H 345 346 1.81 0 F ~HN' _ _ F_ WO 2010/062559 PCT/US2009/062071 68 tan 3 H N N NN N H 3 H j 7F NH OH 3 446 447 3 t 03u.,O N Example 8

CH

3 H N N HN) CH N

CH

3 8

CH

3

SO

2 CI pyridine CH2c6 A mixture of compound 2 (0.15 g) and DCM (10 mL) was treated with pyridine (50 L) and then CH 3

SO

2 CI (50 iL). After 24 hr, additional pyridine (25 pL) and

CH

3

SO

2 CI (25 jiL) were added. After 2 hr, the reaction mixture was concentrated and purified on silica gel plates (2, 1000 uL) 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 P) and eluted as above to give additional compound 8 as a yellow solid (0.028 g). LCMS: M is 389. Found M+1 is 390 at 0,79, 2.04 min. The fouowi pounds were obtained in a similar manner: Ex.No. Structure MW LCMS R i E x ._ N o . M + 1 WO 2010/062559 PCT/US2009/062071 69

CH

3 N N 'N H3CO 8A 1H0 403 404 2,09 (uv)

NHSO

2

CH

3 H N N N 8B cI 408 408, 410 2.45 (uv) N H N N N HcO N. 74403 404 2.25 ( N C 2.37 N L _ CH3 Example 9 CH3 H / N0 N H43C, N //N CH3

NH

2 9 A solution of 3Q (59 mg) in DCM (1 mL) was treated with trifluoroacetic 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

CO

3 solution. The organic layer was dried (K 2 CO3), concentrated in vacuo, and the residue was purified on silica gel plates (2, 1000 Lt) eluting with WO 2010/062559 PCT/US2009/062071 70 DCM:MeOH:NH 4 0H (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

CH

3

CH

3 O YNH2 H N N N

H

3 C.. 0 H * N H N CH 3 N CH 3 HN NH 2 HN NH2 Trimethylsilyl isocyanate (55 tL) was added to compound 9 (121 mg) in dry dioxane (15 mL) at 60 "C. The mixture was heated for 70 min. 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 j-t) eluting with DCM:MeOH (9:1) to give a yellow foam (92 mg). This foam was purified on a reverse phase HPLC column (10 p; 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 10 A as an orange solid (63 mg) and 10-B as a yellow solid (22 mg). LCMS for 10-A: 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: WO 2010/062559 PCT/US2009/062071 71 Ex. No. Structure MW LCMS R M+1

CH

3 H N N N ___ _________O NH 2 I

OH

3 H N N

OH

3 H N N ZN HCO 10E N CH 3 368 369 1.99 (uv) F CH N I~H NH

OH

3 NH _ _ _ _ _ N HCO N O''H 3 1C358 359 10uv) F N F O H335 F ~0 NH 2

____

WO 2010/062559 PCT/US2009/062071 72

CH

3 10G

N

9 H 1 372 373 2.03(uV)i

OH

3 H N N CII 10H N CH 3 372 373 2,00 (uV) NII CCHC3 H~ NNH N 10H (N) ~~H 3 32332,0(v N OH 3 C H 11 Step 1:

OH

3 N H " N NN C"3 HH00 H BOH 11::1 Compound 1-5 was treated with N-BoC-piperazine in a similar manner as described in Example 3 to give Compound 1.1_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.

WO 2010/062559 PCT/US2009/062071 73 Step_2:

CH

3

CH

3 Mel, K 2

CO

3 N N

CH

3 CN N 80 *C Hc% 0 N Boc 11:2 Under a nitrogen atmosphere, a solution 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 pL). After 1 hr, additional

CH

3 1 (100 mL) and CH3CN (1.5 mL) were added. After 2.5 hr., additional CH 3 1 (100 uL) was added. The mixture was heated at 60 *C for 18 h. The reaction mixture was purified on silica gel plates (4, 1000 t) eluting with DCM:MeOH 9:1 to give an amber oil (70 mg). This oil was purified on silica gel plates (2, 1000 p) 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 pL) was treated with trifluoroacetic acid (250 pL). 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 CO3, The organic layer was dried

(K

2

CO

3 ) and concentrated in vacuo. The residue was purified on a silica gel plate (1000 t) eluting with DCM:MeOH:NH 4 0H (90:10:1) to give compound 11 as a yellow solid (12 mg). LCMS: M is 325. Found: M+ I is 326 at 2+37 min (uv). The following compounds were prepared in a similar manner: WO 20 10/062559 PCT/US2009/062071 74 I 2 LOMS Ex. No., Structure MW M+1

CH

3

CM

3 F.N N 1ACM 3 338 F 339 3,48 NN

C

3

CH

8 5 5341 N~ N. N N lie H 3 CO 340 341 2.33 NM

CM

3 F 'P N C) NH

CM

3 12 48%MHBr HM3 M 100OCN N H . 0 o CM 3 :12- WO 2010/062559 PCT/US2009/062071 75 Compound 1-5 (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 solid which was used in the next step without purification. LCMS: M is 229. Found: M+1 is 230 at 1.96 min. Step 2:

CHCH

3 H Ac H H Ac 2 O N I N pTSA / N N j Ac, N HO 0 o CH 3 o CH3 12-1 1 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 *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: CHaH Ac CH 3 Ac H I N I N N, Oxalyl chloride N N Ac., N 1 l, N CH 2

CI

2 yA~ Ac Ac~ 0 CH 3 cl CH3 12!2 12-3 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+I is 332 at 4.41 min. Step 4:

H

3 C-N .NH PhCF 3 dioxane WO 2010/062559 PCT/US2009/062071 76 A microwave vial was charged with compound 12-3 (0.20 g), trifluoromethyltoluene (2 mL), dioxane (2 mL), and N-methylhomopiperazine (0.6 mL). The vial was purged with nitrogen, sealed, and heated at 165 'C in a microwave reactor. The reaction mixture was purified on silica gel plates (4, 1000 p) eluting with DCM:MeOH (9:1) to give a yellow solid (0.27 g). This residue was purified on silica gel plates (2, 1000 p) using DCM:MeOH:NH 4 0H (90:10:1) as the solvent to give a yellow solid. The chromatography was repeated using silica gel plates (4, 1000 p) to yield compound 12 (0.76 g) as a yellow solid. LCMS: M is 325. Found: M+1 is 326 at 0.91: 1.43 min. Example 13 cH 3 H N N Hc N CH3 N oc 1 3 Step 1: CH3 KcN,DMSO, N NH 1100C N 1-6 --A-__ N H3CO CN CH3 13-1 A solution of compound 1-5 (4.6 g) and KCN (12 g) in DMSO (120 mL) was stirred at 110 CC overnight. The reaction mixture was cooled, diluted with water and filtered. The precipitate was washed with water, ether and DCM to yield compound 13 1 (-3 g). LCMS: M is 252. Found: m/z 253 (MH). Step 2: CH3 DIBAL N N iI N toluene N

H

3 CO CHO CH3 c1o 02 WO 2010/062559 PCT/US2009/062071 77 DIBAL (42 mL, IM in hexane) was slowly added to a solution of compound 13-1 (3 g) in toluene (150 mL) at -78 *C. The mixture was warmed to RT and stirred overnight. The mixture was quenched at -78 4C 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 (12 g), which was used in the next step without purification. LCMS: M is 326, m/z 256 [M+H]*. Step 3: 0 NH NaBH{OAc) 3 cH 2 ci 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 0, 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*). Rt is 2.20 min. The following comounds were prepared in a similar manner: Ex. No. Structure MW LMS R C N K TM+fi-K HcO N 13A CH3 340 4 341 2,25 WO 20 10/062559 PCT/US2009/062071 78

CH

3 -__ ____ ___ __ _ N N NHH 13aB H3C/ 342 34322

CH

3 N_ NJ 13C H 3

OCH

3 354 355 22 13DH 3 C 9 9 2.58 N CCH3 N N 13D

CM

3 323325

H

3 O 4 31 0 _ _ _ _ _ j HH WO 2010/062559 PCT/US2009/062071 79

CH

3 N H N N N 13G H 3 CO 326 327 193 H3CH HON CH3 H N N N 13H H NCo 314 325 208

CH

3

CH

3 H N N N 131 H 3 CO 310 311 2 21 CH3 OCH3 H N, N N 13J H 3 Co 356 327 2.16 CH

CH

3 N N

OCOH

3 N 13K H3Co 326 327 2 19 CH3 CH3 H NN |N 13LH3Co 325 326 2,02 CH3 N

HN,,

WO 20 10/062559 PCT/US2009/062071 80 F -CH3 13N H 3 CO A N I340 341 1.9

CCH

3 rN HN HN Ni N N N

H

3 CO CNQ CH 339 1340 22

CH

3 2,1 N _ _ ~HNI _ -_____ ____ CH- 3 _ _ _

CH

3 N

ONH

3 36 5 0 WO 2010/062559 PCT/US2009/062071 81

OH

3 N H N N, N 13S H 3 CO 340 341 2.24

CH

3 CN CH3

CH

3 N N 13T

CCH

3 324 325 2.18 N ~13U FaC OH 3 364 365 2 38 (N I N 13V Br 459 49461 2.82 CCH Example 14 N H N N, HO N 'N4 A mixture of AIGis (1.029g) and DCE (30 mrL) was Cooled to O C2. EtSH (760 pL) was added dropwise. The resulting solution was stirred at 0 C2 for 10 min, then a mixture of 13S (351 mg) and DOE (30 mL) was added. The solution was warmed to RT and stirred 3 h, H 2 0 (150 nmL) and sat NaHCO 3 (150 miL) were added. The mixture WO 2010/062559 PCT/US2009/062071 82 was extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to give compound 1_4, which was used without further purification. Example 15 H N_ N, MeO, N N o 15 A mixture of 14 (32 mg), K 2

CO

3 (31 mg), 2-bromoethyl methyl ether (10 pL) and DMF (2 mL) was heated at 80 *C for 3 h. H 2 0 (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 15 as a yellow oil, LCMS: M is 384. Found: M+1 is 385, Rt = 2.07 min. Example 16 N H N N N MeO OH N 16 Step : HcI H POBr 3 H MeOH N N, DMF N% N. F Jim- 1 N N A MeO A MeO OH Br 16 -- iu2 WO 2010/062559 PCT/US2009/062071 83 A mixture of 1-5 (5.45 g), IM HCI (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. H20 (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 cool to RT and sat. NaHCO 3 (50 mL) was added slowly.

H

2 0 (200 mL) was added and the mixture was filtered. The filtrate was dried at 50 OC in a vacuum oven, affording 3.98 g of compound 16-2 as a brown solid, which was used without further purification. Step 2: NaH, SEM-CN SEM 1) n-BuLi, THF SEM THFN N, -78 * N, N, j-2 1 -0-N / N MeO CHO MeO Br 2 OH N N / -78 'C to rt 16-4 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 min. 4-Pyridinecarboxaldehyde (220 pL) 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 0 (20 mL) was added. The mixture was extracted with EtOAc (2 x 30mL). The combined organic extracts were WO 2010/062559 PCT/US2009/062071 84 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 0 (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 0 (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, Rt = 1.95 min. Example 17 N, H N N MeO 0 N 17 SEM IBX HCI, H2O DMSO N MeOH 16A 01W MeO 0- 17eO A N / 17. 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 0 (3 x 10 mL). The organic phase was dried (MgSO 4 ) and concentrated in vacua to give 17-1. The residue was used without further purification. A mixture of 17-1, HCI (250 pL), H 2 0 (500 pL), and EtOH (500 pL) 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 0 (10 mL) were added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic WO 2010/062559 PCT/US2009/062071 85 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 (MgSO4) and concentrated in vacuo to give 5 mg of compound 7 as a yellow solid. LCMS: M is 332. Found: M+1 is 333, Rt = 3.57 min. Example 18 H N N I 1 N MeO F N18 SEM DAST N, N HCi, H 2 0 CH2c/N MeOH ON- MeO -L 18 A F N/ DAST (5 drops) was added via syringe to a solution of 16-4 (12 mg) in CH2Cl2 (2 mL). The resulting solution was stirred at RT for 5 min, then sat. NaHCO 3 (2 mL) and

H

2 0 (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 pL), H 2 0 (500 pL), and EtOH (500 pL) was stirred at RT for 2 h, then at 75 'C for 30 min. Sat NaHCO 3 (2 mL) and H20 (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, eluting with 0,1% HCOOH in CH3CN / 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 18 as a yellow oil. LCMS: M is 336. Found: M+1 is 337, R, = 2.68 min.

WO 2010/062559 PCT/US2009/062071 86 The following compounds were prepared in a similar manner: Ex. No. I Structure MWT-7LCM-4S V I H N N N 18A Meo 365 366 4,92 lN F H N N N 18B Meo 336 337 I 3.71 I%;Z F N I N NH H N N MeO 18C 363 364 4.90 F H N N N MeO 18D 395 396 4.54 MoO F OMe ____ Example 19 H N NN

H

3 CON N

H

2 N 0 19 A mixture of compound 13-1 (7 mg) in conc. H 2

SO

4 (-400 [L) was heated at 60 "C for 3 days. The mixture was cooled and added to ice water. The resulting solution WO 2010/062559 PCT/US2009/062071 87 was neutralized with 15% NaOH solution and filtered. The precipitate was washed with DCM and then recrystalized from MeOH to afford compound 19 (1 mg). Example 20

CH

3 H NN N,

CH

3 N N N NH OH Step 1: cH 3 CH3 H + H 2 N NfCu powderC C0 2 H I'-. 1?Z1* i NI. H203, reflux Co 2 H A mixture of 1-iodo-3-methylbenzoic acid, 20-1, (5 g), 1-benzyl-3-methyl-1H pyrazol-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 CC to give 20-3 (3.05 g). LCMS: M is 321. Found: MH 4 is 322. The solid was used without further purification, The following compound was prepared in a similar manner. HfrO MeO N N, N MeO Co 2

H

WO 2010/062559 PCT/US2009/062071 88 SteR 2:

CH

3 POCIs N_ N, / N 100*c cl 20-4 A mixture of 20-3 (3.05 g) and POCi 3 (5 mL) in a 50 ml round bottom flask was purged with nitrogen and heated at 100 OC for 2 h. The mixture was concentrated in vacuo at 70 'C . Ice was added to the mixture and the pH was adjusted to -8 with 20% NaOH. The mixture was extracted with CH 2

C

2 , dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on Si0 2 , eluting with a gradient of 0 to 10% EtOAc in hexanes to afford 184 mg of 204. LCMS: MW is 321. Found: MH* is 322. The following compound was prepared in a similar manner. MeO N N N MoO C I Step 3:

CH

3 150 0 C ..... /. N , N, 20::4 NH 2 N N H overnight O A mixture of compound 20-4 (184 mg) and 4 -aminotetrahydropyran (462 mg) was heated at 150 *C overnight. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with CH 2

CI

2 , dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on Si0 2 , eluting with a WO 2010/062559 PCT/US2009/062071 89 gradient of 0 to 3% MeOH in CH 2 Cl2 to afford 216 mg of 20-5. LCMS: M is 386. Found: MH* is 387. The following compound was prepared in a similar manner. Meo N N, MeO r y~ KJrNH LCMS: M is 432. 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 4C for 36 h. The mixture was filtered and concentrated in vacuo. Aqueous NaHCO3 solution was added to the residue. The resulting mixture was extracted with 10% MeOH in

CH

2

CI

2 , dried (MgSO4), 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: MeON MeG , QJNH LCMS: M is 342, Found: MH* is 343. Retention time: 2,03 min.

WO 2010/062559 PCT/US2009/062071 90 Example 21

CH

3

CH

3 OMe N HNN H N N, N I N C, N CI CI ZJZA tY L 2j-- Q Step 1: MeO MeO

CH

3 H

CH

3 CH 3 C N N- N N N N 0 N~ c , -N 4 ,N - IN 1 N cl Cl '0CI 4 C CI MeO MeO 1. n-BuLi, THF, -78 OC

CH

3 C 21-3 2. DMF, -78 *C to RT N N N N N N N C C1 CHO 21-4 Z:A Compound 21-3 was prepared using procedures similar to those described in earlier examples. n-BuLi (0.31 mL, 1.6 M in hexane) was added to a solution of 21-3 (199 mg) at 78 'C. The mixture was stirred at -78 OC for 1 hr. DMF (0.32 mL) was added. The mixture was slowly 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 2 , eluting with a WO 2010/062559 PCT/US2009/062071 91 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:

CH

3 H 1. Et 3 N, NaBH(OAc) 3 , N N

CH

2

CI

2 , RT N 2. TFA, reflux NI 21-4 - ci CN A mixture of 214 (500 mg), 2-methylmorpholine (266 mg), Et 3 N (0.74 mL) and NaBH(OAc) 3 in CH 2 Cl 2 (30 mL) was stirred at RT overnight. The reaction was quenched with 1 N NaOH, extracted with EtOAc, dried (MgSO 4 ) and concentrated in vacua. The residue was treated with TFA (13 mL) and the resulting mixture was heated at 73 'C for 40 h. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO 3 , extracted with CH 2

C

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

C

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: Ex. No STRUCTURE MW LC/MS R I ~~CH 3 j .. H I N NN 21 D ci 344 345 2.53 C 34 N

CH

WO 2010/062559 PCT/US2009/062071 92 CH3 0 N H N-' N N ci 21E CH3 421 422 2,77 N JCH -H3 HN CH - - H N N 21F cl 314 315 235

CH

3 Example 22

CH

3 H N, N N CI OH 22 Cyclopropyl magnesium bromide (1 mL, 0.5 M in THF) was added to a suspension of 21-4 (93 mg) in THF at -40 OC and stirred for 1 hr. The mixture was warmed to RT, treated with saturated aqueous NaHCO 3 solution, extracted with EtOAc, dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography on SiQ 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 'C overnight. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO 3 , extracted with CH 2

C

2 , dried (MgSO4) 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.

WO 2010/062559 PCT/US2009/062071 93 Example 23

CH

3 H N N / N CI NH

K.-NCH

3 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 0C for 3.5 hr. The mixture was cooled to RT, and treated with H 2 0 (0.02 mL), 10% NaOH (0.03 mL), and H 2 0 (0.02 mL). The resulting mixture was diluted with

CH

2

C

2 , stirred for 90 min, filtered and concentrated. The residue was purified by column chromatography on SiO 2 , eluting with a gradient of 0 % to 10% MeOH in CH 2 Cl 2 to afford 9.5 mg of 23. LCMS: MW is 359. Found: MH' is 360. Retention time: 1.97 min. Example 24

CH

3 Boc N~N ./N N MeO OH 0 24 cH3 Boc TEA N N 1. n-BuLi/THF BoczO N . / 2. _ DMA P Meo THF Br 00 H 24-1 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 Na 2

CO

3 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 WO 2010/062559 PCT/US2009/062071 94 chromatography on SiO 2 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 n-BuLi (0F51 mL, 1.6 M ), and tetrahydro-2H-pyran-4-carbaldehyde (93 mg) in THF (8 mL). LCMS: MW is 441. Found: MH*: 442. Retention time: 4.65 min. Example 25

CH

3 H N N, 1P N MeO OH 0 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

C

2 and aqueous NaHCO 3 . 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, retention time: 2.92 min. Example 26 H N' N N.0 OH HN 26 WO 2010/062559 PCT/US2009/062071 95 Step 1: N H N H N N n-Bull, THF I N N O If 0 CHO Br OH N 26-1 .oN 16-2 BocN Boc i~ n-BuLi in hexane (1 mL, 1.6 M) was added to a solution of 16-2 (50 mg) in anhydrous THF at -78 *C dropwise. After stirring for 1 h, a solution of 26-1 (175 mg) in THF was added to the mixture slowly. The solution was stirred at -78 *C for at least 1 h, slowly warmed to RT and stirred overnight. The reaction was cooled to -78 "C and quenched with H20. The solution was warmed to RT, extracted with EtOAc, dried (Na 2 SO4), and concentrated. The residue was purified by silica gel chromatography eluting 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

C

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 CH2Cl2 to afford 26 (7,5 mg). LCMS: M is 340. Found: M+1 is 341, retention time: 2.12 min. Example 27 H N N IN 0 S%: OH F 27 WO 2010/062559 PCT/US2009/062071 96 N N n-BuL, THF N rN O p-F-PhCHO Br iun n-BuLi in hexane (2 mL, 1.6 M) was added to a mixture of 16-2 (200 mg) in anhydrous THIF at -78 *C dropwise. After stirring for -40 min, p-fluorobenzylaldehyde (200 mg) was added slowly. The mixture was stirred at -78 *C for -1 h, slowly warmed to RT (-1 hr) and stirred at RT for 1 hr. The reaction was cooled to -78 *C, quenched with H20, 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 eluting 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: Ex. No. Structure MW IES-MS R _CH, H N N N 27A HHcO N33 3 4 3.28

CH

3 I OH 2B H co 363 364 3 24 cH 3 OH N N cH 3 N cOH _ _ r N f t

_-

WO 2010/062559 PCT/US2009/062071 97

CH

3 H N N N 27D H3CO 335 336 2.71

H

3 COI N OH

CH

3 H N N N 27E H 3 CO 347 348 CH7 354 OH

CH

3

CH

3 H N N N H3CO 27F H 3 CH 3 361 362 3.95 OH CH CH3 CH H---t------ N N N

H

3 CO 27G HCO CH 3 393 394 3.33 OH OCH

CH

3 H N N N 27H H 3 CO 375 376 410

CH

3

OH

WO 2010/062559 PCT/US2009/062071 98

CH

3 N N 271 H3C H 27CCC H 401 402 447 OH j ci Example 28 NN I N MeO N 0 28 A mixture of 27A (12.7 mg) and Dess-Martin periodinane (19.4 mg) in CH 2

C

2 was stirred at RT for 2 h. The mixture was treated with saturated aqueous NaHCO 3 . 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: H N MeO IM0 MeO WO 2010/062559 PCT/US2009/062071 99 Example 29

CH

3

CH

3 N H N H N, N~ N N

H

3 CO H 3 CO CH3 CH N N 29 Step 1: CH3 H PdC 2 (PPhz) 2 , Cul, N N N_ N dilsopropylamine, N / I toluene H 3 CO N 1 N H C O 0 CH3 Br N 16-2 INA A mixture of 16-2 (100 mg), 2-ethynylpyridine (41 mg), PdC 2 (PPh 3

)

2 (19.4 mg), Cul (5.3 mg), diisopropylamine (1.5 mL) in toluene (-3 mL) was degassed and charged with N 2 . The mixture was heated at -90 *C overnight. The resulting mixture was cooled and filtered, The precipitate was washed with CH 2

C

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 0, 0.01% HCOOH, 10% to 100% gradient) to yield 29B (9 mg). LCMS: M is 332. Found: M+1 is 33$, retention time: 2.25 min. The following compounds were prepared in a similar manner: Ex. No. Structure MW ES-MS Rt WO 20 10/062559 PCT/US2009/062071 100

CH

3 ~H

N

1 29 3 0CH 3 1 327 328 5.20 CH3 ~ - __ TC3 331 332 3.82

CM

3 -H N , 29E H 3

OCM

3 328 329 3.84 N CH3) 29F H 3 CO N NHN 32 33 22 N N N

K

3 CO 29G CH 3 357 3550 35 50 --- - __ -- --- - _ __ %S 13 WO 2010/062559 PCT/US2009/062071 101

OH

3 N H N 29H C 361 362 3.75 N H3CO 29H C 357 358 5.25

IC

CH3 N H 29J C'13 361 362 3.80 OCH F - C H3 N H N

H

3 CO 29K CH3 346 347 219 NH _ ~~~NH2 - _ ~** WO 2010/062559 PCT/US2009/062071 102 Example 30 N N N 0 HN 0 N N 30 To a mixture of 16-2 (500 mg) in anhydrous THF (10 mL) in a microwave vial was sequentially added 4-(aminomethyl)pyridine (540 mg), DBU (760 mg), Herrmann's catalyst (40 mg), t-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 '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 0 2 MeOH, and followed by HPLC (CH 3

CN-H

2 0, 0.1% HCO 2 H) to yield 30 (206 mg). LCMS: M is 361. Found: M+1 is 362, retention time: 2.14 min. The following compound was prepared in a similar manner: Ex. No. Structure MW ES-MS Rt H NN N 30A 354 355 2.94 HN 0 Example 31 N N IN 0 0 31 WO 2010/062559 PCT/US2009/062071 103 To a solution of 4-hydroxy-tetrahydropyran (-5 mL) in N-methyl-2-pyrrolidinone (-5 mL) was added NaH (764 mg of 60% in oil) at 0 0 C. After stirring for 0.5 h, compound 1-5 (500 mg) was added to the reaction mixture. The mixture was heated at 110 "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 31. (-76 mg). LCMS: M is 327. Found: m/z 328 (MH), retention time: 2.79 min. Example 32 H H N H *N H NN,N, , N IN 0 0 N N Step 1: To a solution of KI (60 mg) in N-methyl-2-pyrrolidinone (-1 mL) in a microwave vial was added NaH (60 mg of 60% in oil) and then compound 1-5 (100 mg). The mixture was sealed, purged with N 2 , and placed in a microwave reactor, The mixture was heated at 150 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 0C was added DIBAL (323 uL, 1 M in hexane). The mixture was warmed to RT and stirred for 2 h. The mixture was cooled -78 C, treated with MeOH (140 uL), sat. NH 4 CI (200 uL). The mixture was warmed to RT and partitioned between 1 N NaOH and EtOAc. The organic iayer 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: mlz 309 (MH*), retention time: 2.22 min.

WO 2010/062559 PCT/US2009/062071 104 Example 33 N N /N MeO N 33 A mixture of 16-2 (133 mg), 4-pyridineboronic acid (80 mg), Pd(PPh 3

)

4 (96 mg), Na 2

CO

3 (40 mg), toluene (8 mL), EtOH (2 mL), and H 2 0 (2 mL) was heated in a microwave reactor at 120 "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 (MgSQ 4 ) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0 to 70% EtOAc in hexanes. The resultant residue was further purified by reverse phase HPLC, equipped with a silica gel column 6 pm; 25 x 100 mm 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 37 mg of 33 as a yellow solid. LCMS: M is 304. Found: M+1 is 305, Rt = 2.46 min. Example 34 N H N N NH MeO MN NI ANMeO N N aAN 34B Preparation of 34A: A mixture of 16-2 (124 mg), 4-vinylpyridine (110 pL), 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 "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 0 (2 x 20 WO 2010/062559 PCT/US2009/062071 105 mL). 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, Rt = 2.43 min. Preparation of 34B: Compound 162 (315 mg) was subjected to the Heck conditions as described above. Following flash column chromatography, the residue was dissolved in EtOH (8 mL) 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, 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 11 mg of 34B as a yellow oil. LCMS: M is 332. Found: M+1 is 333, Rt = 2.17 min. Example 35 NH N N, MeO NH 35 Step 1: Br 1) n-BuLi, THF 78 "c B(O H)2 2) B(OMe) 3 -78 *C Nd TIPS 3) MeOH N -78 0

TIPS

WO 2010/062559 PCT/US2009/062071 106 A solution of 35-1 (TIPS is triisopropylsilyl) (1.35 g) in THF (25 mL) was cooled to -78 *C. n-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 pL) was added. The mixture was stirred at -78 0C for 1 h, whereupon a 1:1 solution of MeOH and H 2 0 (4 mL) was added. The mixture was warmed to RT and H 2 0 (20 mL) was added. The mixture was extracted with Et 2 O (3 x 40 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to obtain 35-2. Step 2: N* H 16-N2 N, /N 2§--2 Pd(PPh4) 3 , Na 2 cO 3 MeO PhCH 3 , EtOH, H 2 0, A microwave Q-3 NTIPS A mixture of 16-2 (300 mg), the crude 35-2, Pd(PPh 3

)

4 (96 mg), Na 2

CO

3 (40 mg), toluene (8 mL), EtOH (2 mL), and H 2 0 (2 mL) was heated in a microwave reactor at 120 *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 (IM solution in THF, 450 pL, 0.45 mmol) was added. The mixture was stirred at RT for 30 min. H 2 0 (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 gel chromatography, eluting with a gradient of 0 to 35% EtOAc in hexanes. The residue was purified by reverse phase HPLC, eluting with 0.1% HCOOH in CH 3 CN 10.1% 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 WO 2010/062559 PCT/US2009/062071 107 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, Rt = 2.89 min. Example 36 N N4 N _s F3cO N ..

N 36 NN N N* N LDA,NaH,THF ' + N FaCO N78 -+-) rt

F

3 00 N Br To a cold (0 0C), stirred solution of diisopropyl amine (135 mg) in anhydrous THIF (5 mL) was added n-BuLi (0.81 mL of 1.6 M solution in hexane) dropwise via syringe. After being stirred at 0 0C for 20 min, the solution was cooled to -78 *C and 4 methylpyrimidine (118 mg) was added dropwise via syringe. The resulting solution was stirred at -78 0C for 1 h. In a separate flask, 36-1 (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 *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 0 (20 mL). The resulting layer was extracted with CH 2

C

2 (3 x 20 mL). The combined organic layer 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

C

2 :MeOH 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: WO 20 10/062559 PCT/US2009/062071 108 Structure Ex. No. I mw LCMS R _____ ___ _ ____ ____ ____ M+1 _ _ NN 36A rco 32 $7 2.5 N N N~ N N NI 3B F 3 CO 40847 2.786 N N N ,N 36D 40238 8727 IN' NN N ____ ~e _N WO 20 10/062559 PCT/US2009/062071 109 N N

F

3 CO 36F 1 458 459 i4.15 NN N NI N

F

3 CO 36G 1442 443 I3.11 N. N- N 3flt~lF 3 C0 361441 442 2.90 N I ~ N N-N N 1 N N 36H Ff0o 40340 F K_______ -~N OMe _ ___- WO 2010/062559 PCT/US2009/062071 110 N H 1N N 361 417 418 4.42 N N OEt H _N N N, N N N 36J F3cO 373 374 415 H N N 36K F 3 CO 373 374 372 N L _ _ _ _ _ _ N ' 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. Gennaro (ed.), The Science WO 2010/062559 PCT/US2009/062071 111 and Practice of Pharmacy, 2 0th Edition, (2000), Lippincott Williams & Wilkins, 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 WO 2010/062559 PCT/US2009/062071 112 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 11 can be determined by the following procedures. In Vitro PDE10 assay PDE1OA1 activity was measured in white opaque 384-well Opti-Plates (Perkin Elmer Life Sciences) using a scintillation proximity assay (GE Healthcare). Human recombinant PDE10AI was purchased from BPS Bioscience, Inc. The reaction mixture contained PDE10A1 (0.02 nM), 10 nM [3H]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, 8.3 mM MgC 2 , 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 pI. 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 pg 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 hydrolyzed 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, 3V, 3BB, 4, 4A, 4B, 4F, 4H, 41, 4K, 4L, 5, 5F, 5G, 5K, SM, 50, 50, 5R, 5S, 6H, 7A, 7B, 7E, 8, 8A, 8B, 8C, 9, 1OA, 10C, 10D, 10E, 1OF, 1OG, 10H, 13, 13-1, 13A, 13B, 13C, 13D, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 13Q, 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21B, 21D, 21F, 22, 23, 24, 26, 27, 27A, 27B, 27C, 28, 29A, 29B, 29D, 29E, 29F, 32B. 33, 34A, 34B, 35, 36C, 36E, 36F and 36G2. Compounds of Formula I having a Ki of less than 100 nM are Examples 3E, 3F, 3S, 3V, 4, 4B, 4F, 4H, 41, 4K, 5, 5F, 5K, 5M, 50, 5Q, 5R, 5S, 6H, 7E, 8B, 8C, 9, 10A, 10C, 10D, 10E, 1OF, lOG, 10H, 13, 13A, 13C, WO 2010/062559 PCT/US2009/062071 113 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 13Q, 13R, 13S, 13V, 14,15, 16,17, 18, 21B, 21D, 21F, 22, 26, 27, 27A, 276, 27C, 296, 29F, 328, 34B, 35, 36C, 36E, 36F and 36G2. Using the test procedures described above, the following compounds of Formula 11 were found to have Ki values of less than 500 nM: Examples 3, 3D, 3G, 31, 3M, 3N, 30, 3R, 3T, 3W, 3Y, 3AA, 3CC, 4C, 40, 4P, 4Q, 4R, 4S, 4U, 4V, 5A, 5C, 5D, 5E, 5H, 5J, 5L, 5P, 5T, 5V, 5W, 5X, 5Y, 6, 6A, 6D, 61, 6K, 6L, 6M, 6N, 60, 6P, 7, 7D, 12, 13U, 20A, 20C, 21C, and 21E. Compounds of Formula 11 having a Ki of less than 100 nM are those in Examples 3, 3D, 3G, 31, 30, 3R, 3T, 3W, 3Y, 3AA, 3CC, 4C, 40, 4P, 4Q, 4R, 4S, 4V, 5H, 5P, ST, 5V, 5W, 5Y, 6, 6A, 61, 6K, 6L, 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. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims (19)

1. A compound of Formula I: EUN N/R4 RR2 > R3 RU Formula I or a pharmaceutically acceptable salt thereof, wherein Q1 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 0, provided that when it is a 5 membered heteroaryl containing two heteroatoms, R 2 is absent; R 1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO 2 H, -C(0)N(RA) 2 , -N(R 6 B) 2 , -alkylN(R 6 B) 2 , -NR 6 -C(O)N(RsA) 2 , -N(R6)C(O)Oalkyl, -N(R6)S0 2 -alkyl, phenyl, CN, -N -N 0 -S0 2 R', -SR 6 , trimethylsilyl-, -SF 5 , -OSF5, -C(=NOR 6 )-R 6 , hr r, or -(CH 2 )n-X-(CH 2 )m-R 8 , wherein X is -0- -S-, or -NR 6 -, n is 0, 1 or 2, m is 1, 2 or 3, and R 18 is selected from the group consisting of R s N S /N N N N Nm N] N NN N N - - N \N s NC N ,z and N'. WO 2010/062559 PCT/US2009/062071 115 R2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C0 2 H, -C(O)N(R6A) 2 , -N(R 6 B) 2 , -alkylN(R6B) 2 , -NR6-C(O)N(RA) 2 , -N(R6)C(O)Oalkyl, -N(R 6 )SO 2 -alkyl, phenyl or CN; or R' and R2 on adjacent ring carbon atoms together form -O-CH 2 -O- or -O-(CH 2 ) 2 -0-; R 3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R 6 B) 2 , -OCF 3 , -CF 3 , -SF 5 , -OSF 5 or -CN; R 4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, S0 2 -alkyl, -C(O)N(RA) 2 or -C(0)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy; R 5 is alkyl, -CN, -C(O)OR6A, -C(O)N(R6A) 2 , aryl-((R 17 a, R'%7)-alkylene)-, heteroaryl-((R1 7 ,, R 7 by)-alkylene)-, heterocycloalkyl-((R1 7 a, R' 7 b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalky, -alkyl-O-aryl, -alkyl-O-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-0-heterocycloalkyl, -alkyl-N(R)-aryl, -alkyl-N(R)-heteroaryl, -alkyl-N(R 6 )-cycloalkyl, -alkyl-N(R 6 )-heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocycloalkyl-heteroaryl-alkylene-, cycloalkyl, 0 -(CH 2 )b-NR6 0 (CH 2 )bNR 6 NR 14 -N NH 0 R12 R3 R--NR6-(CH2)b,- -N o -N NR1 3 -N r) r NR1 -- NR6(CH2)b -NR6-(CH2)b NR 14 -NR 6 -(CH2)b 0 WO 2010/062559 PCT/US2009/062071 116 1-4 1-Q-R0 t or N b is 1, 2 or 3; r is 1 or 2; t is 0, 1 or 2; each Re is independently selected from H and alkyl; each R 6 A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two RA groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two ReA groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring; each R 68 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-, -SO 2 alkyl, -S0 2 -aryl, -S0 2 -heteroaryl, -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -C(0)0-heteroaryl, -C(O)N(R6) 2 , -C(O)NR 6 -aryl, and -C(O)NR 6 -heteroaryl; or two RB groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring; R 9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0; R" 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 single carbon ring member with -(CH 2 )2-C- or -O-(CH 2 ) 2 -0-; R2 is 1 or 2 substituents independently selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl; R 13 is hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalkyl, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-alkylaryl, -C(O)O-aryl WO 2010/062559 PCT/US2009/062071 117 -C(0)0-alkylaryl, heteroaryl, heteroarylalky-, -C(O)-heteroaryl, -C(O)N(RA) 2 , -C(O)-alkyl-NR 6 -C(O)-aryl, -C(O)-alkyl-NR 6 -C(O)O-aky, -C(O)-alkyl-NR 6 -C(O)O benzyl, -SO 2 alkyl, -S0 2 -aryl, -S0 2 -alkylaryl, -S0 2 -heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with halo; R 14 is H, alkyl, hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalkyl-, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-alkylaryl, -C(0)0-aryl, -C(0)0-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(RA) 2 , -C(O)-alky-NR 6 -C(O)-aryl, -C(O)-aikyl-NR 6 -C(O)O alkyl, -C(O)-alkyl-NR 6 -C(O)O-benzyl, -SO 2 alkyl, -S0 2 -aryl, -S0 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, hydroxyalkyl, halo, -CF 3 , -C(O)Oalkyl, -C(O)N(R 6 A) 2 , aminoalkyl-, -N(R 6 B)2, -NR 6 -C(O)N(RA) 2 , -NR 6 -C(O)-alkyl, -NR6-C(O)Oalkyl, -NR-S0 2 -alkyl, -alkyl-imidazolyl, wherein the imidazolyl is optionally substituted with alkyl, and phenyl, or two hydrogen atoms on a carbon ring member are replaced by -(CH 2 ) 2 -6- or -0 (CH2)2O-; and R 17 a is H or alkyl and R1 7 b is H, alkyl, OH, F, -N(R6B) 2 , -NOR 6 , alkoxy, CN, -CH 2 OH, -CH 2 -0-alkyl, -CON(R 6 a%), -CH 2 N(R%) 2 or -C0 2 R; or R 17 ' and R1 7 b are each F; or R 17 a and R 1b are on the same carbon atom and together are =0, =NOR 6 or -(CH 2 ) 2 - 6 ; provided that when R5 is heterocycloalkyl-((Ra, R1 7 b)-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the Rl7b substituent on the a-carbon is H, alkyl, CN, -CH 2 OH, -CH 2 -0-alkyl, -CON(Rea) 2 , -CH 2 N(R ) 2 or -C02R3. Ae

2. The compound of claim 1 wherein 5 forms a phenyl ring. WO 2010/062559 PCT/US2009/062071 118

3. The compound of claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo.

4. The compound of claim 1 wherein: R 1 is alkyl, and R 2 is alkoxy; or R' is alkyl and R 2 is -OCF 3 ; or R is alkyl and R 2 is H, OH, halo or alkoxyalkoxy ; or R is alkoxy and R 2 is alkoxy or H; or R' is alkoxyalkoxy and R 2 is H: or R' is halo and R2 is H; or R' is halo and R 2 is -OCF 3 ; or R1 and R 2 together are methylenedioxy.

5. The compound of claim 1 wherein R 3 is alkyl or H, and R 4 is H, -C(0)0-akyl, or -SO 2 alkyl.

6. The compound of claim 1 wherein R 5 is selected from the group consisting of -CN, -C(O)N(RsA) 2 , aryl-((R 1 7a, R 7 b)-alkylene)-, heteroaryl-((R 7 a, Rl)-alkylene)-, heterocycloalkyl-((R" 7a, R 17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl-, heteroaryl, Ri" R12 R9 -7<N N NNR 3 -NR -(CH 2 )b-NR 6 O N NH -- N - r 0 NR 6 (CH 2 )b - N -NR 6 -(CH,)b -NR 6 -(CH 2 )b NR 4 R Cand -N R 6 (OH 2 )bO WO 2010/062559 PCT/US2009/062071 119

7. The compound of claim 1 wherein R 5 is -CN; -C(O)NH-alkyl-pyridyl; -CH(OH)-phenyl; -alkylene-phenyl; -alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl; / NR -CH(OH)-pyridyl; -CH=CH-(CH 2 ) 3 -OH; -CH=CH-pyridyl; -C-C-pyridyl; CH 3 / R N CHb'--NR 6 0 _N NH -N NH CH 2 OH CH 3 CH3 -N 0 -N 0 N 0 CH 3 ; 0 -NR 6 (CH 2 )b R 4 wherein R 14 is H, alkyl or hydroxyalkyl; -NR6(CH2)b -N R- (CH2)b- NRI4 wherein R 14 is H or alkyl; -NR 6 -(CH2)b heterocycloalkyl-((R' 7 a, R 7 b)-alkylene)- selected from the group consisting of -cCNH -c 0C H and H heterocycloalkyl-((R 7 a, R 7 b )-alkylene)-, wherein R 17 ' and R1 7 b are independently H or alkyl, selected from the group consisting of (CH2)b-N NR(H2)bN R 9 -(C H2 b -R and ~NR , w herein b is 1, 2 or 3; r is 1 or 2; R is H, alkyl or -S0 2 -alkyl; R 8 is I or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, halo, WO 2010/062559 PCT/US2009/062071 120 and -CF 3 ; R 9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0; and R'( is H, alkyl or hydroxyalkyl; -N NR 13 , wherein r is 1, R 9 is H or alkyl, and R 13 is -SO 2 alkyl, -CONH 2 , -C(O)heteroaryl or -C(O)cycloalkyl; -N NR' 3 r , wherein r is 2, R 9 is H and R 13 is -SO 2 alkyl or -CONH 2 : N -- R15 r wherein r is 2, and R 15 is alkyl, allkoxy, -CF 3 , OH, hydroxyalkyl, halo, NH 2 , -C(O)NH 2 , -CH 2 NH 2 , -C(0)0-alkyl, -NHSO 2 alkyl or -NHC(O)NH 2 ; -N R1 r wherein r is 2, and R 15 is hydroxyalkyl; or N R5 r wherein r is 1, and R 15 is OH or hydroxyalkyl.

8. The compound of claim 1 selected from the group consisting of Examples 3E, 3F, 3S, 3V, 313, 4, 4A, 4B, 4F, 4H, 41, 4K, 4L, 5, 5F, 5G, 5K, 50, 5Q, 5R, 5S, 6H, 7A, 7B, 7C, 7F, 8, 8A, 8B, 8C, 9, 10A, 10C, 1OD, 10E, 1OF, 1OG, 1OH, 13, 13-1, 13A, 138, 13C, 13D, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 13Q, 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21B, 21D, 21F, 22, 23, 24, 26, 27, 27A, 27B, 27C, 28, 29A, 298, 29D, 29E, 29F, 32B, 33, 34A, 34B, 35, 36C, 36E, 36F.

9. A pharmaceutical composition for treating phosphodiesterase 10 modulated disorders comprising an effective amount of at least one compound of claim 1 in a pharmaceutically acceptable carrier. WO 2010/062559 PCT/US2009/062071 121

10. A use of a compound of claim 1 for the manufacture of a medicament for treating phosphodiesterase 10 modulated disorders.

11. The use of claim 10 wherein the disorder is schizophrenia.

12. A use of a compound of formula Il for the manufacture of a medicament for treating phosphodiesterase 10 modulated disorders wherein said compound of Formula i1 has the formula: R4 R1 N Al /N RR2 R5A R3 Formula II or a pharmaceutically acceptable salt thereof, wherein C\ 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 0, provided that when it is a 5 membered heteroaryl containing two heteroatoms, R 2 is absent; R' is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -0-alkyl-C0 2 H, -C(O)N(RA) 2 , -N(R 6 6) 2 , -alkylN(R 6 B) 2 , -NR6-C(O)N(RA) 2 , -N(R 6 )C(0)Oalkyl, -N(R 6 )S0 2 -alky, phenyl, CN, - N 0 -SO2Rt, -SR 6 , trimethylsilyl, -SF 5 , -OSF 5 , -C(=NOR6)-R6 r , or -(CH 2 )n-X-(CH 2 )m-R' 5 wherein X is -0-, -S-, or -NR 6 -. n is 0, 1 or 2, m is 1, 2 or 3, and R'8 is selected from the group consisting of WO 2010/062559 PCT/US2009/062071 122 R 6 ,D S N ~ N N N NO N N N \NX NN NO Ny andNN A R 2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyakyl, -CF 3 , -OCF 3 , halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO 2 H, -C(O)N(R 6 A) 2 , -N(R 6 B) 2 , -alkylN(R 6 B)2, -NR 6 -C(O)N(R 6 A) 2 , -N(R 6 )C(O)Oalkyl, -N(R 6 )S0 2 -alkyl, phenyl or CN; or R and R 2 on adjacent ring carbon atoms together form -O-CH 2 -0- or -O-(CH2)rO0-; r is 1 or 2; R 3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R6B) 2 , -OCF 3 , -SF 5 , -OSF 5 or -CN; R 4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, S0 2 -alkyl, -C(O)N(R6A) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy; R 5 A is H, halo, OH, alkoxy, -O-alkyl-N(alkyl) 2 , -0-heterocycloalkyl, -O-alkyl-heterocycloalkyI, aryloxy-, arylalkoxy-, heteroaryloxy-, -N(RA) 2 , -NR 6 -alkyl-N(alkyl) 2 , -NR 6 -alkyl-0-alkyl-OH, -NR 6 -hydroxyaikyl, -S-alkyl, -S-hydroxyalkyl, -S-aryl, -S-alkylaryl, -S-heteroaryl, -S-alkyl-heteroaryl, -S-heterocycloalkenyl, -SC(O)-alkyl, -S0 2 -alkyl, -S-alkyl-C(O)OH, -S-alkyl-N(alky) 2 , -N N-alkyl -S-alkyl-NHC(O)H,-S-alkyl-C(O)NH-alkyl-pyrrolidinone, r -N o ~~N NRO each R 6 is independently H or alkyl; each R6A is independently selected from the group consisting of H, aky, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylaiky-; or two R6A groups are alkyl and WO 2010/062559 PCT/US2009/062071 123 together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R6A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring; and each R 6 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-, -SO 2 alkyl, -S0 2 -aryl, -S0 2 -heteroaryl, -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(0)0-alkyl, -C(0)0-aryl, -C(0)0-heteroaryl, -C(O)N(R 6 ) 2 , -C(O)NR 6 -aryl, and -C(O)NR 6 -heteroaryl; or two R 8 groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 68 groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyl ring.

13. The use of claim 12 wherein forms a phenyl ring.

14. The use of claim 12 wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo.

15. The use of claim 12 wherein: R 1 is alkyl, and R 2 is alkoxy; or R' is alkyl and R 2 is -OCF 3 ; or R' is alkyl and R 2 is H, OH, halo or alkoxyalkoxy ; or R' is alkoxy and R 2 is alkoxy or H; or RI is alkoxyalkoxy and R 2 is H; or R' 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. WO 2010/062559 PCT/US2009/062071 124

16. The use of claim 12 wherein R 3 is alkyl or H, and R 4 is H, -C(O)O-alkyl, or -SO 2 alkyl.

17. The use of claim 12 wherein R 5 A is H, halo, -O-alkyl-N(alkyl) 2 , -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl, -N(R 6 A) 2 , -NR 6 -alkyl-0-alkyl-OH. -NR-hydroxyalkyl, -S-hydroxyalkyl, -S0 2 -alkyl, or -S-alkyl-NHC(O)H. -o o

18. The use of claim 17 wherein R 5 A is is H; Cl; -O-(CH 2 ) 2 -N(CH 3 ) 2 ; -0 -H 2 0 ; -N(CH 3 ) 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-alkyl-morpholinyl; -S-CH 2 CH(OH)-CH 2 OH; -S02CH 3 ; -N(R 6 )-(cycloalkyl), wherein cycloalkyl is cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and wherein the cycloalkyl potion is optionally substituted by 1 or 2 ring system substituents; -N(R)-(heterocycloalkyl), wherein heterocycloalkyl is or , wherein R 9 is H, alkyl or -SO 2 alkyl; -NR 6 -alkyl-aryl, optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are independently selected from the group consisting of OH, alkoxy or -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -O-(CH 2 ) 2 -O-; -NRt-alkyl-heteroalkyL; or -N(R 6 A) 2 ,wherein the two RCA groups and the nitrogen to which they are attached form a ring selected from the group consisting of WO 2010/062559 PCT/US2009/062071 125 -N4 q -N-N q 0 N S q, N\__ , s and wherein q is 1 or 2, s is 2 or 3 and R 6 is as defined in claim 12.

19. The use of claim 12 wherein the compound of Formula If is selected from Examples 3, 3D, 3G, 31, 3M, 3N, 30, 3R, 3T, 3W, 3Y, 3AA, 3CC, 4C, 40, 4P, 4Q, 4R, 4S, 4U, 4V, 5A, SC, 5D, 5E, 5H, 5J, 5L, 5P, 5T, 5V, 5W, 5X, 5Y, 6, 6A, 6D, 61, 6K, 6L, 6M, 6N, 60, 6P, 7, 7D, 12, 13U, 20A, 20C, 21C, and 21E.