Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

• the present invention relates to substituted pyrazoioquino ⁇ ines and derivatives thereof, to the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors for the treatment of PDE10-modulated disorders, to pharmaceutical compositions comprising the compounds, and to the use of additional substituted pyrazoloquinolines and derivatives thereof for the treatment of PDE10-modu!ated diseases.
• PDE10 phosphodiesterase 10
• Schizophrenia a debilitating psychiatric illness affecting 1% of the world's population, is thought to be at least partly due to excessive nigral dopaminergic and insufficient corticostriatal glutamatergic input to the striatum. These neurochemical abnormalities lead to reduced striatal output to other areas of the brain, resulting in inappropriate behavioral activation.
• the efficacy of existing antipsychotics is largely due to antagonism of D2 dopamine receptors in the striatal medium spiny neurons (MSNs) that project to the globus pallidus (also known as the striatopailidal indirect output pathway).
• D2 dopamine receptor antagonism increases striatal output via the indirect striatopal ⁇ dal pathway, which improves some of the aspects of schizophrenia, but does not affect striatal output via the direct striatonigral output pathway.
• PDE 10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehier et ai, "The potential therapeutic use of phosphodiesterase 10 inhibitors' ' , Expert Opin. Ther. Patents (2007) 17(2):147-158.
• PDE10 is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery.
• MSNs striatal medium spiny neurons
• PDE10 inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopaliidai output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striata! output that characterizes schizophrenia.
• PDE10 inhibition should improve the cognitive dysfunction that characterizes schizophrenia.
• the discrete localization of PDE 10 should lead to an improved side effect profile: typical side effects inciude extrapyramidal syndrome, diabetes, weight gain, hyperproiactinemia, sedation and QT C prolongation.
• PDE10 inhibitors have also been reported to be useful in treating in other CNS disorders such as psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome.
• Papaverine has been identified as a PDE10 inhibitor, and has been shown to be effective in animal models of schizophrenia.
• Heteroaromatic quinoline compounds useful as PDE 10 inhibitors are disclosed in VVO 2006/072828, and pyrrolodihydroisoquinoline PDE 10 inhibitors are disclosed in WO 2006/089815.
• Antiviral and/or antitumor pyrazoloquinolines are disclosed in US 5,459,146, US 5,506,236 and US 5,608,067, and by Crenshaw et al, J. Med. Chem., 19(2), 262-275 (1976). Pyrazoloquinolines useful as activators of caspases and inducers of apoptosis are disclosed in US 2007/0253957 A1.
• the present invention provides a novel class of substituted pyrazoloquinoline PDE 10 inhibitor compounds and derivatives thereof represented by Formula I, below, pharmaceutical compositions comprising one or more of said compounds, and methods of treating PDE10 inhibitor mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds or pharmaceutical compositions.
• CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds or pharmaceutical compositions.
• the invention also provides for methods of treatment of PDE10 inhibitor- mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome, using a class of substituted pyrazo ⁇ oquinoii ⁇ e PDE10 inhibitor compounds and derivatives thereof represented by Formula II,
• Novel compounds of the invention have the structural Formula I:
• Formula or a pharmaceutically acceptable salt thereof wherein all substituents are independently selected; and the carbon atoms to which it is attached form a phenyl ring, a heteroaryl ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R 2 is absent;
• R 1 is H, alkyl, alkoxy, aikoxyalkoxy, OH 1 hydroxyalkyl, -CF 3 , -OCF 3 , halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO 2 H, -C(O)N(R 6A ) 2! -N(R 6 ⁇ ) 2 , -alkySN(R 6B ) 2l -NR 6 -C(O)N(R 6A ) 2 , -N(R 6 )C(O)Oalky(, -N(R 6 )SO 2 -alkyl, phenyl, CN,
• R 2 is H 1 aikyl, alkoxy, alkoxyalkoxy, OH 5 hydroxyalkyl, -CF 3 , -OCF 3 , halo, -O-cycloalkyl, benzyloxy, -C(O)Oaiky!, -O-alkyl-CO 2 H, -C ⁇ O)N(R ⁇ A ) 2[ -N(R 6B ) 2i -aikylN(R 6B ) 2 , -NR 6 ⁇ C(O)N(R 6A ) 2 , -N(R 6 )C(O)Oatkyl, -N(R 6 )SO 2 -alkyi, phenyl or CN; or R 1 and R 2 on adjacent ring carbon atoms together form -O-CH 2 -O- or ⁇ O-(CH 2 ) 2 -O-;
• R 3 is H, alkyl, halo, fluoroalkyl, alkoxyalkyl, hydroxyaikyl, cycloalkyi, ⁇ N(R 6B ) 2 , -OCF 3 , -CF 3 , -SF 5 , -OSF 5 or -CN;
• R 4 is H, alkyi, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -aikyi-OC(O)-alkyi, -SO 2 -alkyl, -C(O)N(R ⁇ A ) 2 or -C(O)O-benzyl, wherein benzyl is optionally substituted by halo or alkoxy;
• R 5 is alkyl, -CN, -C ⁇ O)OR 6A , -C(O)N ⁇ R 6A ) 2 , aryI- ⁇ (R 17a , R 17b )-alkylene)-, heteroary! ⁇ ((R 17a , R 17b )-alkylene)-, heterocyc ⁇ oa!kyl-((R 17a , R 17b )-aikylene)-, hydroxyalkenyl, heteroarylalkenyl-, arylalkynyi- 5 heteroaryiaikynyh bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl, -alkyl-O-heteroaryl, -atkyl-O-cycloalkyl, -alkyl-O-heterocycloalkyl, -a!kyl-N(R 6 ) ⁇ aryl, -atkyi-N(R 6
• R 6B groups are afky! and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morphoiinyl, homomorphoiinyl, thiomorphofinyl or hornothiomorpholi ⁇ yl ring;
• R 11 is alkyl, phenyl or two hydrogen atoms on a single carbon ring member are replaced by a spirocyclic group is formed by replacing two hydrogen atoms on a singte carbon ring member with -(CH 2 ) 2 _ 6 - or ⁇ O ⁇ (CH 2 ) 2 -O-;
• R 12 is 1 or 2 substituents independently selected from the group consisting of aikyi, hydroxyalkyl and fluoroalkyl;
• R 13 is hydroxyaikyl, cycloalkyl, -C(O)-cycloaIkyi, -C(O)-a!kyl-cycloaikyi, aryi, aiyialkyh -C(O)alkyl, -C(O)Oatkyl, -C(O)aryl, -C(O)-alkylaryl, -C(O)O-ary1, -C(O)O-alkylaryl, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryi, -C(O)N(R 6A ) 2 , -C(O)-alky!-NR 6 -C(O)-ary! !
• R 14 is H, alky!, hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalky j -, -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-a!kylaryl, -C(O)O-aryl, -C(O)O-alkylaryl, heteroaryl, heteroaryiaikyh -C(O)-heteroaryl, -C(O)N(R 6A ) 2 , -C(O)-alkyi-NR 6 -C(O)-aryi, -C(O)-alkyl-NR 6 -C(O)O ⁇ alkyl, -C(O)-alkyl-NR 6 -C(O)O-benzyI, -S0 2 aS
• R 15 is 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, OH, hydroxyaikyl, halo, -CF 3 , -C(O)Oalkyi, -C(O)N(R 6A ) 2t aminoalkyh -N(R 6B ) 2 , -NR 6 -C(O)N(R 6A ) 2 , -NR 6 ⁇ C(O)-aikyi, -NR 6 -C(O)OaJkyl, -NR 6 -SO 2 -alkyl, -alkyl-imidazolyl, wherein the imidazolyl is optionally substituted with alky!, and phenyl, or two hydrogen atoms on a carbon ring member are replaced by -(CH 2 J 2 -S- or -O- (CH 2 ) 2 ⁇ O-; and
• R 5 is heterocycloa!kyl-((R 17a , R m ) ⁇ E ⁇ lky ⁇ ene)- and the heterocycloalkyl ring is joined to the alkyiene group by a ring nitrogen
• the R 17b substituent on the ⁇ -carbon is H, alkyl, CN, -CH 2 OH 5 -CH 2 -O-alkyf, ⁇ CON(R 6a ) 2 , ⁇ CH 2 N(R ⁇ ) 2 or -CO 2 R 6 .
• R 3 for Formula i is H, alkyl, halo, fluoroaikyl, aikoxyalkyl, hydroxyaikyl, cycloaikyi, -N(R 6B ) 2 , -OCF 3 , -SF 5 , -OSF 5 or -CN,
• R 5 for Formula I is alkyl, -CN, -C(O)OR 6A , -C ⁇ O)N(R 6A ) 2 , aryi- «R 17a , R 17b )-alkylene)-, heteroaryI-((R 17a , R 17b )-alkylene)-, heterocycloalkyKfR 178 , R 17b )-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, aryialkynyl- heteroarylaikynyh bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl - alkyl-O-heteroaryi, -alkyi-O-cycloalkyl, -alkyi-O-heterocycloalkyl, ⁇ alkyl-N(R 6 )-aryl, -alkyl-N(R 6 )-heteroaryl,
• 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.
• the present invention relates to a method of treating PDE 10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering a therapeutically effective amount of at least one compound of Formuia I or a pharmaceutica ⁇ ly acceptable salt thereof to a mammal in need of such treatment.
• CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome
• administering comprising administering a therapeutically effective amount of at least one compound of Formuia I or a pharmaceutica ⁇ ly acceptable salt thereof to a mammal in need of such treatment.
• the invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceuticaliy acceptable carrier.
• CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome
• a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceuticaliy acceptable carrier.
• the present invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of structural Formula il:
• Formula Il or a pharmaceutically acceptable saft thereof, wherein all substrtutents are independently selected;
• R 1 is H, aikyi alkoxy, alkoxyalkoxy, OH, hydroxyaikyl, -CF 3 , -OCF 3 , halo, -O-cycl ⁇ alky!, benzyloxy, -C(O)OaikyL -O-aIkyl ⁇ CO 2 H, -C(O)N(R 6A ) 2) -N(R 6B ) 2 , -afkyiN(R 6B ) 2 , -NR 6 -C(O)N(R 6A ) 2s -N(R 6 )C ⁇ O)Oalkyl.
• R ,18 is selected from the group consisting of
• R 2 is H, aikyi, alkoxy, aikoxyaikoxy, OH, hydroxyafkyi, -CF 3 , -OCF 3 , halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-a ⁇ kyl-CO 2 H, -C(O ⁇ N(R 6A ) 2 , -N(R 6B ) 2 , -aikylN(R 6B ) 2 , -NR 6 -C(O)N(R 6A ) 2 , -N(R 6 )C(O)Oalky[ !
• R 1 and R 2 on adjacent ring carbon atoms together form -0-CH 2 -O- or -O-(CH 2 ) 2 -O-; r is 1 or 2;
• R 3 is H, aikyi, halo, fluoroalkyi, aikoxyalkyl, hydroxyaikyl, cycioalkyl, -N(R 6B ) 2 , -OCF 31 -SF 5 , -OSF 5 or -CN;
• R 4 is H, alky!, alkoxyaikyk benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl ⁇ OC(O)-alky!, - SO 2 -alkyt, ⁇ C(0)N(R 8A ) 2 or -C(O ⁇ O-benzyl, wherein benzyf is optionally substituted by halo or alkoxy;
• R SA is H, halo, OH, alkoxy, -O-alkyl-N(alkyl) 2t -O-heterocycloalkyl, -O-alkyl-heterocycloafkyf, aryloxy-, arylalkoxy-, heteroaryloxy-.
• each R 6 is independently H or alkyi; each R 6A is independently selected from the group consisting of H 5 alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl- and heteroarylalkyl-; or two R 6A groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 6A groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homornorpholinyl, thiomorpholinyl or homothiomo ⁇ hol ⁇ nyl ring; and each R 6B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl-, heteroarylalkyl-, -SC ⁇ alkyl, -SCVaryi, -SO 2 -heteroaryi !
• R 6B groups are alkyl and together with the nitrogen to which they are attached form a 4 to 7 membered ring; or two R 6B groups and the nitrogen to which they are attached form a piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorphoitnyl or homothiomorphoiinyi ring.
• the invention in another embodiment, relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula Il or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome
• a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula Il or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• R 1 and R 2 are independently selected from the group consisting of R 1 is H, alkyl, alkoxy, alkoxyalkoxy, -CF 3 , -OCF 3 and halo.
• R 1 is alkyl, preferably methyl, and R 2 is alkoxy, preferably methoxy; or R 1 is alkyl, preferably methyl, and R 2 is -OCF 3 ; or
• R 1 is alkyl, preferably methyl, and R 2 is H, OH, haio or alkoxyalkoxy (preferably methoxyethoxy); or
• R 1 is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or R 1 is alkoxyalkoxy (preferably methoxyethoxy) and R 2 is H; or R 1 is halo and R 2 is H; or R 1 is haio and R 2 is -OCF 3 ; or R 1 and R 2 together are methylenedioxy,
• R 3 is alkyl, preferably methyl, or H.
• R 3 is -CF 3 .
• R 4 is H, -C(O)O-alkyl, wherein alkyl is preferably t-butyl, or -SOaalkyl, preferably -SO 2 CH 3 .
• b is 1.
• R 5 is selected from the group consisting of -CN, -C(O)N(R 6A ) 2 , aryK(R 17a , R 17b )-alkylene)-, heteroaryl-((R 17a , R 17b )-alkylene)-, heterocycloalkyi-((R 17a , R 17b )-alkylene) ⁇ , hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyf, heteroary!
• R 5 is -CN; -C(O)NH-alkyl-pyridyi; -CH(OH)-pheny); -alkylene-phenyl; -aikylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyI;
• R 14 is H, alkyi (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);
• R 14 is H or atkyl; or In another embodiment of Formula I 1 when R 5 is heterocycloa!kyl-((R 17a , R 17b ) ⁇ aikylene)-, (R 17a , R 17b )-aikylene- is preferably -C(OH)-, and R 5 is a group such as
• R 5 is heterocycloalkyl-((R 17a , R 17b )- alkylene)-, wherein R 17a and R 17b are independently H or aikyl, R 5 being preferably
• R 7 is H, a!kyl or -SO 2 -aiky!
• R 8 is 1 or 2 substituents independently selected from the group consisting of H, aikyl, OH 1 hydroxyalkyf, halo, and -CF 3 ;
• R 10 is H, aikyl or hydroxyalkyl.
• R 13 is -SO 2 alkyl, -CONH 2 , -C(O)heteroary! f for example
• R 13 is -SO 2 aikyl or
• R 5 is W r r is 2
• R 9 is H and R 13 is
• R 5 is r j s 2
• R 15 is alky! (preferably methyl), allkoxy (preferably methoxy), -CF 3 , OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH 2 , -C(O)NH 2 , -CH 2 NH 2 , -C(O)0-alkyl, -NHSO 2 alkyl Or -NHC(O)NH 2 , where R 15 is preferably in the
• R 5 is M r js s 2 2,
• R 15 is hydroxyalkyl, preferably hydroxymethyl, in the 3-position.
• R 6 is r is 1. and R 15 is OH or hydroxyalkyl (preferably hydroxymethyl).
• heterocycloalkyl-heteroaryl-alkylene- R 5 group for Formula I is:
• heterocycloalkyf-heteroaryl-aikyiene- R 5 group for Formula I is
• heterocycloalkyf-heteroaryf-aikylene- R 5 group for Formula I is
• R 5 cycJoalkyl group is cyclopropyl
• R 1 and R 2 are independently selected from the group consisting of H, aikyf, afkoxy, alkoxyaikoxy, -CF 3 , -OCF 3 and halo.
• R 3 is H or alky!
• R 4 is H 1 -C(O)O-aikyl or -S0 2 alkyl
• R 5 is selected from the group consisting of -CN 1 -C(O)N ⁇ R 6A ) 2( aryi-((R 17a , R 17b )- alkylene)-, heteroaryl-((R 17a , R 17b )-alky ⁇ ene) ⁇ , heterocycloalkyK ⁇ R 17a s R 17b )-alkylene)-, hydroxyalkenyl, heteroarylalkenyh heteroarylalkynyl-, heterocycloalkenyi, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen),
• R 1 is alky!, preferably methyi s and R 2 is alkoxy, preferably methoxy; or
• R 1 is alkyj, preferably methyl, and R 2 is -OCF 3 ; or
• R 1 is alky!, preferably methyl and R 2 is H, OH, haio or alkoxyaikoxy (preferably methoxyethoxy); or
• R 1 is aikoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or
• R 1 is alkoxyaikoxy (preferably methoxyethoxy) and R 2 is H; or
• R 1 is halo and R 2 is H;
• R 1 is halo and R 2 is -OCF 3 ; or R 1 and R 2 together are methyleneciioxy; R 3 is alkyl; R 4 Is H; and
• R 5 is -CN; -C(O)N H-alkyf-pyridy ⁇ ; ⁇ CH(OH) ⁇ phenyi; -alkylene-phenyl; -a ⁇ kylene-pyridyl, -C(O)-pyridyi, -CH(F)-py ⁇ dyl; -CH(OH)-pyridy);
• hydroxyalkyi preferably hydroxyethyl
• R is preferably H or alkyl; heterocycloalkyl-((R 17a , R 17b )-alkylene)-, wherein (R 17a , R 17b )-alkylene is heterocyc ⁇ oatkyl-((R 17a , R' 7b )-aikyiene) ⁇ , wherein R 17a and R 17b are independently H or alky!, preferably
• R 9 is H or a!kyi s and R 13 is -S0 2 alkyl, -CONH 2 , -C(0 ⁇ heteroaryi, for example OH , or -C(0)cycloalkyi, for example
• R 13 is -S0 2 alky! or -CONH 2 ;
• R 9 is H and R 13 is -S0 2 alkyl or -CONH 2 ; wherein r is 2, and R 15 is alkyl (preferably methyl), alikoxy (preferably methoxy), -CF 3 , OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH 2 , -C(O)NH 2 , -CH 2 NH 2 , -C(O)O-alkyl, -NHSO 2 alkyl or -NHC(O)NHa, where R 15 is preferably in the 4-position; wherein r is 2, and R 15 is hydroxyaikyl, preferably hydroxymethyi, in the 3-positio ⁇ ; or wherein r is 1 , and R » 15 ; i,s OH or hydroxyaikyl (preferably hydroxymethyl).
• Preferred compounds of Formula I are those in Examples 3E, 3F, 3S, 3V, 3BB, 4i 4A t 4B, 4F, 4H t 41, 4K, 4L 5, 5F, 5G, 5K 1 5M, 50, 5Q, 5R, 5S 1 6H, 7A, 7B 5 7E, 8, 8A, 8B, 8C, 9, 1OA, 10C 1 1OD, 1OE, 10F, 10G 1 1OH, 13, 13-1 , 13A, 13B, 13C 1 13D, 13F, 13G 1 13I 1 13J, 13K 1 13L, 13N, 130, 13P, 13Q 1 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 23, 24, 26 S 27, 27A, 27B, 27C, 28, 29A 1 29B, 29D, 29E, 29F, 32B, 33, 34A 1 34B, 35, 36C, 36E 1 36F 1 and 36G2.
• More preferred compounds of Formula I are Examples 3E 1 3F, 3S 1 3V S 4, 4B 1 4F, 4H, 4I 1 4K, 5, 5F, 5K 1 5M, 50, 5G, 5R, 5S 1 6H, 7E 1 8B, 8C, 9, 1OA, 1OC, 1OD, 1OE, 10F 1 10G 1 1OH, 13, 13A 1 13C, 13F 1 13G, 131, 13J, 13K 1 13L, 13N 1 130, 13P, 13Q, 13R 1 13S, 13V, 14, 15, 16, 17, 18, 21 B 1 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B, 29F, 32B, 34B, 35, 36C, 36E 1 36F, and 36G2.
• the compound of Formula i is 3E. In another embodiment the compound of Formula ! is 3F. In another embodiment the compound of Formula i is 3S. in another embodiment the compound of Formula I is 3V. In another embodiment the compound of Formula I is 3BB. in another embodiment the compound of Formula 1 is 4. In another embodiment the compound of Formula I is 4A. In another embodiment the compound of Formula I is 4B. In another embodiment the compound of Formula I is 4F, In another embodiment the compound of Formula i is 4H. In another embodiment the compound of Formula I is 41. In another embodiment the compound of Formula I is 4K. In another embodiment the compound of Formula I is 4L, In another embodiment the compound of Formula I is 5. In another embodiment the compound of Formula I is 5F. In another embodiment the compound of Formula I is 5G.
• the compound of Formula f is 5K. In another embodiment the compound of Formula 1 is 5M. In another embodiment the compound of Formula I is 50. In another embodiment the compound of Formula ! is 5Q. In another embodiment the compound of Formula I is 5R. In another embodiment the compound of Formula S is 5S. In another embodiment the compound of Formufa I is 6H. in another embodiment the compound of Formula I is 7A. fn another embodiment the compound of Formula I is 7B. in another embodiment the compound of Formula I is 7E. In another embodiment the compound of Formula I is 8. In another embodiment the compound of Formula I is 8A. In another embodiment the compound of Formula I is 8B. In another embodiment the compound of Formula 1 is 8C. In another embodiment the compound of Formula I is 9.
• the compound of Formula I is 1OA. fn another embodiment the compound of Formula I is 1OC. In another embodiment the compound of Formula ! is 1OD. In another embodiment the compound of Formula I is 1OE. In another embodiment the compound of Formula I is 1OF. In another embodiment the compound of Formula I is 10G. In another embodiment the compound of Formula I is 10H. In another embodiment the compound of Formula I is 13. In another embodiment the compound of Formula I is 13- 1. In another embodiment the compound of Formula I is 13A. In another embodiment the compound of Formula I is 13B. In another embodiment the compound of Formula I is 13C. In another embodiment the compound of Formula i is 13D. In another embodiment the compound of Formula ! is 13F. In another embodiment the compound of Formula I is 13G.
• the compound of Formula I is 131. In another embodiment the compound of Formula I is 13J. In another embodiment the compound of Formula I is 13K. In another embodiment the compound of Formula I is 13L. In another embodiment the compound of Formula I is 13N. In another embodiment the compound of Formula I is 130. In another embodiment the compound of Formula I is 13P. In another embodiment the compound of Formuia I is 13Q. In another embodiment the compound of Formuia I is 13R. In another embodiment the compound of Formula I is 13S. In another embodiment the compound of Formula I is 13T. In another embodiment the compound of Formula I is 13V. In another embodiment the compound of Formula I is 14. In another embodiment the compound of Formula I is 15. In another embodiment the compound of Formula Ms 16. In another embodiment the compound of Formula ! is 17.
• the compound of Formuia I is 18. In another embodiment the compound of Formuia I is 21 B. Sn another embodiment the compound of Formula I is 21 D. In another embodiment the compound of Formula ! is 21 F. In another embodiment the compound of Formuia f is 22. In another embodiment the compound of Formula I is 23. In another embodiment the compound of Formula I is 24. in another embodiment the compound of Formula ! is 26. In another embodiment the compound of Formula ! is 27. In another embodiment the compound of Formula I is 27A. In another embodiment the compound of Formula I is 278, In another embodiment the compound of Formula I is 27C. tn another embodiment the compound of Formula ! is 28, In another embodiment the compound of Formula I Is 29A.
• the compound of Formula I is 298, In another embodiment the compound of Formula i is 29D. in another embodiment the compound of Formula i is 29E. In another embodiment the compound of Formula I is 29F. In another embodiment the compound of Formula I is 32B. In another embodiment the compound of Formula I is 33. In another embodiment the compound of Formula I is 34A. in another embodiment the compound of Formula I is 34B. In another embodiment the compound of Formula I is 35. In another embodiment the compound of Formula I is 36C. In another embodiment the compound of Formula I is 36E. in another embodiment the compound of Formula I is 36F. in another embodiment the compound of Formula I is 36G2.
• R 1 and R 2 are independently selected from the group consisting of R 1 is H, alkyl, aikoxy, alkoxyaikoxy, -CF 3 , -OCF 3 and halo.
• R 1 is aikyl, preferably methyl, and R 2 is alkoxy, preferably methoxy; or R 1 is alkyl, preferably methyl, and R 2 is -OCF 3 ; or
• R 1 is alkyl, preferably methyl, and R 2 is H, OH, halo or alkoxyaikoxy (preferably methoxyethoxy); or
• R 1 is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or R 1 is aikoxyalkoxy (preferably methoxyethoxy)and R 2 is H; or R 1 is halo and R 2 is H; or R 1 is halo and R 2 is -OCF 3 ; or R 1 and R 2 together are methyienedioxy.
• R 3 is alkyl, preferably methyl s or H
• R 4 is H. in another embodiment of Formula Ii 1 b is 1 ,
• R 5A is H, halo, -O-alkyi-N(aikyl)2, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, -N(R 6A ) 2 , -NR 6 -alkyl-O ⁇ alky1-OH, -NR 6 -hydroxyalkyi s -S-hydroxyalkyl, -SO 2 -alkyl, 0r -S-alky!-NHC(O)H.
• R 5A is H, Cl, -O-(CH 2 ) 2 -N(CH 3 ) 2 , , -N(CHs) 2 , -NH(CHa) 3 CH 3 , -NH-(CH 2 ) 2 -O-(CH 2 ) 2 -OH,
• R 5A when R 5A is -N(R 6A ) 2 , R 5A is -N(R 6A )-(cycioalkyl), wherein R 6A is H or alkyl, and wherein cycioalkyl is cyclobutyl, cyciopentyl, cyclohexyi or cycloheptyl, and wherein the cycloalkyl potion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably 1 or 2 substituents independently selected from the group consisting of alkyl, OH 1 hydroxyalkyl, halo, and -CF 3 .
• R 5A when R 5A is -N(R 6A ) 2l R 5A is -N(R 6A )-(heterocycloalkyl), wherein R 6A is H or alkyl, and wherein heterocycloalkyl is or wherein R 19 is H, alkyl or -SO 2 alkyl.
• R 5A when R 5A is -N(R 6A ) 2 , R 5A is -NR 6 -alkyl ⁇ aryi, wherein R 6A is H or alkyl, and wherein aryl is preferably phenyl, and further wherein the phenyl portion is optionally substituted by 1 or 2 ring system substituents, wherein the optional sobstituents are preferably 1 or 2 substituents independently selected from the group consisting of OH, alkoxy or -OCF 3 , or two hydrogen atoms on adjacent carbon ring members are replaced by -0-(CH 2 J 2 -O-.
• R 5A when R 5A is ⁇ N(R 6A ) 2) R 5A is -NR 6A -afkyi-heteroalky! wherein R 6A is H or alkyi, and wherein the heteroary! portion is preferably pyridy ⁇ , e.g.
• R 5A is -N(R 6A ) 2
• the two R 6A groups and the nitrogen to which they are attached form a ring selected from the group consisting of
• R 1 and R 2 are independently selected from the group consisting of H, alkyi, alkoxy, alkoxyaikoxy, -CF 3 , -OC F 3 and halo.
• R 3 is H or aikyl
• R 4 is H 1 -C(O)O-alky) or -SO 2 alkyl
• R 5A is selected from the group consisting of H, halo, -O-alkyl-N(alkyl)2, -O-heterocycloaikyl, -O-alky ⁇ -heterocycloaikyi, -N(R 6A ) 2 , -NR 6 -alkyf-O-alkyl-OH, -NR 6 -hydroxyalkyl, -S-hydroxyalkyl, -SO 2 -alkyl and ⁇ S-a!ky ⁇ -NHC(O)H,
• R 1 is alkyi, preferably methyl, and R 2 is alkoxy, preferably methoxy; or
• R 1 is alkyi, preferably methyl, and R 2 is -OCF 3 ; or
• R 1 is alkyi, preferably methyl, and R 2 is H, OH, halo or alkoxyaikoxy (preferably methoxyethoxy); or
• R 1 is alkoxy, preferably methoxy, and R 2 is alkoxy, preferably methoxy, or H; or
• R 1 is alkoxyaikoxy (preferably methoxyethoxy ⁇ and R 2 is H; or
• R 1 is halo and R 2 is H;
• R 1 is halo and R 2 is -OCF 3 ; or
• R 1 and R 2 together are methylenedioxy
• R 3 is alkyi
• R 4 is H; and R 5A is H; Cl; -O-(CH 2 ) 2 -N(CH 3 ) 2 ; -N(CHa) 2 ;
• cycioaikyl is cyciobutyl, cyciopentyl, cyclohexyl or cyc ⁇ oheptyl, and wherein the cycioaikyl potion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably 1 or 2 substituents independently selected from the group consisting of alkyl, OH 1 hydroxyalkyl, fluoro, and -CF 3 ;
• R 6 is as defined above, and wherein the R DA in "N(R 6A )-(cycfoalkyl) 5 -N(R 6A )-(heterocycloalkyl), -NR ⁇ A -alkylaryl and -NR 6A -aIkyi ⁇ heteroaryl is preferably H or aikyl.
• Preferred compounds of Formula Il are those in Examples 3, 3D, 3G, 3I 1 3M, 3N, 30, 3R, 3T 1 3W 1 3Y 1 3AA, 3CC, 4C, 40, 4P, 4Q 1 4R 1 4S, 4U 1 4V, 5A 1 5C, 5D 1 5E, 5H 1 5J r 5L 1 5P 1 5T. 5V S 5W 1 5X 1 5Y, 6, 6A, 6D, 61, 6K 1 6L 5 6M 5 6N, 60, 6P 1 7, 7D 1 12, 13U, 2OA, 2OC, 21 C 5 and 21 E.
• More preferred compounds of Formula II are those in Examples 3, 3D, 3G, 3I, 30, 3R, 3T 1 3W 1 3Y 1 3AA, 3CC 5 4C 1 40, 4P, 4Q, 4R, 4S, 4W, 5H ; 5P, 5T 1 5V 1 5W 1 5Y S 6, 6A 1 61, 6K 1 6L, 6M, 6N, 6P ! 7, 7D S and 12.
• the compound of Formula Il is 4Q. In another embodiment the compound of Formula Il is 4R. In another embodiment the compound of Formula Il is 4S. in another embodiment the compound of Formula Il is 4U. In another embodiment the compound of Formula Il is 4V, In another embodiment the compound of Formula Il is 5A. In another embodiment the compound of Formula Il is 5C. In another embodiment the compound of Formula H is 5D. In another embodiment the compound of Formula Ii is 5E. Sn another embodiment the compound of Formula Il is 5H. in another embodiment the compound of Formula I! is 5J. ⁇ n another embodiment the compound of Formula Il is 5L. In another embodiment the compound of Formula Il is 5P. In another embodiment the compound of Formula Ii is 5T. Jn another embodiment the compound of Formula Ii is 5V.
• the compound of Formula H is 5W. In another embodiment the compound of Formula Ii is 5X. In another embodiment the compound of Formula Il is 5Y. In another embodiment the compound of Formula il is 6. In another embodiment the compound of Formula Il is 6A. In another embodiment the compound of Formula il is 6D, In another embodiment the compound of Formula Il is 61. In another embodiment the compound of Formula Il is 6K. In another embodiment the compound of Formula II is 6L. In another embodiment the compound of Formula Il is 6M. In another embodiment the compound of Formula Il is 6N. In another embodiment the compound of Formula Il is 6O. In another embodiment the compound of Formula Il is 6P. In another embodiment the compound of Formula I! is 7. In another embodiment the compound of Formula Il is 7D. In another embodiment the compound of Formula Il is 12. In another embodiment the compound of Formula Il is 13U. in another embodiment the compound of Formula II is 2OA. In another embodiment the compound of Formula Il is 2OC. In another embodiment the compound of Formula Ii is 21 C. In another embodiment the compound of Formula Il is 21 E.
• Mammal means humans and other mammalian animals.
• alkyl refers to “alky)” as well as the “alkyl” portions of "hydroxyalkyl”, “haioalkyl”, “alkoxy”, etc.
• Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
• Preferred alkyi groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyf groups contain about 1 to about 6 carbon atoms in the chain.
• Branched means that one or more tower alky! groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
• AIkylene means a difunctional alkyl group obtained by removal of a hydrogen atom from a C1-C3 alkyl group as defined above.
• Non-limiting examples of aikyiene include methylene, ethylene and propylene ⁇ i.e., -CH 2 -, -(CH 2 J 2 --, -(CH 2 ) S -).
• the R 17a and R 17b groups can be on the same or different carbon atoms.
• R 5 is heterocycioaikyi-((R 17a , R 17b )-alky1ene)- and the heterocycloalkyt ring is joined to the alkylene group by a ring nitrogen
• the R 17b substttuent on the ⁇ -carbon is H 5 alkyi, CN, -CH 2 OH, -CH 2 ⁇ O-alkyi, -CON(R aa ) 2 , -CH 2 N(R 6 J 2 Or -CO 2
• R 6 is intended to eliminate unstable compounds, e.g., compounds wherein the ⁇ -carbon (herein meaning the carbon adjacent to the ring nitrogen) is substituted by OH.
• Hydroxyalkyl represents an alkyt group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alky! group.
• Alkoxy means an alkyl-O- group in which the aikyl group is as previously described.
• suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aminoalkyl means an amino-alkyl group in which the a!ky! group is as previously described. The bond to the parent moiety is through the alkyi.
• Halogen represents fluoro, chloro, bromo and iodo.
• Hydroxyalky means a HO-aikyi- group in which alkyi is as previously defined. Preferred hydroxyalkyls contain lower alkyi. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
• Alkenyi means means a straight or branced aliphatic hydrocarbon group containing at least one carbon-carbon double bond and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkeny! groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain,
• “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• suitable alkenyl groups include ethenyj, propenyf, n-butenyi, 3-methy!but-2 ⁇ enyf n-pentenyl, octenyi and decenyl.
• Hydroxyalkenyl refers to an aikenyl group substituted by one or more hydroxy! groups, preferably 1 or 2 hydroxy groups, provided that a hydroxy! group is not present on a carbon that is part of a double bond.
• Alkynyr means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkynyi groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
• Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyi chain.
• Lower aikynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• suitable alkynyi groups include ethynyl, propynyl, 2-butyny! and 3-rnethylbutynyl.
• “Aryi” means an aromatic monocyclic or multicyclic ring system comprising about 8 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• the aryi group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
• suitable aryi groups include phenyl and naphthyl.
• ⁇ eteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
• Preferred heteroaryis contain about 5 to about 6 ring atoms.
• the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
• a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
• suitable heteroaryis include pyridyl, pyrazinyl, furanyl, thienyL pyrimidinyi, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyi, thiazolyl, pyrazolyl, furazanyl, pyrroiyl, pyrazolyi, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxaiinyl, phthalazinyl, oxindoly!, imidazo[1 ,2-a]pyridinyI, imsdazo[2,1 ⁇ blthiazoiyf, benzofurazanyl, indoiyl, aza ⁇ dolyl, benzimidazolyl
• Aralky! or "arylafky! means an aryl-alkyl- group in which the aryi and alkyi are as previously described.
• Preferred araikyls comprise a lower alky! group.
• suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
• Ring system substituent means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aikenyl, alkynyl, aryi, heteroaryl, aralkyi, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyiheteroaryl, -CH(Yi)(Y 2 ), -O-Y1, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxy, -C(O)Y 1 , halo, nitro, cyano, -C(O) 2 -Yi, -S(O) 2 -Yi, -S-Y 1 , cycloalkyi, cycloalkylaikyi, heterocycloalkylalky
• alkyl, cyci ⁇ afkyl, aryS, heteroaryl and heterocycioalkyl portions of Yi, Y 2 or Y 3 can be optionally substituted with 1 or 2 substttuents independently selected from the group consisting of halo, OH, -CF 3 , CN, aikoxy, -NH 2 , -NH-aikyl, -N(aikyl) 2 and Si(alkyl) 3 .
• Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CHa ⁇ - and the like which form moieties such as, for example:
• a single divalent moiety such as a divalent alkyi chain or a -O-(CH 2 ) 2 -O ⁇ group can simultaneously replace two available hydrogen atoms on one carbon atoms on a ring system.
• An example of such spiro moieties is:
• -Heterocyciyl means a non-aromatic saturated monocyclic or multicycl ⁇ c ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclyls contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclyi root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• Any -NH in a heterocyclyi ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
• the heterocyclyi can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the nitrogen or sulfur atom of the heterocyclyi can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• Non-limiting examples of suitable monocyclic heterocyclyi rings include piperidyf, pyrrolidinyl, piperazinyi, morpholinyl, thiomorpholinyl, thiazo ⁇ di ⁇ yl, 1.4-dioxanyL tetrahydrofuranyf, tetrahydroth ⁇ ophenyi, lactam, lactone, and the like.
• hetero-atom containing ring systems of this invention there are no hydroxy! groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
• N, O or S there are no N or S groups on carbon adjacent to another heteroatom.
• Heteroarylalkyl means a heteroaryt-aikyl- group in which the heteroaryl and alky! are as previously described. Preferred heteroaralkyls contain a lower alky! group. Non-limiting examples of suitable heteroaralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
• cycloalkylalkyl and heterocycloalkylalkyl mean cycloaikyl-alkyl and heterocycloaikyl-alkyl groups wherein cycloalkyl, heterocycloalkyl and alky! are as previously described, wherein the alky! portion is preferably lower alkyl.
• the bond to the parent moiety is through the alkyl portion.
• 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.
• stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a usefui degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• 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
• purified or 'in purified form for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, pyrrolyl, thiazoiyl, imidazolyl and furanyl. Examples of such groups are shown in the following partial structures:
• Cycloaikyl means a non-aromatic mono- or mult ⁇ cyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms.
• the cycfoaikyi can be optionally substituted with one or more "ring system subststuents" which may be the same or different, and are as defined above.
• Non-limiting examples of suitabfe monocyclic cydoalkyis include cyclopropyi cyclopenty), cyclohexyi, cycloheptyl and the like.
• Non-iimiting examples of suitable multicyclic cydoalkyis include 1- decalinyl, norbornyl, adamantly and the like.
• Cycloalkenyl means partially saturated species such as, for example, cyclopentene, cyclohexene, indanyl, tetrahydronaphthy! and the like.
• bridged heterocycfoa ⁇ kyt means a piperidinyl, ptperazinyl, rnorpholinyl, tetrahydropyranyl or tetrahydrofuranyl ring wherein a carbon on one side of the ring is joined by a C1-C3 alkyl group, or a hydroxy substituted C1-C3 alkyl group, to a carbon on the opposite side of the ring, provide that when the bridge is a C1 bridge both carbon atoms to which the bridge is bound to are not adjacent to the same heteroatom,
• Non-limiting examples include:
• fused ring heterocycioalkyl means a 5 or six- membered heterocycioalkyl ring joined to a cycloalky! or heterocycloalky! ring through two adjacent shared carbon ring members.
• Non-limiting examples include
• Haloalkyl represents an afkyl group as defined substituted by one or more halo atoms.
• haio is fluoro
• ft should afso be noted that any carbon as we!! as heteroatom with unsatisfied valences in the text, schemes, examples and Tabtes herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
• protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene ef al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
• variable e.g., alkyl, halo, etc.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• Prodrugs, solvates and co-crystais of the compounds of the invention are also contemplated herein.
• prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) (or Formuia II) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as, for example, through hydrolysis in blood.
• a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference thereto.
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-CsJalkyt (C 2 -Ci 2 )a!kanoyloxymethyf, 1- ⁇ alkanoyioxy)ethy! having from 4 to 9 carbon atoms, 1-methyi-1 ⁇ (aikanoy!oxy)-ethy: having from 5 to 10 carbon atoms, alkoxycarbonyioxymethy!
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-pCeJaikanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C 6 )alkanoyfoxy)ethyl, (Cr Ce)alkoxycarbony!oxymethyi, N-(Ci -C 6 )a!koxycarbonylaminomethyl, succinoyf, (Ci- C 6 )alkanoy!, ⁇ -amino(Ci-C 4 )a!kanyl, arylacyi and ⁇ -aminoacyl, or ⁇ -aminoacyi- ⁇ - arninoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
• “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
• a co-crystal is a crystalline superstructure formed by combining an active pharmaceutical intermediate with an inert molecule that produces crystallimty to the combined form
• Co-crystais are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I of this invention in different proportions depending on the nature of the co-crystal.
• a dicarboxlyic acid such as fumaric acid, succinic acid etc.
• 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.
• the compounds of Formula i or El can form salts which are also within the scope of this invention.
• Reference to a compound of Formula I or M herein is understood to include reference to salts thereof, unless otherwise indicated.
• the term "salt(s)' ⁇ as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as we!! as basic salts formed with inorganic and/or organic bases.
• zwitterions inner salts
• Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesujfonat.es, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesuSfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toiuenesulfonates (also known as tosylates) and the like.
• Exemplary basic salts include ammonium salts, atkafi metal salts such as sodium, lithium, and potassium salts, aikaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, f-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialky! sulfates (e.g.
• dimethyl, diethyl, and dibutyi sulfates dimethyl, diethyl, and dibutyi sulfates
• long chain haiides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
• aralkyl halides e.g. benzyl and phenethyl bromides
• All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, co-crystals and prodrugs of the compounds as well as the salts and solvates, co-crystals of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents. including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemptated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
• individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with ail other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms “satt” , “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautorners, positional isomers, racemates or prodrugs of the inventive compounds.
• Isomers can be prepared using conventional techniques, either by reacting optically pure or opticaliy enriched starting materials or by separating isomers of a compound of Formula I. isomers may aiso include geometric isomers, e.g., when a double bond is present
• 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.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H 1 11 C, 13 C, 14 C 5 15 N, 18 0, 17 0, 31 P, 32 P. 35 S, 18 F, 36 CI and 123 I 5 respectively.
• Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes.
• those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single photon emission computed tomography (SPECT).
• PET Positron Emission Tomography
• SPECT Single photon emission computed tomography
• substitution with heavier isotopes such as deuterium (i.e., ⁇ H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo haif-iife or reduced dosage requirements) and hence may be preferred in some circumstances.
• substitution with heavier isotopes such as deuterium 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.
• isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
• lsotopicaily labeled compounds of Formula fl in particular those containing isotopes with longer half lives (T1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopicaiiy labeled reagent for a non-isotopically labeled reagent.
• Polymorphic forms of the compounds of Formula i or H 1 and of the salts, solvates, co-crystals and prodrugs of the compounds of Formula I or II, are intended to be included in the present invention.
• the term "at least one compound of Formula I (or Formula II)" means that one to three different compounds of Formula ! or Il may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I or il is used.
• Chloro compounds 5 can be converted to the R 5 -susbtituted compounds of formula 6 using methods known in the art and described in the examples below.
• Compounds of Formula Il can be prepared by methods similar to those described for compounds of Formula I, and by methods known in the art, for example the procedures described in US 5,459,146, US 5,506,236, US 5,608,067, and US 2007/0253957, all incorporated herein by reference, and by Crenshaw et al, J, Med. Chem., 19(2), 262-275 (1976).
• CS 2 (4.5 mL) was added to a mixture of 4-methoxy-2-methyIaniiine (9.0 g), absolute EtOH (25 mL) and NH 4 OH (6 mL). After 1 hr ; chioroacetic acid (7.0 g), NaHCO 3 (4.5 g) and water (20 mL) were added. After an additional hour, H 2 NNH 2 monohydrate (7.5 mL) was added dropwise to the black mixture. The resulting mixture was refrigerated overnight. The mixture was filtered and washed with cold EtOH. The purple solid was dried in a vacuum oven at 50 D C to give a purple-white solid (11.52 g).
• HCi salt was prepared by adding -1 equivalent of HCI/ether to a solution of compound 5 in ether and then evaporating to dryness.
• Trimethylsilyl isocyanate (55 ⁇ l) was added to compound 9 (121 mg) in dry dioxane (15 mL) at 60 0 C, The mixture was heated for 70 mirs. The reaction mixture was cooled to RT, MeOH (5 mL) was added, and the mixture was concentrated in vacuo to give a yellow solid (142 mg). This solid was purified on silica gel plates (4, 1000 ⁇ ) eluting with DCM:MeOH (9:1) to give a yellow foam (92 mg).
• the foilowing compounds were prepared in a similar manner:
• 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).
• Compound 21-3 was prepared using procedures simitar to those described in earlier examples.
• rt-8uLi in hexane (1 ml, 1.6 M) was added to a solution of 16-2 (50 mg) in anhydrous THF at -78 0 C dropwise. After stirring for 1 h s a solution of 26-1 (175 mg) in THF was added to the mixture slowly. The solution was stirred at -78 0 C for at least 1 h, slowly warmed to RT and stirred overnight. The reaction was cooled to -78 0 C and quenched with H 2 O. The solution was warmed to RT, extracted with EtOAc, dried (Na 2 SO ⁇ , and concentrated.
• Step 1
• 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.
• 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 Gen ⁇ aro (ed.), The Science and Practice of Pharmacy, 20 th Edition, (2000), Lippincott Williams & Wiikins, Baltimore, MD.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral Injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• 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.
• the compound is administered orally.
• the pharmaceutical preparation is in a unit dosage 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.
• a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
• the activity of the compounds of Formula I or I! can be determined by the following procedures. In Vitro PPE10 assay
• PDE10A1 activity was measured in white opaque 384-weil Opti-Piates (Perkin Elmer Life Sciences) using a scintillation proximity assay (GE Healthcare).
• Human recombinant PDE10A1 was purchased from BPS Bioscience, Inc.
• the reaction mixture contained PDE10A1 ( 0.02 nM), 10 nM [ 3 H]cAMP ((5 ⁇ 8- 3 H]Adenosine 3 ⁇ 5"-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in 50 mM Tris-HCI, pH 7.5 S 8.3 mM MgCI 2 , 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 ⁇ l.
• 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 hydroiyzed in the absence of compound. Ki values were determined as described by Cheng and Prusoff (1973).
• Compounds of Formula I having a Ki of less than 100 nM are Examples 3E, 3F 1 3S 5 3V 1 4, 4B, 4F, 4H, 41, 4K 1 5, 5F 5 5K, 5M 1 5O 1 5Q 1 5R 1 5S, 6H, 7E, 8B, 8C 1 9, 10A 1 10C, 10D, 10E, 10F, 10G, 10H, 13, 13A 1 13C, 13F 1 13G 1 131, 13J, 13K, 13L 1 13N 1 13O r 13P, 13Q, 13R, 13S, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B 1 29F, 32B, 34B, 35, 36C, 36E, 36F and 36G2.
• Compounds of Formula tl having a Ki of less than 100 nM are those in Exampfes 3, 3D, 3G S 3I 1 3O, 3R, 3T 1 3W 1 3Y, 3AA ; 3CC 1 4C, 40, 4P 1 4G, 4R, 4S, 4V, 5H 1 5P 1 5T S 5V 1 5W, 5Y, 6, 6A 5 61, 6K, 6L S 6M, 6N, 6P, 7, 7D, and 12.

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