CA2741303A1

CA2741303A1 - Substituted pyrazoloquinolines and derivatives thereof

Info

Publication number: CA2741303A1
Application number: CA2741303A
Authority: CA
Inventors: Ginny D. Ho; Shu-Wei Yang; Elizabeth M. Smith; William Thomas Mcelroy; Kallol Basu; Jennifer Smotryski; Zheng Tan; Brian A. Mckittrick; Deen B. Tulshian
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2008-10-28
Filing date: 2009-10-26
Publication date: 2010-06-03
Also published as: EP2350072A1; JP2012506873A; WO2010062559A1; AU2009320125A1

Abstract

The present invention relates to substituted pyrazoloquinolines of formula I
and derivatives thereof, the use of the compounds as phosphodiesterase 10 (PDE1O) inhibitors for the treatment of PDE1O -modulated disorders, to pharmaceutical compositions comprising the compounds, and to the use of additional substituted pyrazoloquinolines and derivatives thereof for the treatment of PDE1O -modulated disorders.

Description

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 PDEI0--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

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 QT, 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 at, J. Med. Chem., 19(2), 262-(1976). Pyrazoloquinolines useful as activators of caspases and inducers of apoptosis are disclosed in US 2007/0253957 Al.

Summa 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.

3 The invention also provides for methods of treatment of PDE10 inhibitor-mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome, using a class of substituted pyrazoloquinoline PDE1 0 inhibitor compounds and derivatives thereof represented by Formula II.
Novel compounds of the invention have the structural Formula I:

N

f R
R
Formula I
or a pharmaceutically acceptable salt thereof, wherein all substituents are independently selected;
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, R2 is absent;
R1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-C02H, -C(O)N(R6A)2, -N(R6B)2=
-alkyIN(Rss)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)S02-alkyl, phenyl, CN, -No -N X 0 -S02R6, -SR6, trimethylsilyl-, -SF5, -OSF6, -C(=NOR6)-R6, ) r , or -(CH2)n-X-(CH2)n-R18, wherein X is -0-, -S-, or --NR6-, n is g, 1 or 2, m is 1, 2 or 3 and R18 is selected from the group consisting of

4 R6~

`N / N / N / -- NN /
N I \ :\ /
C4 / N \ N ! S
N / CN \ N \
and iN ~ ,~
~

R2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2 -N(ROB)2, -alkylN(R68)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)S02-alkyl, phenyl or CN;
or R1 and R2 on adjacent ring carbon atoms together form -O-CH2-O- or -0-(CH2)2-O_;
R3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(ReB)2, -OCF3, -CF3, -SF5= -OSF5 or -CN;
R4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, -S02-alkyl, --C(O)N(R6A) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;
R5 is alkyl, -CN, -C(O)OR6A, -C(O)N(R6A)2, aryl-((R '7a, R17b)-alkylene)--, heteroaryl-((R17a R17b).alkylene)-, heterocycloalkyl-((R17a R17b)-alkylene)-, hydroxyalkenyl, heteroarylaikenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-0-aryl, -alkyl-O-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R6)-aryl, -alkyl-N(R6)-heteroaryl, -alkyl-N(R6)-cycloalkyl, -alkyl-N(R6)-heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocycloalkyl-heteroaryl-alkylene-, cycloalkyl (e.g., cyclopropyl), C
N...- R6 R

R12 R s Q

......N -N NR N R N \ LA r -T) t I)r R14 NR6-(CH2), -NR6-(CH2), '-"NR51CH2)b, NR14 O
H HO

Qot N-R14 or Qt , bis1,2or3, r is 1 or 2;
t is 0, 1 or 2;
each R6 is independently selected from H and alkyl;
each R6A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two R6A 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 R68 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl--, heteroarylalkyl-, -S02alkyl, -S02-aryl, -S02-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(R6)2, -C(O)NR6-aryl, and -C(O)NR6-heteroaryl; or two 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 horrothiomorphoiinyl ring;

R9 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 -(CH2)2.6- or -O-(CH2)2-0-;
R12 is 1 or 2 substituents independently selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl;
R16 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, -C(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R6A)2, -C(O)-alkyl-NR6-C(O)-aryl, -C(O)-alkyl-NR6-C(O)O-alkyl, -C(O)-alkyl-NR6-C(O)O-benzyl, -S02alkyl, -S02-aryl, -S02-alkylaryl, -S02-heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with halo;
R'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(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R6A)2 -C(O)-alkyl-NR6-C(O)-aryl, -C(O)-alkyl-NR6-C(O)O-alkyl, -C(O)-alkyl-NR6-C(O)O-benzyl, -S02alkyl, -S02-aryl, -S02-alkylaryl, -heteroaryl or diphenylmethyl, optionally substituted on a phenyl ring with halo;
R15 is 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, OH, hydroxyalkyl, halo, -CF3, -C(O)Oalkyl, -C(O)N(R6A)2:
aminoalkyl-, -N(R6B)2, -NR6-C(O)N(R6A)2, -NR6-C(O)-alkyl, -NR6-C(O)Oalkyl, -NR6-S02-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 -(CH2)2.6- or -O-(CH2)2-0-; and 8172 is H or alkyl and RI7b is H, alkyl, OH, F, -N(R66)21-NOR6, alkoxy, CN, -CH2OH, -CH2-O-alkyl, -CON(R6a)2, -CH2N(R6)2 or -C02R6, or R17a and R1 7b are each F;
or R17 and R17b are on the same carbon atom and together are =0, =NOR6 or provided that when R5 is heterocycloalkyl-((R17 R171, )-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the R17b substituent on the cc-carbon is H, alkyl, CN, -CH2OH, -CH2-O-alkyl, -CON(ROa)2, -CH2N(R6)2 or -C02R6.
In one example, R3 for Formula I is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R6s)2, -OCF3, -SF5, -OSF5 or -CN.
In one example R5 for Formula I is alkyl, -CN, -C(O)OR6A, -C(O)N(R6A)2, aryl-((R17 R17b)_alkylene)-, heteroaryl-((R17a R176)-alkylene)-, 17a , R17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, -alkyl-O-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R6)-aryl, -alkyl-N(R6)-heteroaryl, -alkyl-N(R6)-cycloalkyl, -alkyl-N(R)-heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, heteroaryl, O
N .- R6 R11 r j-~
-(CH
2)b--NR6 -CO -(CH2)b-"NR6 NR14 N
U NH

~~"N NR s N R15 -.N R6_(CHZ)t,~

N t !r Jr \-Ar NR 14 -NR-(CZ)b -NR6~'(CH2)b O -NR6-(CH2)b NR14 r HEM H

or The present invention further includes the compound of formula I in all its isolated forms.
The present invention also relates to a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method of treating 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
R
Formula 11 or a pharmaceutically acceptable salt thereof, wherein all substitutents are independently selected;
(2A
~Iz 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, R2 is absent;
R' is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -0-alkyl-C02H, -C(O)N(R6R)2, -N(R6B)2, -alkylN(R68)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R5)S02-alkyl, phenyl, CN, -NO N/--\
-S02R6, -SR6, trimethylsilyl-, -SF5, -OSF5, -C(=NOR6)-R6, )r r or -(CH2) X-(CH2),,,-R13, wherein X is -0-, -S-, or -NR6-, n is 0, 1 or 2, m is 1, 2 or 3, and R13 is selected from the group consisting of IN DI
Z:c N

N ~~N~ N
-YN
N N and N /

R2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -0-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(ReA)2, -N(R6B)2, --alkylN(R6B)2, -NR 6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)S02-alkyl, phenyl or CN;
or R1 and R2 on adjacent ring carbon atoms together form -O-CH2-0- or -O-(CH2)2-0-;
r is 1 or 2:
R3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, _N(R6B)2, -OCF3, -SF5, -OSF5 or -CN;
R4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl--OC(O)-alkyl, -S02-alkyl, -C(O)N(R6A) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;

RSA is H, halo, OH, alkoxy, -O-alkyl-N(alkyl)2, -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl, aryloxy-, arylalkoxy-, heteroaryloxy- N(R6A)2, -NR6-alkyl-N(alkyl)2, -NR6-alkyl-O-alkyl-OH, -NR5-hydroxyalkyl, -S-alkyl, -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 or - N \.-L.X
r each R6 is independently H or alkyl;
each WA is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylaikyl- and heteroarylalkyl-; or two R6A 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, morphollnyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyi ring; and each R66 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-, -SO2alkyl, -S02-aryl, -S02-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(R6)2, -C(O)NR6-aryl, and -C(O)NR6-heteroaryl; or two R6s groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R66 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 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 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Detailed Description CA, In one embodiment of Formula !, forms a phenyl ring.
In some embodiments of Formula 1, R' and R2 are independently selected from the group consisting of R1 is H, alkyl, alkoxy, alkoxyalkoxy, -CF3, - OCF3 and halo.
In other embodiments of Formula I:
R1 is alkyl, preferably methyl, and R2 is alkoxy, preferably methoxy; or R1 is alkyl, preferably methyl, and R2 is -OCF3; or R' is alkyl, preferably methyl, and R2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R1 is alkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H;
or R1 is alkoxyalkoxy (preferably methoxyethoxy) and R2 is H; or R' is halo and R2 is H; or R1 is halo and R2 is -OCF3; or R' and R2 together are methylenedioxy.
In another embodiment of Formula I, R3 is alkyl, preferably methyl, or H.
In another embodiment of Formula 1, R3 is -CF3.
In another embodiment of Formula 1, R4 is H, -C(O)O-alkyl, wherein alkyl is preferably t-butyl, or --SO2alkyl, preferably -SO2CH3.
In another embodiment of Formula 1, b is 1.
In another embodiment of Formula I, R5 is selected from the group consisting of -CN, -C(O)N(ReA)2, aryl-((R'7 R"b)-alkylene)-, heteroaryl-((R "a R'7b)-alkylene)-, heterocycloalkyl-((R"a R17b)_alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), -(CH z)b-NR6 O -N NH 1~ -N 0 --N NR13 -N Rte ~/ Jr lr i 3 f } Y

._N R6"'(CH2)) 14 N\ `-NR6_(CH2)b -0- NR6-(CH2)b NR
R'4 and -N R6- (CH2)b r , wherein b, r, R6, RBA, R9, R11, R12, R13, R14 R15, 8173 and R"b are as defined above.
In other embodiments of Formula I, R5 is -CN; -C(O)NH-alkyl-pyridyl;
-CH(OH)-phenyl; -alkylene-phenyl; -alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl;

-CH(OH)-pyridyl; -GH-CH-(CHI)3-OH; -CH=CH-pyridyl; -C=C-pyridyl;

~/ \ /N --{CHz}b-N R6 O --- N NH N~ NH
}
;
(CH3 O
CH2OH CH3 -NR 6-(CH

; CH3 ; R14 wherein R14 is H, alkyl (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);

w`NR6-'(CH2)b -NR6-(CH2)b NR14 wherein R14 is H or alkyl; or -NR6-(CH2)b In another embodiment of Formula 1, when R5 is heterocycloalkyl-((R'7 R'71,)-alkylene)-, (R17, R'7')-alkylene- is preferably -C(OH)-, and R5 is a group such as OH OH
C NH ---C O
H and H C;

In another embodiment of Formula 1, R5 is heterocycloalkyl-((R 17a, R'7b')-alkylene)-, wherein R97' and R17b are independently H or alkyl, R5 being preferably -(CHI)bN NR7 (CMz)b _N R~ \) r R9 -(CH2)b-N
r or R , wherein bis1,2or3;
r is 1 or 2;
R7 is H, alkyl or --S02-alkyl;
R$ is I or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, halo, and -CF3;
R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0; and R1 is H, alkyl or hydroxyalkyl.
Additional embodiments of compounds of Formula I wherein R5 is heterocycloalkyl-((R17' R'7b)-alkylene)- are CH2W N \-/ N H , -CH2-N \,-/ NH
C M
-CH2-N IS02CH _ CHz-1 0 1 _CM2_ N
optionally substituted by methyl or hydroxymethyl, optionally substituted by OH, F or CF3, and optionally substituted by methyl or OR

"`N NR13 In another embodiment of Formula 1, R5 is r , r is 1, R9 is H or alkyl, N
and R13 is -SO2alkyl, -CONH2, -C(O)heteroaryl, for example OH , or-I[
C
C(O)cycloalkyl, for example 03; more preferably, R13 is -SO2alkyl or /->( R9 -CONH2. In another embodiment, R5 is r is 2, R9 is H and R13 is -SO2alkyl or -CONH2.

In another embodiment of Formula !, R5 is \-A r r is 2, and R15 is alkyl (preferably methyl), alikoxy (preferably methoxy), -CF3, OH, hydroxyalkyl, preferably hydroxymethyl, halo (preferably F), -NH2, -C(O)NH2, -CH2NH2, -C(O)O-alkyl, -NHSO2alkyl or -NHC(O)NH2, where R15 is preferably in the 4-position. In another embodiment, R5 is N r is 2, and R15 is hydroxyalkyl, preferably hydroxymethyl, in the 3-position.

/"1 R15 In another embodiment of Formula 1, R5 is ~ ) r r is 1. and R15 is OH
or hydroxyalkyl (preferably hydroxyraethyl).
Examples of the heterocycloalkyl-heteroaryl-alkylene- R5 group for Formula I
include, but are not limited to:

NN
N N N
and N N
Q

Thus, in one example the heterocyeloalkyl-heteroaryl-alkylene- R5 group for Formula I is:
.nrLnn r yl N r N
(N) In another example the heterocycloalkyl-heteroaryi-alkylene- R5 group for Formula I is:

N N

In another example the heterocycloalkyl-heteroaryi-aikylene- R$ group for Formula I is:

N
In one example the R5 cycloalkyl group is cyclopropyl.

In another embodiment of the compounds of Formula I:
R' and R2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.
R3 is H or alkyl;
R4 is H, -C(O)O-alkyl or ---SO2alkyl; and R5 is selected from the group consisting of -CN, -C(O)N(R6A)2, aryl_((R17a R17b)-alkylene)-, heteroaryl-((R17, R17b)_alkylene)-, heterocycloalkyl-((R' 7a R17b)_alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), Rg /-1-1 R11 ~/ R12 N N '13 N R15 - CH2)b-NR6 O -N NH N NO ~r Jr O~
""'N R6-(CH2)b~ Q
N` NRs-(CH2)b `-NR6-(CH2)b NR14 R14 S f , and '" NRs" (CH2)b r 0, wherein b, r, R6, R6R R9, R1 1R12 R13, R'4 R15, R17a and R17b are as defined above.
In yet another embodiment of the compounds of Formula 1:
R1 is alkyl, preferably methyl, and R2 is alkoxy, preferably methoxy; or R1 is alkyl, preferably methyl, and R2 is -OCF3; or R1 is alkyl, preferably methyl, and R2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R' is afkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H;
or R1 is alkoxyalkoxy (preferably methoxyethoxy) and R2 is H; or R' is halo and R2 is H; or R' is halo and R2 is ---OCF3; or R1 and R2 together are methylenedioxy;
R3 is alkyl;
R4 is H; and R5 is -CN: -C(O)NH-alkyl-pyridyl; --CH(OH)-phenyl; -alkylene-phenyl;
-alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl; -CH(OH)-pyridyl;
-CH=CH-(CH2)3-OH; -CH=CH-pyridyl; -C=C-pyridyl;

CH3 -- ~CH2OH
-- (CH2),-NR -N NH -N NH N 0 ,CH3 0-~
CH3 -N -NR6-(CH2)b N
CH3; \ R14 wherein R14 is H, alkyl (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);

"NR6^(CH2)b -NR6-(CH2)b NR14 wherein R14 is preferably H or alkyl--N Rs--(CH2)b heterocycloalkyl-((R17a R17b)_alkylene)-, wherein (R 17, R17b)-alkylene is H H
C NH -C C
-C(OH)-, such as H and H ;
heterocycloalkyl-((R17a R17b)-alkylene)-, wherein R'78 and R17b are independently H or alkyl, preferably -(CH2}b-N NR7 R3 }r R (CH2)b-N (C-i2)b N
r r or R10, wherein b is 1, 2 or 3; r is 1 or 2; R7 is H, alkyl or -S02-alkyl; R8 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, halo, and -CF3; R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0; and R1 is H, alkyl or hydroxyalkyl;

r wherein r is 1, R9 is H or alkyl, and R'3 is -SO2alkyl, -CONH2, -c N
-C(O)heteroaryl, for example OH , or -C(O)cycloalkyl, for example --C
CH3; more preferably R13 is --S02alkyl or -CONH2;
R s ....... NR13 r , wherein r is 2, R9 is H and R13 is -S02alkyl or -CONH2;
-N//'-~ R15 r wherein r is 2, and R15 is alkyl (preferably methyl), allkoxy (preferably methoxy), -CF3, OH, hydroxyalkyl, preferably hydroxymethyl, halo (preferably F), -NH2, -C(O)NH2, -CH2NH2, -C(0)0-alkyl, -NHSO2alkyl or -NHC(O)NH2, where R15 is preferably in the 4-position;

l R15 ) r wherein r is 2, and R15 is hydroxyalkyI= preferably hydroxymethyl, in the 3-position; or , \'~)r wherein r is 1, and R'5 is OH or hydroxyalkyl (preferably hydroxymethyl).

Preferred compounds of Formula I are those in Examples 3E, 3F, 3S, 3V, 31313, 4, 4A, 413, 4F, 4H, 41, 4K, 4L, 5, 5F, 5G, 5K, 5M, 50, 5Q, 5R, 5S, 6H, 7A, 78, 7E, 8, 8A, 813, 8C, 9, 10A, 1 OC, 1 OD, 1 OE, 1 OF, 1 OG, 1 OH, 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;
21 B, 21 D, 21 F, 22, 23, 24, 26, 27, 27A, 27B, 27C, 28, 29A, 2913, 29D, 29E, 29F, 3213, 33, 34A, 3413, 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, 5S, 6H, 7E, 813, 8C, 9, 1OA, 1OC, 1OD, 1OE, 1OF, IOG, 10H, 13, 13A, 13C, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 13Q, 13R, 13S, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 26, 27, 27A, 2713, 27C, 298, 29F, 3213, 34B, 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 3B8. 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 5S. 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. I n another embodiment the compound of Formula I is 8. In another embodiment the compound of F--; r n._'a I is 8A. In another embodiment 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 10C. 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 101-1. 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 138. 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 131.... 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 21 B.
In another embodiment the compound of Formula I is 21 D. In another embodiment the compound of Formula I is 21 F. 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 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 328. 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.

CA, In one embodiment of the compound of Formula 11 forms a phenyl ring.
In some embodiments of Formula II, R' and R2 are independently selected from the group consisting of R1 is H, alkyl, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.
In other embodiments of Formula #I:
R1 is alkyl, preferably methyl, and R2 is alkoxy, preferably methoxy; or R' is alkyl, preferably methyl, and R2 is -OCF3; or R' is alkyl, preferably methyl, and R2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy); or R' is alkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H;
or R` is alkoxyalkoxy (preferably methoxyethoxy)and R2 is H; or R1 is halo and R2 is H; or R1 is halo and R2 is -OCF3; or R1 and R2 together are methylenedioxy.
In another embodiment of Formula 11, R3 is alkyl, preferably methyl, or H.

In another embodiment of Formula II, R4 is H.
In another embodiment of Formula li, b is 1.
In another embodiment of Formula II, R5A is H, halo, -O-alkyl-N(alkyl)2, -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl, -N(R6A)2, -NR6-alkyl-O-alkyl-OH, -NR6-hydroxyalkyl, -S-hydroxyalkyl, -S02-alkyl, or -S-alkyl-NHC(O)H.
In other embodiments of Formula II, RA is H, Cl, -O-(CH2)2-N(CH3)2, -o o _CH2CO -N(CH3)2, -NH(CH2)3CH3, -NH-(CH2)2-O_(CH2)2-OH, -NH-(CH2)2-OH, -NH-CH2-CH(OH)-CH3, -NH-alkyl-morpholinyl, -S-CH2CH(OH)-CH2OH, or -SO2CH3.
In another embodiment, when R 5A is --N(R6A)2, R5A is -N(R6A)-(cycloalkyl), wherein R6A 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 -CF3.
In another embodiment, when R6A is -N(R6A)2, R6A is -N(R6A)-(heterocycloalkyl), wherein R6A is H or alkyl, and wherein heterocycloalkyl is or _R19 wherein R19 is H, alkyl or -S02alkyl.
In another embodiment, when RSA is -N(R6A)2, R 5A is -NR6-alkyl-aryl, wherein 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 -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -O-(CH2)2-0-.

In another embodiment, when R5A is -N(R6A)2, R5A is -NR 6A-alkyl-heteroalkyl wherein R6A is H or alkyl, and wherein the heteroaryl portion is preferably pyridyl, e.g., NH-"" (CH2)i_2--./'~~

In another embodiment, when R5A is -N(R6A)2, the two R6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of /-4\)q /'~Cd) -N
- N
_N N-R3 _N S
q, -~ s and wherein q is 1 or 2, s is 2 or 3, and R6 is as defined above.
In another embodiment of the compounds of Formula II:
R' and R2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.
R3 is H or alkyl;
R4 is H, -C(O)O-alkyl or --S02alkyl; and RSA is selected from the group consisting of H, halo, -O-alkyl-N(alkyl)2, -0-heterocycloalkyl, -0-alkyl-heterocycloalkyl, -N(R6A)2, -NR6-alkyl-O-alkyl-OH, -NR6-hydroxyalkyl, -S-hydroxyalkyl, -S02-alkyl and -S-alkyl-NHC(O)H, In yet another embodiment of the compounds of Formula II:
R' is alkyl, preferably methyl, and R2 is alkoxy, preferably methoxy; or R' is alkyl, preferably methyl, and R2 is -OCF3; or R' is alkyl, preferably methyl, and R2 is H, OH, halo or alkoxyalkoxy (preferably methoxyethoxy), or R1 is alkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H:
or R' is alkoxyalkoxy (preferably methoxyethoxy) and R2 is H; or R1 is halo and R2 is H; or R' is halo and R2 is -OCF3; or R1 and R2 together are methylenedioxy;
R3 is alkyl;
R4 is H; and RSA is H; Cl- -O-(CH2)2 l -N(/CH3)2, v; -CO -C 2C3 -Nt/CHI)2;
, , -NH(CH2)3CH3; -NH-(CH2)2-0-(CH2)2-OH; _NH-(CH2)2-OH; -NH-CH2-CH(OH)-CH3;
-NH-alkyl-morpholinyl; -SWCH2CH(OH)-CH2OH; -SO2CH3; or -N(R6A)2 selected from the group consisting of:
-N(R6A)-(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 -C F3;

-N(R6A)-(heterocycloalkyl), wherein heterocycloalkyl is --CO or wherein R19 is H, alkyl or -S02alkyl;
-NR 6A-alkyl-aryl, preferably -NR 6A-alkylphenyl, wherein the phenyl portion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably independently selected from the group consisting of OR
alkoxy or -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -O-(CH2)2-0-;
-NR 13A-alkyl-heteroalkyl wherein the heteroaryl portion is preferably pyridyl; and -N(R6A)2 wherein the two R6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of -N ..-.... 0 N-R6 and N

wherein q is I or 2, s is 2 or 3, and R6 is as defined above, and wherein the R6A in -N(R6A)-(cycloalkyl), -N(R6A)-(heterocycloalkyl), -NR6' -alkylaryl and --NR6A-alkyl-heteroaryl is preferably H or alkyl.

Preferred compounds of Formula II 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, 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, 21 C, and 21 E.
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, 5T, 5V, SW, 5Y, 6, 6A, 61, 6K, 6L, 6M, 6N, 6P, 7, 7D, and 12.
In one embodiment the compound of Formula 11 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 11 is 31. In another embodiment the compound of Formula If is 3M. In another embodiment the compound of Formula 11 is 3N. In another embodiment the compound of Formula 11 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 II is 3Y. In another embodiment the compound of Formula I I is 3AA. In another embodiment the compound of Formula 11 is 3CC. In another embodiment the compound of Formula 11 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 11 is 4R. In another embodiment the compound of Formula 11 is 4S. In another embodiment the compound of Formula 11 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 SC. In another embodiment the compound of Formula 11 is 5D. In another embodiment the compound of Formula 1i is 5E. In another embodiment the compound of Formula 11 is 5H. In another embodiment the compound of Formula 11 is 5J, In another embodiment the compound of Formula If is 5L. in another embodiment the compound of Formula 11 is 5P. In another embodiment the compound of Formula 11 is 5T. In another embodiment the compound of Formula 11 is 5V. In another embodiment the compound of Formula 11 is 5W. in another embodiment the compound of Formula 11 is 5X. In another embodiment the compound of Formula II is 5Y. In another embodiment the compound of Formula 11 is 6. In another embodiment the compound of Formula li is 6A. In another embodiment the compound of Formula II is 6D. In another embodiment the compound of Formula 11 is 61. In another embodiment the compound of Formula 11 is 6K. In another embodiment the compound of Formula II is 6L.
In another embodiment the compound of Formula 11 is 6M. In another embodiment the compound of Formula II 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 11 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 11 is 20C. In another embodiment the compound of Formula II is 21C. In another embodiment the compound of Formula II is 21 E.
As used herein, the following terms are as defined below unless otherwise indicated:
Mammal means humans and other mammalian animals.
The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of " alkyl" applies to "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 I 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 methyleAne, ethylene and propylene (i.e., -CFI2-, w(C 2))2-, -(CH2)3-). When substituted, the R17a and R17b groups can be on the same or different carbon atoms.
The proviso that when R5 is heterocycloalkyl-((Rl7a R17b)-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the R17b substituent on the a-carbon is H, alkyl, CN, -CH2OH, -CH2-O-alkyl, -CON(R6a)2, -CH2N(R6)2 or-CO2R6 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.
F EHydroxyalkyl" 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-butenyl, 3-methylbut-2-enyl, n-pentenyl, 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.

"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), isoxazofyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyf, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo 1,2-a]pyridinyl, imidazo[2,1-b]thiazofyl, benzofurazanyl, indolyl, azaindolyi, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,24-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetra hydroisoquinolyl, 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, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, -CH(Y1)(Y2), -O-Y1, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxy, -C(O)Y1, halo, nitro, cyano, -C(O)2-Y1, -S(O)2-Y1, -S-Y1, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkenyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), -NY1Y2, -alkyl-N Y1Y2, -C(O)NY1Y2, and -SO2NY1Y2, wherein Y1, Y2 and Y3 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 -SF5, -OSF5, -Si(Y4)3, -S(O)N(Y1)(Y2), -C(=NOY1)Y2, -P(O)(OY1)(OY2), -N(Y1)C(O)Y2, -CH2-N(Y1)C(O)Y2:
-CH2-N(Y1)C(O)N(Y1)(Y3), -N(Y1)S(O)Y2, -N(Y1)S(O)2Y2, -CH2-N(Y1)S(O)2Y2, -N(Y1)S(0)2N(Y2)(Y3), -N(Y1)S(O)N(Y2)(Y3), -N(Y1)C(O)N(Y2)(Y3), -CH2-N(Y1)C(O)N(Y2)(Y3), -N(Y1)C(0)2(Y2), -CH2-N(Y1)C(0)2(Y2), -S(O)Y1, =NOY1, and -N3, wherein Y1, Y2 and Y3 are as defined above and each Y4 is independently selected from alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl and heteroarylalkyl.
Furthermore, the alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl portions of Y1, Y2 or Y3 can be optionally substituted with or 2 substituents independently selected from the group consisting of halo, OH, -CF3, CN, alkoxy, -NH2, -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

on each carbon) on a ring system. Examples of such moieties are methylenedioxy, etbylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
--.0 CO)c 0 and Similarly, a single divalent moiety such as a divalent alkyl chain or a -O-(CH2)2-0- group can simultaneously replace two available hydrogen atoms on one carbon atoms on a ring system. An example of such Spiro moieties is:

_N a O
"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, tetra hydrothiophenyl, 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 are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

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 O
I Cal 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 former for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

When CA, is phenyl, Formula I or II has the structure R' lz~
N
R2~0 /N

R5 or RSA;
When CA, 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:

1 3 - 5 3 R1 R1--__ ]]
R2 R2 R2 N \

N\ R N N~ R1.->~i~~ N
R

N N
R,1 N N R~N ( NZ-11 R1/ N\

R N R N~, R1 N
2_~ 2 R2 S
R NON R

N R1 N S N, R1\ R' R2 3 f R2 N N

N N R N \V R1 I N`S' R1 ssl 1 -</
N
-</
:j :1 S

N R\ N
N
R1 ~/ R1 / ~S' R2 N

N S N~ 0 N
RN\ S N~ , N N`_ (S

CA, 5ZZ One skilled in the art will recognize that when is a five membered ring containing two heteroatoms, there is only one substitutable carbon, hence R2 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 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 Cl-C3 alkyl group, or a hydroxy substituted Cl-C3 alkyl group, to a carbon on the opposite side of the ring, provide that when the bridge is a Cl bridge both carbon atoms to which the bridge is bound to are not adjacent to the same heteroatom, Non-limiting examples include:

- NZN H ''- NaN H - N\O NO N~
-<J~N --CO -N -N TO N O
F
and "N\ OOH
}''pta 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 (CH2)3 s _NN-- "/IO_ N 1-3 1-3 1-3 ]QN Haloalkyl represents an alkyl group as defined substituted by one or more halo atoms. Examples wherein halo is fluoro are -CH2F, -CHF2, -CF3, -CH2CF3, -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 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 11, 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 (I) (or Formula Il) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as, for example, through hydrolysis in blood. A
discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference thereto.
For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl. (C2-C,2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-l-(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-i-(alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-y1, di-N,N-(Cl-C2)alkylamino(C2-C3)alkyl (such as 3-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1 C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prod rug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Cj-C6)alkanoyloxymethyl, 1-((C,-C6)alkanoyloxy)ethyl, 1-methyl-l-((C1-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, a-amino(Ci-C4)alkanyl, arylacyl and a-aminoacyl, or (x-aminoacyl-a-aminoacyl, where each cx-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate"
encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
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).

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective as inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula I or lI 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 11 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) qq1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217, Anderson et a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, 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 prod rugs 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 prod rugs), 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 /L1PAC 1974 Recommendations. The use of the terms "salt", "solvate" "pro ' ,_Ã
@' and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates 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 I. 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 11, 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 2H, 3H, 11G 13C 14C, 15N, 180, 170, 31P 32P, 35S, 18F, 36CI and 1231, respectively.

Certain isotopically-labelled compounds of Formula (1) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays.
Tritiated (i.e., 3H) 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 1'C or '8F 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., `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., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half lives (T/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 11, and of the salts, solvates, co-crystals and prodrugs of the compounds of Formula I or 11, are intended to be included in the present invention.
In this specification, the term "at least one compound of Formula I (or Formula II)"
means that one to three different compounds of Formula 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.

H
NH2 h1. EtqH,NH4OH,CS2 R9 N NHNH2 2. CICH2co2H, Na2CO3 q' AJ 3. NH T+iH s O O
N N' JAI IN
Ct .._ OEt 3 H H
KOH, EtOH, Q N N' N
a R2 o POC [3 N` N`

Cl N N
RI N
R2 '2A /"N

RS
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 refiux and then cooled. On acidification, the acid 4 is isolated. The acid 4 is treated with POCI3 under refiux, followed by cooling and adjusting the pH with 20% NaOH to give the chloro compound S. Chloro compounds 5 can be converted to the R5-susbtituted compounds of formula 6 using methods known in the art and described in the examples below.

Compounds of Formula II can be prepared by methods similar to those described for compounds of Formula I, and by methods known in the art, for example the procedures described in US 5,459,146, US 5,506,236, US 5,608,067, and US
2007/0253957, all incorporated herein by reference, and by Crenshaw et al, J.
Med.
Chem., 19(2), 262-275 (1976).
In the scheme above and in the following preparative examples, the following abbreviations are used: RT - room temperature; Ac - acetyl; Me - methyl; Et -ethyl;
Ph - phenyl; iPr -- isopropyl; t-Bu - t-butyl ; tBOC - N-tert-butoxycarbonyl:
DCM -dichloromethane; DMSO - dimethylsulfoxide; DIBAL - diisobutylaluminum hydride;
DCE - dichloroethane; DMF -- dimethylformamide; THE - 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-1 OA LC system. Column:
Phenomenex Gemini C18, 5 micron, 50 mm x 4.6 mm ID; Gradient: From 90% water, 10% CH3CN and 0.05%TFA, 5 min to 5% water, 95% CH3CN, 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 Il.
Example I

H
jb~ N N
> / rt cl CH3 Step 1:

CH3 't. Et0H, NH4OH, CS2 CH3 H
NH2 2. CICH2CO2H, Na2CO3 N NHNH2 CH3.~ N H H3C,O s CS2 (4.5 mL) was added to a mixture of 4-methoxy-2-methylaniline (9.0 g), absolute EtOH (25 mL) and NH4OH (6 mL). After 1 hr, chloroacetic acid (7.0 g), NaHCO3 (4.5 g) and water (20 mL) were added. After an additional hour, H2NNH2 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 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 CH2CI2 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:

/ N~NHNH2 ~oEt N N' H3C` ` ) S H3C` \ / -N
o EtOH 0 1-2 1-3 Oft 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 C.
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.

Step 3:

N NH H
KOH, EIOH, H3C` O H3C,0 0 OEt OH
KOH (13.7 g) in water (80 mL) was slowly added to a mixture of compound 1-3 (7653 g) and absolute EtOH (40 ml-) over 4 min. The resulting mixture was heated under reflex 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:

' N Nt F~OC13 N` H
H3c, I H3c, / N

OH cl A mixture of compound 1-4 (4.50 g) and POCK (5 mL) was purged with nitrogen and heated under reflex for 1 hr. The mixture was cooled to 70 C and concentrated in vacuo (bath at 70 C). 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.

j/;-) ' ci F
C[ C[ Cl C( H
N N
zN
CI
Example 2 Alternate Synthesis of Analogs of 1-22 H
/ N= c , NH2NH2 / I N o'~s E
\ NHNH2 Hydrazine monohydrate (2 g) was added to a solution of isothiocyanate 21 (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+).
The following compounds were similarly prepared.
OCF3 H oMe H CH3 H
N,c iS N C~,s H3C I:t N C~,,S
Br \ NHNH2 Me0 \ NHNH2 NHNH2 F F H Et i-Pr H
H jbr N.C/ N'S / N,C
H3C 's NHNH2 F \ ' NHNH2 \ NHNH2 \ NHNH2 H CH3 H Br H Br H
N,CrrS N,Cr~S N,c N,C.s i-Pr ~` NHNi2 NHNH2 NINii2 NHN##2 Ct Example 3 H
N
HScQ0 I ,`iv H

N

c6H5CF3 dioxane microwave Compound 15 (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 vacua. The residue was partitioned between EtOAc and water. The organic layer was dried (K2CO3) and concentrated in vacua to give a residue (0.51 g). The residue was purified on silica gel plates (6, 1000 t) eluting 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:
L.CIIS
Ex. No. Structure MW + 1 Rt 3A ; H3CO 296 297 2.42 N

- - - - ----------- ------------H

N
H 3C O t /Jy 0.71 3B .9 CH3 297 298 32 N~
H H -~
N N
N
3C N CH3 0.92, 267 268 1.22 N

&;) NN

3D H3CO 310 311 2.56 N H
IN
3E H3CO 325 326 1.64 (uv) H
N
N, N 0.79, N CH3 1.66 (uv) rx;N
3G H3CO 312 313 2.13 (uv) N
H3CO 0.93 3H C H3 311 312 .44 E 4 i E

N` [

CH, 311 312 0.94, 1.57 N "C H3 IN
3J 266 267 2.34 N H

3K N c3 281 282 .42 E'CH3 281 282 1.35 H

N NN

3Ãi cÃ 315 316 1.81 N Nk 3N Ci 316 317 2.35 (N) CH3 H
NON
30 H3CO [ 325 326 1.60 (uv) ÃE f [ t=
NH

3P H3CO 325 326 11 1.84 (uv) (1.,H3 H

N N
N

30 CH3 425 426 2.73 (uv) f ~O"11 ,N
3R CI 329 330 ` 1.96 (uv) H E E
N1 4 Ã 3 =1 3S C 329 330 1.94 (uv) Ju N [
N
3T C' CH3 343 344 1.85 (uv) D

C } 3 i J

N
3U C CH 329 330 _9 (N)*
NCH
H

N
N
3V H3CO CH 339 340 0.80.
N 3 1.76 N D

H
t~1 368 369 2.48 H
N

296 297 2.48 Co 1 ~

H
N
N

3y 1 1NH CH3 348 349 2.41 OH

H
N
NN

3Z NH CH3 333 334 0.79 N N~ ! I

3BB CH 340 341 2.24 NH a -----------------N Ni N
HaCO

N CH3 347 348 1,7 `CH3 N {

Example 4 H
jb~
/N
H3CIO , Y

H

Kt, NaH
_.CH3 4 microwave A microwave vial charged with 1-55 (0.100 g), NaH (0.030 g), KI (0.060 g), and 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 (Na2SO4) and concentrated in vacuo to give a residue (0.066 g). This residue was purified on silica gel plates (6, 1000 ) eluting with acetone:DCM (2:8) to give the compound 4 (0.012 g). LCMS: M is 324. Found Mi-1 is 325. Retention time: 2.84 min.
The following compounds were prepared in a similar manner:
LCMS
Ex. No. Structure MW M 1 Rt CH

H
N
N

4A N CH3 382 [ 383 2.68 ' E e 4B Ãa,CO c 340 1 341 2.27 ra 3 F-r 4C* N 1 227 228 2.76 CHg !EiI CH

H

4D N CH3 368 369 2.50 1 if O
OM

4E N CH' 386 387 3.02 329 1 2.40 N cH3 328 ------------------= N

4G H3co 326 327 2.02 UOH

H
= N N, N
4H H3CO 326 327 2.36 o CH3 ------------------- ----N NN
41 H3C 340 341 2.38 N
N

cH 340 341 2.16 H
= ` N
N

4K cH3 378 379 2.78 f Ã~ Ã
CF

[ CH3 4L H3CO 326 327 1.90 f H
N

4M H3CO 378 379 2.85 UCF
* 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 C overnight:

F-I N N
N
H3co 4N NH CH3 416 417 3.08 H [
N`N

40 NH CH3 362 363 2.74 OCH

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:

LCMS , Rt Ex. No Structure MW

H

}
CH3 OH _1 H

4C = ! f j 270 271 2.07 CH '' CH CH3 H
N i l 4RH cH3 362 363 0.66 E f N N%

4S 376 377 2.82 H
N
4T H3CO 320 321 2.46 r Q CH3 4U H3CO 348 349 2.76 H3Cd _._ ...... ___ The following compound was prepared in a similar manner, using dioxane as the solvent without KI:

Ex. No. Structure Midi ~ LCMS R
+ 1 N
*

4V CH 325 326 2.47 C") 3 N

Example 5 CH3.0 H2N neat 00- 5 A mixture of compound 1-5 (41 mg) and 4-aminomethyltetrahydropyran (400 mg) was stirred at 125 C overnight. The reaction mixture was cooled to room temperature and water was added. The mixture was filtered and the precipitate was purified by silica gel column chromatography (hexane-EtOAc) to give compound 5 (16 mg). The mono HCI salt was prepared by adding -1 equivalent of HCllether to a solution of compound 5 in ether and then evaporating to dryness. .CMS: M is 340. m/z 341 [M+H]+. Rt is 2.23 min.
The following compounds were obtained in a similar manner:
LCMS
1 Ex. No. 1 Structure Mw M+1 R~
N NON
5A 300 301 2.32 C)__ N
SS CH3 296 297 2.28 Cod H

5C H3CO 324 1 325 2.71 }~ CH3 H

5D H3co 310 311 2.61 ( CH3 H

3CO 338 339 2.88 N N

C 326 327 2.31 H3 jt i } {

5G H3cO 354 355 2.43 f CH3 H
5H H3CO 326 327 2.21 NH 3 Oa H
N
51 H3CO 324 325 2.82 ~ ~ UCH f 3 CH3 N N*

N

339 340 9.59 NH CHs HC

CH3 N, N

5K cH3 326 327 2.09 OH

N H
N~

5L H3CO 328 329 2.49 (N) CH3 H
5M H3CC 342 343 .9 N CH

HO O

H
N N=
5N ' 296 297 2.14 [ 0 j 50 H3CO 340 341 2.1 N CH

HO

N H

5P H3CO 340 341 2.05 H
N

5Q N CH3 339 340 e53 s H

N NI iN
HsC(3 SR NH CH3 341 342 1.81 o HNJ

i i N N

5S NH CH3 339 340 1.61 N
H

N N
N
ST H3CO 325 326 j 1.89 E

HN

N N.
N
5U Sr 431 431, 433 3.39 CHs (N) O

CHs H E 1, E
N
iN

5V NH CH3 333 334 2.6 N N, [ , t N
H3CO ~ / ~ t ~ ~ III
5W ~ ~ 333 334 2.O4 3 ~
3 ` N

H

N 5X H3cO 347 348 2.13 CIN' NH CH

5Y H3CO 347 348 1.86 NH CH3 [
Example 6 H

H HC[
N NEt3, DMSO
C} 125"C

A mixture of compound 1-5 (50 mg), homomorpholine hydrochloride (200 mg), triethylar ine (-200 mg) in DMSC (1 mL) was stirred at 125 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-McOH to give the compound 6 (5 mg). The mono HCI salt was prepared by adding -equivalent of HCI/ether to a solution of compound 6 in ether and then evaporating to dryness after 1 hr. LCMS: M is 326. Found: m/z 327 (MH). Rt is 2.4 min.

The following compounds were prepared in a similar manner;
~
Ex. No. Structure MW LCMS
1 1+1 Rt 314 315 2,47 N o - - ----------------------r ' 314 i 315 ~ 2.20 N c l I I
F

IIIN
6C F cH3 318 319 2.91 Cz Hs H
6D 310 311 2.33 6E 1-Pr ca3 324 325 2.60 I E l CH 3 ~T-, N

N6F 330 331 2.33 !
Cl N CH3 I i E
O

N
N
(~ = =4 i ' '3CO

i N CH3 ~
H

6H N CH3 353 354 2.00 N H
NON
61 H,CO 340 341 2.19 N N
%
= N

N Cat, 350 351 2.55 OCF

= / N
6K Br 445 445,447 2.53 3 Ã

q cH 326 327 2.08 N

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

LCMS
Ex. No. Structure MW
Rt Br H
N`
IN
6L 361 361,363 1 2.43 N CHg The following compounds were prepared in a similar manner, using NMP as the solvent and (i-Pr)2NEt as the base:

Ex. No. Structure MW LCMS
M+1 R

H
Nj N
6M ct 330 331 I 2.52 CH
NH a o N Ni N

ci 330 331 2.31 t E
D

Br T
N
60 361 361, 363 2.2 NH C~3 o H
N N

6P F13C = / 375 375, 377 2.77 (N CH,, Example 7 N N
_ `N

(N CH3 H
N
OMe HCI
` N` NON 7 I
MeO K2CO3 cl CH3 Phenol 7_1 A mixture of compound 7-1 (92 mg), homomorpholine hydrochloride (74 mg), K2CO3 (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 vacua. 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:

LCMS
Ex. No. STRUCTURE MW
1 Rt N N

7A CH3 355 356 1.84 O

H C.
CH3 ~ ! s N N

H3co 7B NH CH3 385 386 1.62 E ~ j!
HO NV
------------------------- i~-H3C N` N
!~N
7C 310 311 2.05 N
I I !=N
7D H0 312 313 1.98 OD
CH3 i N N

NH CH 3 345 346 1.81 HN

H
NON
cl Q
I .0 N J
t-BU

Example 8 H
N Na H3C,0 (N) I

I
02s, pyridine CH2cl3 A mixture of compound 3 (0.15 g) and DCM (10 mL) was treated with pyridine (50 L) and then CH3SO2CI (50 L). After 24 hr, additional pyridine (25 L) and CH3S02Cl (25 .iL) were added. After 2 hr, the reaction mixture was concentrated and purified on silica gel plates (2, 1000 .L) 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 ) and eluted as above to give additional compound 3 as a yellow solid (0.028 g). LCMS: M is 389.
Found M+1 is 390 at 0.79, 2.04 min.

The following compounds were obtained in a similar manner:
i Ex. No. Structure ' Mitt/ MS Rt 8A ~ H3CO
N CH3 J 403 404 E 2.09 (uv) 3 ~

E
8B c1 CH3 408 408, 410 31 2.45 (uv) CN) SO2CH

H
N

403 404 2.25, 2.37 C
SO CH

Example 9 N N.
H3C.o el N

A solution of 3Q (59 mg) in DCM (1 mL) was treated with trifluoroacetic acid (0.33 mL). After 1.5 h=r, the reaction mixture was concentrated in vacuo. DCM
was added and concentrated in vacuo (twice). The residue was partitioned between DCM
and 2.5N K2CO3 solution. The organic layer was dried (K2CO ), concentrated in vacuo, and the residue was purified on silica gel plates (2, 1000 u) eluting with DCM:MeOH:NH4OH (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 N N N. N.
N N
H3C,0 H3c,0 HN y NH2 HN . NH2 QB

Trimethylsilyl isocyanate (55 .L) 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 vacua to give a yellow solid (142 mg). This solid was purified on silica gel plates (4, 1000 u) eluting with DCM:MeOH (9:1) to give a yellow foam (92 mg). This foam was purified on a reverse phase HPLC column (10 t; 30 x 100 mm) eluting with 0.1 %
HCO2H in CH3CN / 0.1 % HCO2H 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:

I Ex. No. Structure I MW -CMS Rt M+1 CH3 i i f I ~ / 'N

10C 354 355 0.79, (N) CH3 1.92 N

H
N
H3CO - f f N CH3 368 369 1.97 (uv) CD

NH

H

CH3 368 369 1.99 (uv) (N) N H
N.
N
IN Z
C[
10F N CH3 358 359 1.90 (uv) N

----------------- - - - - - -------------- ----- --N N.
N
I
1OG CI N OH3 372 373 2.03 (uv) CD
ON
NH?

cl l 10H N CH3 372 373 2.00 (uv) N cH3 O NHz Example 11 N

N CHa Step 1:

N H
C N N
114, N

Bic CN CH3 ~
N
I
Boo Compound 1-5 was treated with N-Soc-piperazine in a similar manner as described in Example 3 to give compound 11-1 as a brown solid (104 mg), which was used in the next step without purification. LCMS: M is 411. Found: M-1 is 412 at 2.88 min.

Step 2.-Mel, K2CO3 80 C H3C'0 ILA -~-~-ilp (N)CH3 N
BOC
u-Under a nitrogen atmosphere, a solution of 11-1 (100 mg) in CH3CN (3 mL) was treated with freshly ground K2CO3 (168 mg) and then CH3I (90 L). After 1 hr, additional CH3I (100 ml_) and CH3CN (1.5 mL) were added. After 2.5 hr., additional CH3I
(100 L) was added. The mixture was heated at 60 C for 18 h. The reaction mixture was purified on silica gel plates (4, 1000 it) eluting with DCM:MeOH 9:1 to give an amber oil (70 mg).
This oil was purified on silica gel plates (2, 1000 .) 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 1.L) was treated with trifluoroacetic acid (250 L). After 35 min, the reaction mixture was concentrated in vacua. DCM was added and the mixture was concentrated in vacuo two times. The residue was partitioned between DCM and 2.5N K2CO3, The organic layer was dried (K2CO3) and concentrated in vacuo. The residue was purified on a silica gel plate (1000 lt) eluting with DCM:MeOH:NH4OH (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:

Ex. No Structure Mw L~CMS Rt N N

11A C3 338 339 3.48 N N

JIB H3CO CH3 352 353 4.11 11C H3CO 340 341 2.33 O

Example 12 H
N"N
HO

C) N

Step 1 48% HBr CH3 H H
1-5 / 1fl{1C NON
Ht) :12--1 Compound 1-5 (1.0 g) was treated with 48% {Br 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.
Stet 22:
CH CH Ac H H Ac2 H 1 N NprSA / N N.
3 Ac. ~N

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 CH3 H Ac CH3 Ac N N Oxalyl chloride N` N.
Ac ,0 f*N CHZC'2 Ac. 11 N
.Q = 0 0 CH3 cl CH3 12,!.2 23 A mixture of compound 12-2 (0.52 g) in DCM (30 mL) was treated with oxalyl chloride (2.4 ml-) and stirred at RT for 4 hr. The reaction mixture was concentrated in vacuo to give a light tan residue. This residue was triturated with diethyl ether, then filtered to yield compound 12-3 (0.46 g) as an off white solid. LCMS: M is 331. M+1 is 332 at 4,41 min.
Step H3C - N \õ./NH
12-3 .12 PhCF3 dioxane 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 ) eluting with DCM:MeOH (9:1) to give a yellow solid (0.27 g). This residue was purified on silica gel plates (2, 1000 .t) using DCM:MeOH:NH40H (90:10:1) as the solvent to give a yellow solid. The chromatography was repeated using silica gel plates (4, 1000 t) 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 H
H3Co o"'J 13 Step 1:

KCN, DMSO, N H
N

A solution of compound 15 (4.6 g) and KCN (12 g) in DMSQ (120 mL) was stirred at 110 C overnight. The reaction mixture was cooled, diluted with water and filtered. The precipitate was washed with water, ether and DCM to yield compound 13-(-3 g). LCMS: M is 252. Found: m/z 253 (MH) Step 2:

DISAL jb~N_ N
toluene ,N

M- gC Ho CH3 iz DIBAL (42 mL, 1 M 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 C with MeOH (19 mL), and then saturated aqueous NH4CI (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 (Na2SO4) 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:

NaBH(OAc)s 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 (MgSO4) and evaporated to dryness. The crude material was purified by HPLC (CH3CN-H20, 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 (MHO'). Rt is 2.20 min.

The following compounds were prepared in a similar manner:
LCMS
Ex. No. Structure MW M+1 R#
CH

s NH

13A cH3 340 341 2,25 N
[I f H

N H
N
13B H3CO 342 343 2.2 N

N_ H

j I H3Co 13C3 CH3 354 355 2.26 N

~

N

2.58 N

H
N N i i !N

392 393 2.67 N
. f f E
N
13F r~3ca ~~
340 341 2.06 N
H

CHg N
13G H3CO 326 327 1.93 H
N

13H H3CO CH3 324 325 2.08 131 H3CO le I
310 311 2.21 H
N N
H

H N

13K 326 327 2.19 CH

H
1 i N N

325 326 2.02 N
HN

H
l r N N
13N CO '.N 340 341 1.92 N

1 r N. N, j N

130 CH3 340 341 2.02 HN [
!

N, N

13P H3co CH3 339 340 2.20 HN, J

cH3 N H
H3co 13Q ( CH3 339 340 2.16 rN
HN

H

13R cH3 356 357 2.04 N

OH

H
Ni N

13S H3C 'N 340 341 2.24 H

13T CH3 324 325 2.18 ell%

(Ã i 0 3 SÃ{

N
13U F3C CH 364 365 2.38 111 Ã

H
N
I N.
13V Br 459 459,461 2.82 Cti3 N

Example 14 H
HO

0j 14 A mixture of AICI3 (1.02 g) and DCE (30 mL) was cooled to 0 C. EtSH (760 pl...) was added dropwise. The resulting solution was stirred at 0 mC for 10 min, then a mixture of 13S (351 mg) and DCE (30 ml_) was added. The solution was warmed to RT
and stirred 3 h, H2O (150 m) and sat aI CO3 (150 mL) were added. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacua to give compound 14, which was used without further purification.

Example 15 H
N N, MeO, of 15 A mixture of 14 (32 mg), K2CO3 (31 mg), 2-bromoethyl methyl ether (10 pL) and DMF (2 mL) was heated at 80 C for 3 h. H2O (15 mL) was added and the mixture extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacua. 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. NaHCO3 and the product extracted with EtOAc, The organic extract was dried (MgSO4) and concentrated in vacua 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 H
N, N.
/
N
MeO

OH

Step HCI H PoSr3 H
MeOH Na DMF N.
1-5 OM t Meo A MeO
OH Br 16 --1 iu-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 vacua. H2O (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, POBr3 (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. NaHCO3 (50 mL) was added slowly.
H2O (200 ml-) was added and the mixture was filtered. The filtrate was dried at 50 C 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-Cl SEM 1) n-BuLi, THE SEM
THE = N N' -78 C

moo CHO Meo Z) Br OH
N N /
-78 Ctort 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 THE (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 NaHC03 (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 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 THE (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 nC for 45 mire, then allowed to slowly warm to RT
over 1 h.
The solution was stirred at RT for 12 h, whereupon H2O (20 ml-) was added. The mixture was extracted with EtOAc (2 x 30mL). The combined organic extracts were dried (MgSO4) 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), HCl (2 mL), H2O (4 mL), and EtOH (4 rnL) was stirred at RT for 24 h. Sat. NaHCO3 was added until the pH was 7. The mixture was diluted with H2O (50 mL), cooled to 0 'C, and filtered. The precipitate was purified by reverse phase HPLC, eluting with 0.1 % HCOOH in CH3CN 10.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were combined, neutralized with sat NaHCO3, and extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacua 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 H
N` N.
N
MeO

SEM
IBX N N~ HC[, H2O
DMSO =N MeOH
6-4 ---~P MeO - --- - 7 A
O
N

IZA
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 H2O (3 x 10 mL).
The organic phase was dried (MgSO4) and concentrated in vacuo to give 17-1. The residue was used without further purification. A mixture of 17-1, HCl (250 pL), H2O
(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. NaHCO3 (2 ml-) and H2O (10 ml-) were added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC, eluting with 0.1 % HCOOH in CH3CN 10.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give 5 mg of compound 17 as a yellow solid. LCMS:
M is 332. Found: M+1 is 333, Rt = 3.57 min.

Example 18 H
N N~
N
Meo F

SEMI
N DAST , N HC1, H20 CH2C 2 I / N McOH
16-4 3.= Meo -M--30- 18 A
F
N
i1 DAST (5 drops) was added via syringe to a solution of 16-4-4 (12 mg) in CH2CI2 (2 mL). The resulting solution was stirred at RT for 5 min, then sat. NaHCO3 (2 mL) and H2O (10 mL) were added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give 18-1.
The residue was used without further purification. A solution of 18-1, HCl (250 pL), H2O
(500 pL), and EtOH (500 pL) was stirred at RT for 2 h, then at 75 C for 30 min. Sat NaHCO3 (2 mL) and H2O (10 mL) were added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacua. The residue was purified by reverse phase HPLC, eluting with 01% HCOOH
in CH3CN / 0.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat, NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give 1 mg of compound 18 as a yellow oil. LCMS: M is 336. Found: M+1 is 337, RE = 2.68 min.

The following compounds were prepared in a similar manner:
E . No, Structure MW CMS
H
N N.

18A Meo 365 366 4,92 ` F

Meo H
NN

18B Meo 336 337 3.71 F

N

N N.
N
18C Meo 363 364 4.90 i 18D mM 395 ( 396 4.54 F

444i ~ M~ ~ JE

Example 19 H

H2Ni 0 19 A mixture of compound 13-1 (7 mg) in conc. H2SO4 (-400 [LL) was heated at 60 C for 3 days. The mixture was cooled and added to ice water. The resulting solution was neutralized with 15% NaOH solution and filtered. The precipitate was washed with DCM and then recrystalized from MeOH to afford compound 19 (1 mg).

Example 20 H
Ny N C H3 NH ( Z N
o. OH

Step 1:

r-O H r-O
KCO3 N N, + H2N N Cu powder ~N
N
CO2H H2O, reflex ic02H
20- 22-2 z k.3 A mixture of 1-iodo-3-methylbenzoic acid, 20-1, (5 g), 1-benzyl-3-methyl-lH-pyrazol-5-amine, 20-2, (3.93 g), K2CO3 (2.64 g) and copper powder (0.61 g) in water (20 mL) was heated at reflex overnight. The resulting mixture was cooled to RT.
The pH
was adjusted to 14 with 1 N aqueous NaOH and the mixture was extracted with CH2CI2.
Concentrated HCl 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 C to give 20-3 (3.05 g). LCMS: M is 321. Found: MH} is 322. The solid was used without further purification.
The following compound was prepared in a similar manner.
H r-O
MeO , N N' Meo CO2H

Step 2 20-3 Poct N
-Jim- `

Cl A mixture of 203 (3.05 g) and POC13 (5 mL) in a 50 ml round bottom flask was purged with nitrogen and heated at 100 C for 2 h. The mixture was concentrated in vacua at 70 C . Ice was added to the mixture and the pH was adjusted to -8 with 20%
NaOH. The mixture was extracted with CH2C12, dried (MgSO4), and concentrated in vacua. The residue was purified by column chromatography on Si02, eluting with a gradient of 0 to 10% EtOAc in hexanes to afford 184 mg of 20-4. LCMS: MW is 321.
Found: MH+ is 322.

The following compound was prepared in a similar manner. r - O-Z

Mao N N
Meta CI
Step 3:

N
NH2 , N
NH
o c 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 CH2CI2, dried (MgSO4), and concentrated in vacua. The residue was purified by column chromatography on Si02, eluting with a gradient of 0 to 3% MeOH in CH2CI2 to afford 216 mg of 20-5. LCMS: M is 386.
Found:
MH+ is 387.
The following compound was prepared in a similar manner.

moo N~ N
\ I N
Meo (JNH
a 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 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 C for 36 h. The mixture was filtered and concentrated in vacua. Aqueous NaHCO3 solution was added to the residue. The resulting mixture was extracted with 10% MeOH in CH2Cl2, dried (MgSO4), and concentrated in vacua. The residue was purified by column chromatography on Si02, eluting with a gradient of 0 to 5% MeOH in CH2CI2 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:
Mefl N` N`
,o, tN
AeO

O NH

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

Example 21 CH3 4I_0Me N No N H
N N N N.
CI N
N CE
Cl N
o Step 1:

MeO MeO

N N / N. N, 6~N._ N.
1 4e Cl Cl Cl CE CI l 21-1 . 21-2 . .:

MeO Me0 I I
1. n-BuLi, THF, -78 C CH3 .. + CH3 2.DMF,-78 aCtoRT
N
N N
CE N *
CE
CHO
21-4 ZõA
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 C for 1 hr. DMF (0.32 mL) was added.
The mixture was slowly warmed to RT over a 2-hr period. Additional DMF (1 rL) 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 (MgSO4) and concentrated in vacua. The residue was purified by column chromatography on Si02, eluting with a gradient of 0 to 10% hexane in EtOAc to afford 2.4 mg of 21-A (LCMS: M is 351.
Found:
Mt-t"' 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.

Stye 2:

1. Et3N, NaBH(OAc)31 N N
CH2CI2, RT N
2. TEA, ref[ux Cl = ) / `
Y Wig A mixture of 21-4 (500 mg), 2-methylmorpholine (266 mg), Et3N (0.74 mL) and NaBH(OAc)3 in CH2Cl2 (30 mL) was stirred at RT overnight. The reaction was quenched with 1 N NaOH, extracted with EtOAc, dried (MgSO4) 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 vacua, treated with saturated aqueous NaHCO3, extracted with CH202, dried (MgSO4) and concentrated in vacua.
The residue was purified by column chromatography on Si02, eluting with a gradient of 0 to 2% MeOH in CH2CI2 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 ~H S Rt =~ INV

210 cl 344 345 2.53 ~~ - _ Cl 21 E CH3 421 422 2,77 CHI N

o 0 CT

H
N
21F ci 314 315 235 Example 22 H
~ f r CI

Cyciopropyl magnesium bromide (1 mL, 0.5 M in THF) was added to a suspension of 21-4 (93 mg) in THF at -40 C and stirred for 1 hr. The mixture was warmed to RT, treated with saturated aqueous NaHCO3 solution, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on Si02, 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 vacua, treated with saturated aqueous NaHCO3, extracted with CH2Ci2, dried (MgSO4) and concentrated in vacua, The residue was purified by HPLC to afford 10 mg of 22. LCMS: M is 301. Found: MH*
is 302, Retention time: 3.43 min.

Example 23 H
N NN
CI
N

~NCH3 23 LAH (0.46 mL, 2M in THF) was added to a solution of IF (117 mg) in dioxane (1 mL) at 0 C dropwise. The reaction mixture was warmed to RT, stirred for 10 min, and heated at 100 C for 3.5 hr. The mixture was cooled to RT, and treated with H2O (0.02 mL), 10% NaOH (0.03 mL), and H2O (0.02 mL). The resulting mixture was diluted with CH2CI2, stirred for 90 min, filtered and concentrated. The residue was purified by column chromatography on Si02, eluting with a gradient of 0 % to 10% MeOH in to afford 9.5 mg of 23. LCMS: MW is 359. Found: MH+ is 360. Retention time:
1.97 min.
Example 24 CH3 Boc N
JPN
MeC

OH

CHa Boc [. n-BuLi/THF 24 TEA N N!
SOC2 = ! 9 N 2. 24 DMA P M eo os- c THE Br TEA (0.23 mL), DMAP (27 mg), and Boc2O (0.36 mg) were added to 16-2 in THE
(20 mL) and stirred at RT overnight. The reaction was quenched with 10%
aqueous Na2CO3 solution, extracted with EtOAc, washed with 10% aqueous NH4CI solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on Si02 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 (0.51 mL, 1.6 M ), and tetrahydro-2H-pyran-4-carbaldehyde (93 mg) in THE (8 mL). LCMS: MW is 441. Found: MH+: 442. Retention time: 4.65 min.

Example 25 }
MeO

OH

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 CH2C12 and aqueous NaHCO3. The organic layer was dried (MgSO4) 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
p N
\

OH

StG~1:
H
N N
n-But[, THE N
0 CHo Br off 26-1-'1 . td 8oc aoc 29-1 n-BuLi in hexane (1 mL, 1.6 M) was added to a solution of 16-2 (50 mg) in anhydrous THE at -78 C dropwise. After stirring for 1 h, a solution of 26-1 (175 mg) in THE 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 H2O. The solution was warmed to RT, extracted with EtOAc, dried (Na2SO4), 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 CH2CI2 (1 mL) was stirred at RT for 1 h. The mixture was concentrated and partitioned between EtOAc and aq. sat.
NaHCO3.
The organic layer was dried (Na2SO4) and concentrated. The residue was washed with ether, and recrystalized from CH2CI2 to afford 26 (7,5 mg). LCMS: M is 340.
Found:
Ma-1 is 341, retention time: 2.12 min.

Example 27 H
N N, \ OH

N H
N! n-8uL'[, THE
` .= / N 10 0 p-F-PhCHO
Br ii n-Bum in hexane (2 mL, 1.6 M) was added to a mixture of 16-2 (200 mg) in anhydrous THE 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 H2O, warmed to RT, and extracted with EtOAc. The organic layer was dried over Na2SO4 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 ES-MS Rt N
{

27A H3co N
cH3 333 334 3.48 E
OH I

H
N NN

27B 363 1 364 3.24 H
N

R
27C H3CO 334 335 2.12 N

N N
~*N
27D H3CO 335 336 2.71 N OH

N

H
N N

27E H3co 347 348 3,54 \ OH
is s CH3 CH3 361 362 3.95 OH

Nt 27G 3C CH3 393 394 3.33 OCH
CH3 ._.~
N N
N I i 27H H3CO 375 376 4.10 OH

H
l 1 ~

CO ` CH3 401 402 4.47 Example 28 H
N, N.
Meo o A mixture of 27A (12.7 mg) and Dess-Martin periodinane (19.4 mg) in CH2CI2 was stirred at RT for 2 h. The mixture was treated with saturated aqueous NaHCO3.
The organic layer was dried over MgSO4 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 o Meo ZA

Example 29 }{ N H

Step 1:

PdCl2(PPh3)2, Cut, N N.
H J6~14_ diisopropyiamine, N
N toluene H3CO

Br N
N
1 i A

A mixture of 16-2 (100 mg), 2-ethynylpyridine (41 mg), PdCl2(PPh3)2 (19.4 mg), Cut (5,3 mg), diisopropylamine (1.5 mL) in toluene (-3 mL) was degassed and charged with N2. The mixture was heated at -90 C overnight. The resulting mixture was cooled and filtered. The precipitate was washed with CH2CI2, 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 H2 (1 atm) at RT for 2 days. The mixture was filtered and washed with CH2CI2. The filtrate was concentrated. The residue was purified by HPLC (CH3CN-H20, 0.01 % HCOOH, 10% to 100% gradient) to yield 29B (9 mg), LCMS: M is 332. Found: M+1 is 333, retention time: 2.25 min, The following compounds were prepared in a similar manner:
Ex No. Structure i ___ MW ES-MS ~___Rt CH, N N.

29C CH3 327 328 0.20 N

331 332 8.82 T99 1 !

H
N

29E CH3 328 329 3.84 3i N
-------------H
N
` !N

NH3CO 29F p GH3 332 333 2.21 iN

H
N
N

29G CH3 357 358 5.00 ___~ OC H3 N H
N.
[ H3C0 CH3 29H 361 362 3.75 ------ ocH

N
IN

( II CH3 357 358 5.25 OCH

H
N NN

29J cH3 J 361 362 3.80 OCH

346 347 2.19 MHz Example 30 jN N
Q

HN o 0~,IN 30 To a mixture of 16-2 (500 mg) in anhydrous THE (10 mL) in a microwave vial was sequentially added 4-(aminomethyl)pyridine (540 mg), DBU (760 mg), Herrmann's catalyst (40 mg), t-Bu3P=HBF4 (30 mg), and Mo(CO)e (440 mg). The mixture was sealed, purged with N2, 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 MeOH, and followed by HPLC (CH3CN-H20, 0.1 % HCO2H) 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 `1 N

30A 354 355 2.94 HN o S ~ Ã i E

Example 31 FH
\ ,- /r o`

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 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 N, N
N, N
N IN

kH 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 15 (100 mg). The mixture was sealed, purged with N2, 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 THE at -78 C 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. NH4CI (200 uL). The mixture was warmed to RT and partitioned between 1 N NaOH and EtOAc. The organic layer was dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel column chromatography to yield compound 32B (-1 mg). LCMS: M is 308. Found:
miz 309 (MH+), retention time: 2.22 min.

Example 33 H
I s XN
N Meo A mixture of 16-2 (133 mg), 4-pyridineboronic acid (80 mg), Pd(PPh3)4 (96 mg), Na2CO3 (40 mg), toluene (8 mL), EtOH (2 mL), and H2O (2 mL) was heated in a microwave reactor at 120 C for 1 h. Sat. NaHCO3 (15 mL) was added and the mixture extracted with EtOAc (3 x 20 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 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 CH3CN / 0.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) 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 NN N, Meo MeO

34A 3,4B
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 NaHCO3 (10 mL), brine (20 mL), and EtOAc (30 mL) were added. The phases were separated and the organic layer washed with H2O (2 x 20 mL). The organic layer was dried (MgS04) and concentrated in vacua. 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 CH3CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacua 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 16-2 (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 H2. 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 CH3CN 10. 1 % HCOOH in water (10% to 95%
over 20 min). Fractions possessing the product were neutralized with sat NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacua 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 H
N.
i i ,n1 Meg]

Step Br 1) n-BuLi, THE
-78 C B(OH)2 2) B(OMe)3 /
-78 C +
N TIPS 3) McOH N

A solution of 35-1 (TIPS is triisopropylsilyl) (1.35 g) in THE (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 C for 1 h, whereupon a 1:1 solution of MeOH and H2O (4 mL) was added. The mixture was warmed to RT and H2O (20 mL) was added. The mixture was extracted with Et2O (3 x 40 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to obtain 35-2.
Step 2:

H
16-2 N` N' /N
l u- Pd(PPh4)3, Na2CO3 Meo PhCH3, EtOH, H20, A
microwave 35-3 NTIPS
A mixture of 16-2 (300 mg), the crude 35-2, Pd(PPh3)4 (96 mg), Na2CO3 (40 mg), toluene (8 mL), EtOH (2 mL), and H2O (2 mL) was heated in a microwave reactor at 120 C for 1 h. Sat, NaHCO3 (15 mL) was added and the mixture was extracted with EtOAc (3 x 20 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 25% EtOAc in hexanes to give 35-3.
Step 3:
Compound 35-3 (167 mg) was dissolved in THE (10 mL) and TBAF (1 M solution in THF, 450 AIL, 0.45 mmol) was added. The mixture was stirred at RT for 30 min.

(30 mL) was added and the mixture was extracted with EtOAc (3 x 30 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 35%
EtOAc in hexanes. The residue was purified by reverse phase HPLC, eluting with 0.1%
HCOOH
in CH3CN 10.1 % HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacua to give 14 mg of 35 as a yellow solid. LCMS: M is 292. Found: M+1 is 293, Rt = 2.89 miry.

Example 36 H
N N
/N

N N ` LDA, NaH, THE
+ N OP 36 N -78 - rt Br To a cold (0 C), stirred solution of diisopropyl amine (135 mg) in anhydrous THE
(5 mL) was added n-BuLi (0.81 mL of 1.6 M solution in hexane) dropwise via syringe.
After being stirred at 0 C for 20 min, the solution was cooled to -78 C and methylpyrimidine (118 mg) was added dropwise via syringe. The resulting solution was stirred at -78 C for 1 h.
In a separate flask, 36-1 (150 mg) (prepared in a manner similar to compound 16-2) was dissolved in anhydrous THE (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 NH4CI (10 mL) followed by dilution with H2O (20 mL),. The resulting layer was extracted with CH2CI2 (3 x 20 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give a residue which was purified by column chromatography on silica eluting with 30:1 CH2CI2: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:

Structure LCMS
Ex. No. I mw M+l H
N NON
36A F3CO 372 373 2.59 N
Nt j ~Ã !7 36B ( F3CO 406 407 ' 4.65 Cl N

36C F3CO 386 387 2.78 36D [ 402 403 4,11 OMe H
N N
i i N
= l /

36E 403 404 4.35 I I

OMe H
N N
f j F3CO

36F 458 459 4.15 NYN

H
N

36G 442 443 3.11 Y
N

N H [
N

36F1 441 442 2.90 N 1 f E
f N
N
I ', ! I

386 387 2.83 N
i s 36H F3CL) tlN
403 404 4.59 N
t f E

N Cie N

361 417 418 [ 4.42 3 Y
OEt H
N
N N, N
N
..
36J Fsoo 373 374 415 N;N

H

N
N
36K F 3CO 373 374 3.72 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 and Practice of Pharmacy, 20th 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 parenteraf injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 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 l or 11 can be determined by the following procedures.
In Vitro PDE10 assay PDE1OAI 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',8-3H]Adenosine 3',5'-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in mM Tris-HCI, pH 7.5, 8.3 mM MgCl2, 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 MI. 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 g 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, 5M, 50, 5Q, 5R, 5S, 6H, 7A, 7B, 7E, 8, 8A, 8B, 8C, 9; 1 OA, 1OC, 1 OD, 1 OE, 1 OF, 10G, I I OH, 13, 13-1, 13A, 13B, 13C, 13D, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 130, 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 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, SF, 5K, 5M, 50, 5Q, 5R, 5S, 6H, 7E, 8B, 8C, 9, 10A. "IOC, 10D, 10E, 1 OF, 1OG, 10H, 13, 13A, 13C, 13F, 13G, 131, 13J, 13K, 13L, 13N, 130, 13P, 13Q, 13R, 13S, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 26, 27, 27A, 278, 27C, 298,. 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, 5T, 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

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein and the carbon atoms to which it is attached form a phenyl ring, a heteroaryl ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5-membered heteroaryl containing two heteroatoms, R2 is absent;
R1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2, -N(R6B)2, -alkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)SO2-alkyl, phenyl, CN, -SO2R6, -SR6, trimethylsilyl-, -SF5, -OSF5, -C(=NOR6)-R6, , or -(CH2)n-X-(CH2)m-R18, wherein X is -O-, -S-, or -NR6-, n is 0, 1 or 2, m is 1, 2 or 3, and R18 is selected from the group consisting of R2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2, -N(R6B)2, -alkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)SO2-alkyl, phenyl or CN;
or R1 and R2 on adjacent ring carbon atoms together form -O-CH2-O- or -O-(CH2)2-O-;
R3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R6B)2, -OCF3, -CF3, -SF5, -OSF5 or -CN;
R4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, -SO2-alkyl, -C(O)N(R6A )2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;
R5 is alkyl, -CN, -C(O)OR6A, -C(O)N(R6A)2, aryl-((R17a,R17b)-alkylene)-, heteroaryl-((R17a, R17b)-alkylene)-, heterocycloalkyl-((R17a, R17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, arylalkynyl-, heteroarylalkynyl-, bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, -alkyl-O-heteroaryl, -alkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R6)-aryl, -alkyl-N(R6)-heteroaryl, -alkyl-N(R6)-cycloalkyl, -alkyl-N(R6)-heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocycloalkyl-heteroaryl-alkylene-, cycloalkyl, b is 1, 2 or 3;
r is 1 or 2;
t is 0, 1 or 2;
each R6 is independently selected from H and alkyl;
each R6A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two R6A 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 R6B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, aryalkyl-, heteroarylalkyl-, -SO2alkyl, -SO2-aryl, -SO2-heteroaryl, -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-heteroaryl, -C(O)N(R6)2, -C(O)NR6-aryl, and -C(O)NR6-heteroaryl; or two 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;
R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =O;
R11 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 -(CH2)2-6- or -O-(CH2)2-O-;
R12 is 1 or 2 substituents independently selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl;
R13 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, -C(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R6A)2, -C(O)-alkyl-NR6-C(O)-aryl, -C(O)-alkyl-NR6-C(O)O-alkyl, -C(O)-alkyl-NR6-C(O)O-benzyl, -SO2alkyl, -SO2-aryl, -SO2-alkylaryl, -SO2-heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with halo;

R14 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(O)O-aryl, -C(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, -C(O)N(R6A)2, -C(O)-alkyl-NR6-C(O)-aryl, -C(O)-alkyl-NR6-C(O)O-alkyl, -C(O)-alkyl-NR6-C(O)O-benzyl, -SO2alkyl, -SO2-aryl, -SO2-alkylaryl, -heteroaryl or diphenylmethyl, optionally substituted on a phenyl ring with halo;
R15 is 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, OH, hydroxyalkyl, halo, -CF3, -C(O)Oalkyl, -C(O)N(R6A)2, aminoalkyl-, -N(R6B)2, -NR6-C(O)N(R6A)2, -NR6-C(O)-alkyl, -NR6-C(O)Oalkyl, -NR6-SO2-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 -(CH2)2-6- or -0-(CH2)2-O-; and R17a is H or alkyl and R17b is H, alkyl, OH, F, -N(R6B)2, -NOR6, alkoxy, CN, -CH2OH, -CH2-O-alkyl, -CON(R6a)2, -CH2N(R6)2 or -CO2R6;
or R17a and R17b are each F;
or R17a and R17b are on the same carbon atom and together are =O, =NOR6 or -(CH2)2-6;
provided that when R5 is heterocycloalkyl-((R17a, R17b)-alkylene)- and the heterocycloalkyl ring is joined to the alkylene group by a ring nitrogen, the R17b substituent on the .alpha.-carbon is H, alkyl, CN, -CH2OH, -CH2-O-alkyl, -CON(R6a)2, -CH2N(R6)2 or -CO2R6.

2. The compound of claim 1 wherein forms a phenyl ring.

3. The compound of claim 1 wherein R1 and R2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.

4. The compound of claim 1 wherein:
R1 is alkyl, and R2 is alkoxy; or R1 is alkyl and R2 is -OCF3; or R1 is alkyl and R2 is H, OH, halo or alkoxyalkoxy ; or R1 is alkoxy and R2 is alkoxy or H; or R1 is alkoxyalkoxy and R2 is H; or R1 is halo and R2 is H; or R1 is halo and R2 is -OCF3; or R1 and R2 together are methylenedioxy.

5. The compound of claim 1 wherein R3 is alkyl or H, and R4 is H, -C(O)O-alkyl, or -SO2alkyl.

6. The compound of claim 1 wherein R5 is selected from the group consisting of -CN, -C(O)N(R6A)2, aryl-((R17a, R17b)-alkylene)-, heteroaryl-((R17a, R17b)-alkylene)-, heterocycloalkyl-((R17a, R17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyl-, heteroaryl,

7, The compound of claim 1 wherein R5 is -CN; -C(O)NH-alkyl-pyridyl;
-CH(OH)-phenyl; -alkylene-phenyl, -alkylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyl;
-CH(OH)-pyridyl; -CH=CH-(CH2)3-OH; -CH=CH-pyridyl; -C.ident.C-pyridyl; wherein R14 is H, alkyl or hydroxyalkyl, wherein R14 is H or alkyl;

heterocycloalkyl-((R17a, R17b)-alkylene)- selected from the group consisting of heterocycloalkyl-((R17a, R17b)-alkylene)-, wherein R17a and R17b are independently H or alkyl, selected from the group consisting of wherein b is 1, 2 or 3; r is 1 or 2; R7 is H, alkyl or -SO2-alkyl; R8 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, OH, hydroxyalkyl, halo, and -CF3; R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =O; and R10 is H, alkyl or hydroxyalkyl;

,wherein r is 1, R9 is H or alkyl, and R13 is -SO2alkyl, -CONH2, -C(O)heteroaryl or -C(O)cycloalkyl;

wherein r is 2, R9 is H and R13 is -SO2alkyl or -CONH2;

wherein r is 2, and R15 is alkyl, allkoxy, -CF3, OH, hydroxyalkyl, halo, -NH2, -C(O)NH2, -CH2NH2, -C(O)O-alkyl, -NHSO2alkyl or-NHC(O)NH2;

wherein r is 2, and R15 is hydroxyalkyl; or wherein r is 1, and R15 is OH or hydroxyalkyl.

8. The compound of claim 1 selected from the group consisting of Examples 3E, 3F, 3S, 3V, 3BB, 4, 4A, 4B, 4F, 4H, 4I, 4K, 4L, 5, 5F, 5G, 5K, 5O, 5Q, 5R, 5S, 6H, 7A, 7B, 7C, 7F, 8, 8A, 8B, 8C, 9, 10A, 10C; 10D, 10E, 10F, 10G, 10H, 13, 13-1, 13A, 13B, 13C, 13D, 13F, 13G, 13I, 13J, 13K, 13L, 13N, 13O, 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.

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.

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 II for the manufacture of a medicament for treating phosphodiesterase 10 modulated disorders wherein said compound of Formula it has the formula:

or a pharmaceutically acceptable salt thereof, wherein and the carbon atoms to which it is attached form a phenyl ring, a heteroaryl ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5-membered heteroaryl containing two heteroatoms, R2 is absent;
R1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2, -N(R6B)2, -alkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R6)SO2-alkyl, phenyl, CN, -SO2R6, -SR6, trimethylsilyl-, -SF5, -OSF5, -C(=NOR6)-R6, or -(CH2)n-X-(CH2)m-R18; wherein X is -O-, -S-, or -NR6-, n is 0, 1 or 2, m is 1, 2 or 3, and R18 is selected from the group consisting of R2 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2, -N(R6B)2, -alkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalkyl, -N(R)SO2-alkyl, phenyl or CN;
or R1 and R2 on adjacent ring carbon atoms together form -O-CH2-O- or -O-(CH2)2-O-;
r is 1 or 2;
R3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R6B)2, -OCF3, -SF5, -OSF5 or -CN;
R4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(O)-alkyl, -SO2-alkyl, -C(O)N(R6A) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;
R5A is H, halo, OH, alkoxy, -O-alkyl-N(alkyl)2, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, aryloxy-, arylalkoxy-, heteroaryloxy-, -N(R6A)2, -NR6-alkyl-N(alkyl)2, -NR6-alkyl-O-alkyl-OH, -NR6-hydroxyalkyl, -S-alkyl, -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, -S-alkyl-NHC(O)H,-S-alkyl-C(O)NH-alkyl-pyrrolidinone, each R6 is independently H or alkyl;
each R6A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl- and heteroarylalkyl-; or two R6A 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; and each R6B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl-, heteroarylalkyl-, -SO2alkyl, -SO2-aryl, -SO2-heteroaryl, -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-heteroaryl, -C(O)N(R6)2, -C(O)NR6-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 homothiomorpholinyl ring.

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

14. The use of claim 12 wherein R1 and R2 are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.

15. The use of claim 12 wherein:
R1 is alkyl, and R2 is alkoxy; or R1 is alkyl and R2 is -OCF3; or R1 is alkyl and R2 is H, OH, halo or alkoxyalkoxy ; or R1 is alkoxy and R2 is alkoxy or H; or R1 is alkoxyalkoxy and R2 is H; or R1 is halo and R2 is H; or R1 is halo and R2 is -OCF3; or R1 and R2 together are methylenedioxy.

16. The use of claim 12 wherein R3 is alkyl or H, and R4 is H, -C(O)O-alkyl, or -SO2alkyl.

17. The use of claim 12 wherein R5A is H, halo, -O-alkyl-N(alkyl)2, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, -N(R6A)2, -NR6-alkyl-O-alkyl-OH.
-NR6-hydroxyalkyl, -S-hydroxyalkyl, -SO2-alkyl, or -S-alkyl-NHC(O)H.

18. The use of claim 17 wherein R5A is is H; Cl; -O-(CH2)2-N(CH3)2 ;

-N(CH3)2; -NH(CH2)3CH3; -NH-(CH2)2-O-(CH2)2-OH;
-NH-(CH2)2-OH; -NH-CH2-CH(OH)-CH3; -NH-alkyl-morpholinyl; -S-CH2CH(OH)-CH2OH;
-SO2CH3;
-N(R6)-(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(R6)-(heterocycloalkyl), wherein heterocycloalkyl is or , wherein R19 is H, alkyl or -SO2alkyl;
-NR6-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-(CH2)2-O-;
-NR6-alkyl-heteroalkyl; or -N(R6A)2,wherein the two R6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of wherein q is 1 or 2, s is 2 or 3 and R6 is as defined in claim 12.

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