EP2350072A1 - Substituted pyrazoloquinolines and derivatives thereof - Google Patents

Substituted pyrazoloquinolines and derivatives thereof

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Publication number
EP2350072A1
EP2350072A1 EP09748190A EP09748190A EP2350072A1 EP 2350072 A1 EP2350072 A1 EP 2350072A1 EP 09748190 A EP09748190 A EP 09748190A EP 09748190 A EP09748190 A EP 09748190A EP 2350072 A1 EP2350072 A1 EP 2350072A1
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EP
European Patent Office
Prior art keywords
alkyl
compound
ring
formula
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP09748190A
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German (de)
French (fr)
Inventor
Ginny D Ho
Shu-Wei Yang
Elizabeth M Smith
William Thomas Mcelroy
Kallol Basu
Jennifer Smotryski
Zheng Tan
Brian A. Mckittrick
Deen B. Tulshian
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Merck Sharp and Dohme Corp
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Schering Corp
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Publication of EP2350072A1 publication Critical patent/EP2350072A1/en
Withdrawn legal-status Critical Current

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    • 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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Abstract

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

Description

SUBSTITUTED PYRAZOLOQUtNOLINES 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 pyrazoioquinoϊines and derivatives thereof, to the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors for the treatment of PDE10-modulated disorders, to pharmaceutical compositions comprising the compounds, and to the use of additional substituted pyrazoloquinolines and derivatives thereof for the treatment of PDE10-modu!ated diseases.
Background of the Invention
Schizophrenia, a debilitating psychiatric illness affecting 1% of the world's population, is thought to be at least partly due to excessive nigral dopaminergic and insufficient corticostriatal glutamatergic input to the striatum. These neurochemical abnormalities lead to reduced striatal output to other areas of the brain, resulting in inappropriate behavioral activation. The efficacy of existing antipsychotics is largely due to antagonism of D2 dopamine receptors in the striatal medium spiny neurons (MSNs) that project to the globus pallidus (also known as the striatopailidal indirect output pathway). D2 dopamine receptor antagonism increases striatal output via the indirect striatopalϋdal pathway, which improves some of the aspects of schizophrenia, but does not affect striatal output via the direct striatonigral output pathway.
PDE 10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehier et ai, "The potential therapeutic use of phosphodiesterase 10 inhibitors'', Expert Opin. Ther. Patents (2007) 17(2):147-158.
PDE10 is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery. By increasing cAMP and cGJviP levels in ai! striatal MSNs, PDE10 inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopaliidai output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striata! output that characterizes schizophrenia. By increasing corticostriatal transmission, PDE10 inhibition should improve the cognitive dysfunction that characterizes schizophrenia. Furthermore, the discrete localization of PDE 10 should lead to an improved side effect profile: typical side effects inciude extrapyramidal syndrome, diabetes, weight gain, hyperproiactinemia, sedation and QTC prolongation.
PDE10 inhibitors have also been reported to be useful in treating in other CNS disorders such as psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome.
Papaverine has been identified as a PDE10 inhibitor, and has been shown to be effective in animal models of schizophrenia.
Heteroaromatic quinoline compounds useful as PDE 10 inhibitors are disclosed in VVO 2006/072828, and pyrrolodihydroisoquinoline PDE 10 inhibitors are disclosed in WO 2006/089815.
Antiviral and/or antitumor pyrazoloquinolines are disclosed in US 5,459,146, US 5,506,236 and US 5,608,067, and by Crenshaw et al, J. Med. Chem., 19(2), 262-275 (1976). Pyrazoloquinolines useful as activators of caspases and inducers of apoptosis are disclosed in US 2007/0253957 A1.
Summary of the Invention
In its several embodiments, the present invention provides a novel class of substituted pyrazoloquinoline PDE 10 inhibitor compounds and derivatives thereof represented by Formula I, below, pharmaceutical compositions comprising one or more of said compounds, and methods of treating PDE10 inhibitor mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds or pharmaceutical compositions. The invention also provides for methods of treatment of PDE10 inhibitor- mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome, using a class of substituted pyrazoϊoquinoiiπe PDE10 inhibitor compounds and derivatives thereof represented by Formula II,
Novel compounds of the invention have the structural Formula I:
Formula or a pharmaceutically acceptable salt thereof, wherein all substituents are independently selected; and the carbon atoms to which it is attached form a phenyl ring, a heteroaryl ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R2 is absent;
R1 is H, alkyl, alkoxy, aikoxyalkoxy, OH1 hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R6A)2! -N(R6β)2, -alkySN(R6B)2l -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalky(, -N(R6)SO2-alkyl, phenyl, CN,
-SO2R5, -SRfa, trimethylsilyl-, -SF5s -OSF5, " ■ / r , or
-(CH2)n-X~(CH2)m-R18, wherein X is -0-, -S-, or -NR6-, n is O, 1 or 2, m is 1 , 2 or 3 and R18 is selected from the group consisting of
R2 is H1 aikyl, alkoxy, alkoxyalkoxy, OH5 hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oaiky!, -O-alkyl-CO2H, -C{O)N(RδA)2[ -N(R6B)2i -aikylN(R6B)2, -NR6~C(O)N(R6A)2, -N(R6)C(O)Oatkyl, -N(R6)SO2-alkyi, 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, hydroxyaikyl, cycloalkyi, ~N(R6B)2, -OCF3, -CF3, -SF5, -OSF5 or -CN;
R4 is H, alkyi, alkoxyalkyl-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -aikyi-OC(O)-alkyi, -SO2-alkyl, -C(O)N(RδA) 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, aryI-{(R17a, R17b)-alkylene)-, heteroary!~((R17a, R17b)-alkylene)-, heterocycϊoa!kyl-((R17a, R17b)-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(R6)~aryl, -atkyi-N(R6)-heteroary[1 -aikyl-N(Rβ)-cycioalkyl, -aIkyl-N(Re)-heterocycloalkyl, ~a!kyl-heterocycioalkyl, heterocycloalkenyl, heteroaryl, heterocycloaikyl-heteroaryl-aikylene-, cycloalkyl (e.g., cyctopropyl),
b is 1 , 2 or 3; r is 1 or 2; t is O1 1 or 2; each R6 is independently selected from H and alky!; each R6A is independently selected from the group consisting of H, alkyl, aryi, heteroaryi, cycloalkyl, arylaJkyl- and heteroaryiaikyl-; 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, morphoiinyi, homomorpholinyi, thiomorphoJinyi or homothiomorpholinyf ring; each R6B is independently selected from the group consisting of H, aikyl, aryl, heteroaryi, cycloalkyl, arylalkyh heteroarylalky!-, -SO2alky!, ~SO2-aryi, -SOa-heteroaryS, -C(O)a!kyis -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl. -C(O)O-heteroaryi, -C(O)N(R6J2, -C(O)N R6-aryϊ, and -C(O)NR6~heteroaryI; or two R6B groups are afky! 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, morphoiinyl, homomorphoiinyl, thiomorphofinyl or hornothiomorpholiπyl ring; R9 is H, aikyi, 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 singte 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 aikyi, hydroxyalkyl and fluoroalkyl;
R13 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(R6A)2, -C(O)-alky!-NR6-C(O)-ary!! -C{O)-alky!-NR6-C(O)O-a!kyi, -C(O)-alkyϊ-NR6-C(O)O- bertzyl, ~SO2alkyl, -SO2-aryl, -SO2-alkylaryl, -SO2-heteroaryl or diphenylmethyl optionally substituted on a phenyl ring with haio;
R14 is H, alky!, hydroxyalkyl, cycloalkyl, -C(O)-cycloalkyl, -C(O)-alkyl-cycloalkyl, aryl, arylalkyj-, -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(R6A)2, -C(O)-alkyi-NR6-C(O)-aryi, -C(O)-alkyl-NR6-C(O)O~ alkyl, -C(O)-alkyl-NR6-C(O)O-benzyI, -S02aSkyl, -SO2-aryl, -SO2-alkylaryl, -SO2- 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, hydroxyaikyl, halo, -CF3, -C(O)Oalkyi, -C(O)N(R6A)2t aminoalkyh -N(R6B)2, -NR6-C(O)N(R6A)2, -NR6~C(O)-aikyi, -NR6-C(O)OaJkyl, -NR6-SO2-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 -(CH2J2-S- or -O- (CH2)2~O-; and
R17a is H or alkyl and R17b is H} alkyl, OH, F, -N(R6B)2! -NOR6, aSkoxy, CN, -CH2OH1 -CH2-O-alkyl, -CON(Rβa)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 =0, =NORδ or
-iCH2)2-%', provided that when R5 is heterocycloa!kyl-((R17a, Rm)~Eϊlkyϊene)- and the heterocycloalkyl ring is joined to the alkyiene group by a ring nitrogen, the R17b substituent on the α-carbon is H, alkyl, CN, -CH2OH5 -CH2-O-alkyf, ~CON(R6a)2, ~CH2N(Rδ)2 or -CO2R6. in one example, R3 for Formula i is H, alkyl, halo, fluoroaikyl, aikoxyalkyl, hydroxyaikyl, cycloaikyi, -N(R6B)2, -OCF3, -SF5, -OSF5 or -CN,
In one example R5 for Formula I is alkyl, -CN, -C(O)OR6A, -C<O)N(R6A)2, aryi-«R17a, R17b)-alkylene)-, heteroaryI-((R17a, R17b)-alkylene)-, heterocycloalkyKfR178, R17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyl-, aryialkynyl- heteroarylaikynyh bridged heterocycloalkyl, fused ring heterocycloalkyl, -alkyl-O-aryl - alkyl-O-heteroaryi, -alkyi-O-cycloalkyl, -alkyi-O-heterocycloalkyl, ~alkyl-N(R6)-aryl, -alkyl-N(R6)-heteroaryl, -alkyl-N(R6)-cycioalkyl, -alkyi-N(R6)-heterocyc!oalkyl, -alkyl-heterocycϊoalkyl, heterocycloalkenyl, heteroaryi,
The present invention further includes the compound of formula i in all its isolated forms.
The present invention also relates to a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a method of treating PDE 10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering a therapeutically effective amount of at least one compound of Formuia I or a pharmaceuticaϊly acceptable salt thereof to a mammal in need of such treatment. In another embodiment, the invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceuticaliy acceptable carrier.
In another embodiment, the present invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of structural Formula il:
Formula Il or a pharmaceutically acceptable saft thereof, wherein all substrtutents are independently selected;
(S <■" and the carbon atoms to which it is attached form a phenyl ring, a heteroaryi ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R2 is absent;
R1 is H, aikyi alkoxy, alkoxyalkoxy, OH, hydroxyaikyl, -CF3, -OCF3, halo, -O-cycløalky!, benzyloxy, -C(O)OaikyL -O-aIkyl~CO2H, -C(O)N(R6A)2) -N(R6B)2, -afkyiN(R6B)2, -NR6-C(O)N(R6A)2s -N(R6)C{O)Oalkyl. -N(R6)SO2~aIkyf, phenyl, CN,
-SO2R6, -SR6, trimethylsiiyh ~SF5s -OSF5i -C(=NOR6)-R6 <λ ~ or
-(CH2)π-X-(CH2}m-R )18 , wherein X is -0-, -S-, or -NR -, n is O, 1 or 2, m is 1 , 2 or 3, and
R ,18 is selected from the group consisting of
R2 is H, aikyi, alkoxy, aikoxyaikoxy, OH, hydroxyafkyi, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-aϊkyl-CO2H, -C(O}N(R6A)2, -N(R6B)2, -aikylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oalky[! -N(R6)SO2-alkyi, phenyl or CN; or R1 and R2 on adjacent ring carbon atoms together form -0-CH2-O- or -O-(CH2)2-O-; r is 1 or 2;
R3 is H, aikyi, halo, fluoroalkyi, aikoxyalkyl, hydroxyaikyl, cycioalkyl, -N(R6B)2, -OCF31 -SF5, -OSF5 or -CN;
R4 is H, alky!, alkoxyaikyk benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl~OC(O)-alky!, - SO2-alkyt, ~C(0)N(R8A) 2 or -C(O}O-benzyl, wherein benzyf is optionally substituted by halo or alkoxy;
RSA is H, halo, OH, alkoxy, -O-alkyl-N(alkyl)2t -O-heterocycloalkyl, -O-alkyl-heterocycloafkyf, aryloxy-, arylalkoxy-, heteroaryloxy-. -N(RSA)2l -NR6-a!ky!-N(alkyl)2> -NR6-atky^O-alkyi-OH, ~NR6-hydroxyaikyi, -S-alkyi, -S-hydroxyalkyl, -S-aryL -S-alkylaryi, -S-heteroaryi, -S-alkyi-heterσaryl, -S-heterocycloalkenyl, -SC(O)-alkyl, -SO2-aϊkyI, -S-alkyI~C(O)OH, -5-aIkyI-N{aikyI)2,
— N N-a!kyl
-S-alkyl-NHC(O)H, -S-alkyl-C(O)NH-alkyl-pyrrolidinone, r
each R6 is independently H or alkyi; each R6A is independently selected from the group consisting of H5 alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl- 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, homornorpholinyl, thiomorpholinyl or homothiomoφholϊnyl ring; and each R6B is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, aryialkyl-, heteroarylalkyl-, -SC^alkyl, -SCVaryi, -SO2-heteroaryi! -C(O)alkyl, -C(O)aryl, -C(O)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -C(0)0-heteroaryi, -C(O)N(R6)2, -C(O)NR6-aryl, and -C(O)N R6-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, thiomorphoitnyl or homothiomorphoiinyi ring. in another embodiment, the invention relates to a method of treating PDE10 mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet- induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula Il or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Detailed Description
In one embodiment of Formula i, (S <■ forms a phenyl ring,
In some embodiments of Formula I1 R1 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
R1 is alkyl, preferably methyl, and R2 is H, OH, haio 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 R1 is halo and R2 is H; or R1 is haio and R2 is -OCF3; or R1 and R2 together are methylenedioxy,
In another embodiment of Formula I1 R3 is alkyl, preferably methyl, or H.
In another embodiment of Formula I, R3 is -CF3.
In another embodiment of Formula I, R4 is H, -C(O)O-alkyl, wherein alkyl is preferably t-butyl, or -SOaalkyl, preferably -SO2CH3.
In another embodiment of Formula I, b is 1.
In another embodiment of Formula I, R5 is selected from the group consisting of -CN, -C(O)N(R6A)2, aryK(R17a, R17b)-alkylene)-, heteroaryl-((R17a, R17b)-alkylene)-, heterocycloalkyi-((R17a, R17b)-alkylene)~, hydroxyalkenyl, heteroarylalkenyl-, heteroarylalkynyl-, heterocycloalkenyf, heteroary! (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen), , wherein b, r, R6, R6A S R9, R11, R12, R13, R14 R15, R17a and R17b are as defined above.
In other embodiments of Formula I1 R5 is -CN; -C(O)NH-alkyl-pyridyi; -CH(OH)-pheny); -alkylene-phenyl; -aikylene-pyridyl, -C(O)-pyridyl, -CH(F)-pyridyI;
-CH(OH)-pyridyl; -CH=CH-(CHΞ)3-OH;
' 14 wherein R14 is H, alkyi (preferably methyl) or hydroxyalkyl (preferably hydroxyethyl);
wherein R14 is H or atkyl; or In another embodiment of Formula I1 when R5 is heterocycloa!kyl-((R17a, R17b)~ aikylene)-, (R17a, R17b)-aikylene- is preferably -C(OH)-, and R5 is a group such as
In another embodiment of Formula I, R5 is heterocycloalkyl-((R17a, R17b)- alkylene)-, wherein R17a and R17b are independently H or aikyl, R5 being preferably
wherein b is 1 , 2 or 3; r is 1 or 2;
R7 is H, a!kyl or -SO2-aiky!;
R8 is 1 or 2 substituents independently selected from the group consisting of H, aikyl, OH1 hydroxyalkyf, halo, and -CF3;
R9 is H, alky!, or two hydrogen atoms on a carbon ring member are replaced by =0; and
R10 is H, aikyl or hydroxyalkyl.
Additional embodiments of compounds of Formula I wherein R5 is
.0
-CH2-N NH -CH2-N NH heterocycloalkyl-((R > 117/aa, R1 /D)-aikylene)~ are
-CH2-N' "NSO2CH3
optionally substituted by m ethyl or hydroxymethyl, optionally
-CH2-N / substituted by OH, F or CF3, and V—-1 optionally substituted by methyl or OH. Sn another embodiment of Formula I1 R5 is , r is 1 , R9 is H or aikyi,
and R13 is -SO2alkyl, -CONH2, -C(O)heteroary!f for example
C(0)cycloalkyl, for example ; more preferably, R13 is -SO2aikyl or
N NR 13
-CONH2. In another embodiment, R5 is W r r is 2, R9 is H and R13 is
~SO2alky! or -CONH2.
In another embodiment of Formula I, R5 is r js 2, and R15 is alky! (preferably methyl), allkoxy (preferably methoxy), -CF3, OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH2, -C(O)NH2, -CH2NH2, -C(O)0-alkyl, -NHSO2alkyl Or -NHC(O)NH2, where R15 is preferably in the
4-position. In another embodiment, R5 is M r jss 22,, and R15 is hydroxyalkyl, preferably hydroxymethyl, in the 3-position.
In another embodiment of Formula 1, R6 is r is 1. and R15 is OH or hydroxyalkyl (preferably hydroxymethyl).
Exampies of the heterocycfoaikyl-heteroaryl-alkytene- R6 group for Formula I include, but are not limited to:
Thus, in one example the heterocycloalkyl-heteroaryl-alkylene- R5 group for Formula I is:
In another example the heterocycloalkyf-heteroaryl-aikyiene- R5 group for Formula I is
In another example the heterocycloalkyf-heteroaryf-aikylene- R5 group for Formula I is
in one example the R5 cycJoalkyl group is cyclopropyl In another embodiment of the compounds of Formula I:
R1 and R2 are independently selected from the group consisting of H, aikyf, afkoxy, alkoxyaikoxy, -CF3, -OCF3 and halo.
R3 is H or alky!;
R4 is H1 -C(O)O-aikyl or -S02alkyl; and
R5 is selected from the group consisting of -CN1 -C(O)N{R6A)2( aryi-((R17a, R17b)- alkylene)-, heteroaryl-((R17a, R17b)-alkyϊene)~, heterocycloalkyK{R17a s R17b)-alkylene)-, hydroxyalkenyl, heteroarylalkenyh heteroarylalkynyl-, heterocycloalkenyi, heteroaryl (wherein the heteroaryl group can be joined through a ring carbon or a suitable ring nitrogen),
, wherein b, r, R6, R6A Rs, R11, R12, R13, R14, R15 S R17a and R17b are as defined above. in yet another embodiment of the compounds of Formula !:
R1 is alky!, preferably methyis and R2 is alkoxy, preferably methoxy; or
R1 is alkyj, preferably methyl, and R2 is -OCF3; or
R1 is alky!, preferably methyl and R2 is H, OH, haio or alkoxyaikoxy (preferably methoxyethoxy); or
R1 is aikoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H; or
R1 is alkoxyaikoxy (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 methyleneciioxy; R3 is alkyl; R4 Is H; and
R5 is -CN; -C(O)N H-alkyf-pyridyϊ; ~CH(OH)~phenyi; -alkylene-phenyl; -aϊkylene-pyridyl, -C(O)-pyridyi, -CH(F)-pyπdyl; -CH(OH)-pyridy);
■ (CH2)b-NR ,6— < O — 14 wherein R14 is H, alky!
(preferably methyl) or hydroxyalkyi (preferably hydroxyethyl);
~NR6-(CH2}b— / ) -NR6-(CH2)b— / NR14
N ' ; > ' wherein R is preferably H or alkyl; heterocycloalkyl-((R17a, R17b)-alkylene)-, wherein (R17a, R17b)-alkylene is heterocycϊoatkyl-((R17a, R'7b)-aikyiene)~, wherein R17a and R17b are independently H or alky!, preferably
, wherein b is 1 , 2 or 3; r is 1 or 2; R7 is H, alky! or -SO2-aikyI; R8 is 1 or 2 substituenfs independently selected from the group consisting of H, alkyi, OH, hydroxyalkyS, halo, and -CF3; R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0: and R10 is H, alkyl or hydroxyalkyf;
— N NR13 w r , wherein r is 1 , R9 is H or a!kyis and R13 is -S02alkyl, -CONH2, -C(0}heteroaryi, for example OH , or -C(0)cycloalkyi, for example
; more preferably R13 is -S02alky! or -CONH2;
herein r is 2, R9 is H and R13 is -S02alkyl or -CONH2; wherein r is 2, and R15 is alkyl (preferably methyl), alikoxy (preferably methoxy), -CF3, OH, hydroxyaikyl, preferably hydroxymethyl, halo (preferably F), -NH2, -C(O)NH2, -CH2NH2, -C(O)O-alkyl, -NHSO2alkyl or -NHC(O)NHa, where R15 is preferably in the 4-position; wherein r is 2, and R15 is hydroxyaikyl, preferably hydroxymethyi, in the 3-positioπ; or wherein r is 1 , and R » 15 ; i,s OH or hydroxyaikyl (preferably hydroxymethyl). Preferred compounds of Formula I are those in Examples 3E, 3F, 3S, 3V, 3BB, 4i 4At 4B, 4F, 4Ht 41, 4K, 4L 5, 5F, 5G, 5K1 5M, 50, 5Q, 5R, 5S1 6H, 7A, 7B5 7E, 8, 8A, 8B, 8C, 9, 1OA, 10C1 1OD, 1OE, 10F, 10G1 1OH, 13, 13-1 , 13A, 13B, 13C1 13D, 13F, 13G1 13I1 13J, 13K1 13L, 13N, 130, 13P, 13Q1 13R, 13S, 13T, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 23, 24, 26S 27, 27A, 27B, 27C, 28, 29A1 29B, 29D, 29E, 29F, 32B, 33, 34A1 34B, 35, 36C, 36E1 36F1 and 36G2.
More preferred compounds of Formula I are Examples 3E1 3F, 3S1 3VS 4, 4B1 4F, 4H, 4I1 4K, 5, 5F, 5K1 5M, 50, 5G, 5R, 5S1 6H, 7E1 8B, 8C, 9, 1OA, 1OC, 1OD, 1OE, 10F1 10G1 1OH, 13, 13A1 13C, 13F1 13G, 131, 13J, 13K1 13L, 13N1 130, 13P, 13Q, 13R1 13S, 13V, 14, 15, 16, 17, 18, 21 B1 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B, 29F, 32B, 34B, 35, 36C, 36E1 36F, and 36G2. in one embodiment the compound of Formula i is 3E. In another embodiment the compound of Formula ! is 3F. In another embodiment the compound of Formula i is 3S. in another embodiment the compound of Formula I is 3V. In another embodiment the compound of Formula I is 3BB. in another embodiment the compound of Formula 1 is 4. In another embodiment the compound of Formula I is 4A. In another embodiment the compound of Formula I is 4B. In another embodiment the compound of Formula I is 4F, In another embodiment the compound of Formula i is 4H. In another embodiment the compound of Formula I is 41. In another embodiment the compound of Formula I is 4K. In another embodiment the compound of Formula I is 4L, In another embodiment the compound of Formula I is 5. In another embodiment the compound of Formula I is 5F. In another embodiment the compound of Formula I is 5G. In another embodiment the compound of Formula f is 5K. In another embodiment the compound of Formula 1 is 5M. In another embodiment the compound of Formula I is 50. In another embodiment the compound of Formula ! is 5Q. In another embodiment the compound of Formula I is 5R. In another embodiment the compound of Formula S is 5S. In another embodiment the compound of Formufa I is 6H. in another embodiment the compound of Formula I is 7A. fn another embodiment the compound of Formula I is 7B. in another embodiment the compound of Formula I is 7E. In another embodiment the compound of Formula I is 8. In another embodiment the compound of Formula I is 8A. In another embodiment the compound of Formula I is 8B. In another embodiment the compound of Formula 1 is 8C. In another embodiment the compound of Formula I is 9. In another embodiment the compound of Formula I is 1OA. fn another embodiment the compound of Formula I is 1OC. In another embodiment the compound of Formula ! is 1OD. In another embodiment the compound of Formula I is 1OE. In another embodiment the compound of Formula I is 1OF. In another embodiment the compound of Formula I is 10G. In another embodiment the compound of Formula I is 10H. In another embodiment the compound of Formula I is 13. In another embodiment the compound of Formula I is 13- 1. In another embodiment the compound of Formula I is 13A. In another embodiment the compound of Formula I is 13B. In another embodiment the compound of Formula I is 13C. In another embodiment the compound of Formula i is 13D. In another embodiment the compound of Formula ! is 13F. In another embodiment the compound of Formula I is 13G. In another embodiment the compound of Formula I is 131. In another embodiment the compound of Formula I is 13J. In another embodiment the compound of Formula I is 13K. In another embodiment the compound of Formula I is 13L. In another embodiment the compound of Formula I is 13N. In another embodiment the compound of Formula I is 130. In another embodiment the compound of Formula I is 13P. In another embodiment the compound of Formuia I is 13Q. In another embodiment the compound of Formuia I is 13R. In another embodiment the compound of Formula I is 13S. In another embodiment the compound of Formula I is 13T. In another embodiment the compound of Formula I is 13V. In another embodiment the compound of Formula I is 14. In another embodiment the compound of Formula I is 15. In another embodiment the compound of Formula Ms 16. In another embodiment the compound of Formula ! is 17. In another embodiment the compound of Formuia I is 18. In another embodiment the compound of Formuia I is 21 B. Sn another embodiment the compound of Formula I is 21 D. In another embodiment the compound of Formula ! is 21 F. In another embodiment the compound of Formuia f is 22. In another embodiment the compound of Formula I is 23. In another embodiment the compound of Formula I is 24. in another embodiment the compound of Formula ! is 26. In another embodiment the compound of Formula ! is 27. In another embodiment the compound of Formula I is 27A. In another embodiment the compound of Formula I is 278, In another embodiment the compound of Formula I is 27C. tn another embodiment the compound of Formula ! is 28, In another embodiment the compound of Formula I Is 29A. In another embodiment the compound of Formula I is 298, In another embodiment the compound of Formula i is 29D. in another embodiment the compound of Formula i is 29E. In another embodiment the compound of Formula I is 29F. In another embodiment the compound of Formula I is 32B. In another embodiment the compound of Formula I is 33. In another embodiment the compound of Formula I is 34A. in another embodiment the compound of Formula I is 34B. In another embodiment the compound of Formula I is 35. In another embodiment the compound of Formula I is 36C. In another embodiment the compound of Formula I is 36E. in another embodiment the compound of Formula I is 36F. in another embodiment the compound of Formula I is 36G2.
in one embodiment of the compound of Formula Il forms a phenyl ring.
In some embodiments of Formula II, R1 and R2 are independently selected from the group consisting of R1 is H, alkyl, aikoxy, alkoxyaikoxy, -CF3, -OCF3 and halo.
In other embodiments of Formula II:
R1 is aikyl, 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 alkoxyaikoxy (preferably methoxyethoxy); or
R1 is alkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H; or R1 is aikoxyalkoxy (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 methyienedioxy.
In another embodiment of Formula II, R3 is alkyl, preferably methyls or H, In another embodiment of Formula II, R4 is H. in another embodiment of Formula Ii1 b is 1 ,
In another embodiment of Formula IL R5A is H, halo, -O-alkyi-N(aikyl)2, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, -N(R6A)2, -NR6-alkyl-O~alky1-OH, -NR6-hydroxyalkyis -S-hydroxyalkyl, -SO2-alkyl, 0r -S-alky!-NHC(O)H.
In other embodiments of Formula II, R5A is H, Cl, -O-(CH2)2-N(CH3)2, , -N(CHs)2, -NH(CHa)3CH3, -NH-(CH2)2-O-(CH2)2-OH,
~NH-(CH2)2-OH, -NH-CH2-CH(OH)-CH35 -NH-alkyi-morpholinyl, -S-CH2CH(OH)-CH2OH, or -SO2CH3-
In another embodiment, when R5A is -N(R6A)2, R5A is -N(R6A)-(cycioalkyl), wherein R6A 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, OH1 hydroxyalkyl, halo, and -CF3.
In another embodiment, when R5A is -N(R6A)2l R5A is -N(R6A)-(heterocycloalkyl), wherein R6A is H or alkyl, and wherein heterocycloalkyl is or wherein R19 is H, alkyl or -SO2alkyl. In another embodiment, when R5A is -N(R6A)2, R5A is -NR6-alkyl~aryi, wherein R6A 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 -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -0-(CH2J2-O-. In another embodiment, when R5A is ~N(R6A)2) R5A is -NR6A-afkyi-heteroalky! wherein R6A is H or alkyi, and wherein the heteroary! portion is preferably pyridyϊ, e.g.
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
wherein q is 1 or 2, s is 2 or 3, and R6 is as defined above. tn another embodiment of the compounds of Formula II:
R1 and R2 are independently selected from the group consisting of H, alkyi, alkoxy, alkoxyaikoxy, -CF3, -OC F3 and halo.
R3 is H or aikyl;
R4 is H1 -C(O)O-alky) or -SO2alkyl; and
R5A is selected from the group consisting of H, halo, -O-alkyl-N(alkyl)2, -O-heterocycloaikyl, -O-alkyϊ-heterocycloaikyi, -N(R6A)2, -NR6-alkyf-O-alkyl-OH, -NR6-hydroxyalkyl, -S-hydroxyalkyl, -SO2-alkyl and ~S-a!kyϊ-NHC(O)H,
In yet another embodiment of the compounds of Formula II:
R1 is alkyi, preferably methyl, and R2 is alkoxy, preferably methoxy; or
R1 is alkyi, preferably methyl, and R2 is -OCF3; or
R1 is alkyi, preferably methyl, and R2 is H, OH, halo or alkoxyaikoxy (preferably methoxyethoxy); or
R1 is alkoxy, preferably methoxy, and R2 is alkoxy, preferably methoxy, or H; or
R1 is alkoxyaikoxy (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;
R3 is alkyi;
R4 is H; and R5A is H; Cl; -O-(CH2)2-N(CH3)2; -N(CHa)2;
-NH(CH2)3CH3; -NH-(CH2)2-O-(CH2)2-OH; -NH-(CH2)2-OH; -NH-CH2-CH(OH)-CH3; -NH-alky!-morpholinyl; -S-CH2CH(OH)-CH2OH; -SO2CH3; or
-N(RβA)2 selected from the group consisting of:
-N(R6A)-(cycloaikyl), wherein cycioaikyl is cyciobutyl, cyciopentyl, cyclohexyl or cycϊoheptyl, and wherein the cycioaikyl potion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably 1 or 2 substituents independently selected from the group consisting of alkyl, OH1 hydroxyalkyl, fluoro, and -CF3;
-N(R6A)-(heterocycloaikyl), wherein heterocycloalkyl is or , wherein R19 is H, alky! or -S02a!kyl; -NR6A-alkyl-aryl, preferably -NR6A-alkylphenyl, wherein the phenyl portion is optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are preferably independently selected from the group consisting of OH, alkoxy or -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -O-(CH2)2~O-;
-NR6A-alkyl-heteroaIkyi 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
wherein q is 1 or 2, s is 2 or 3, and R6 is as defined above, and wherein the RDA in "N(R6A)-(cycfoalkyl)5 -N(R6A)-(heterocycloalkyl), -NRΘA-alkylaryl and -NR6A-aIkyi~ heteroaryl is preferably H or aikyl. Preferred compounds of Formula Il are those in Examples 3, 3D, 3G, 3I1 3M, 3N, 30, 3R, 3T1 3W1 3Y1 3AA, 3CC, 4C, 40, 4P, 4Q1 4R1 4S, 4U1 4V, 5A1 5C, 5D1 5E, 5H1 5Jr 5L1 5P1 5T. 5VS 5W1 5X1 5Y, 6, 6A, 6D, 61, 6K1 6L5 6M5 6N, 60, 6P1 7, 7D1 12, 13U, 2OA, 2OC, 21 C5 and 21 E.
More preferred compounds of Formula II are those in Examples 3, 3D, 3G, 3I, 30, 3R, 3T1 3W1 3Y1 3AA, 3CC5 4C1 40, 4P, 4Q, 4R, 4S, 4W, 5H; 5P, 5T1 5V1 5W1 5YS 6, 6A1 61, 6K1 6L, 6M, 6N, 6P! 7, 7DS and 12.
In one embodiment the compound of Formula INs 3. In another embodiment the compound of Formula Il is 3D. In another embodiment the compound of Formula Il is 3G. In another embodiment the compound of Formula Il is 31. In another embodiment the compound of Formula Il is 3M. In another embodiment the compound of Formula Il is 3N. in another embodiment the compound of Formula I! is 30. In another embodiment the compound of Formula Il is 3R. In another embodiment the compound of Formula Il is 3T. In another embodiment the compound of Formula Il is 3W. In another embodiment the compound of Formula Il is 3Y. In another embodiment the compound of Formula Il is 3AA. In another embodiment the compound of Formula Il is 3CC. In another embodiment the compound of Formula Il is 4C. In another embodiment the compound of Formula Il is 40. in another embodiment the compound of Formula Il is 4P. In another embodiment the compound of Formula Il is 4Q. In another embodiment the compound of Formula Il is 4R. In another embodiment the compound of Formula Il is 4S. in another embodiment the compound of Formula Il is 4U. In another embodiment the compound of Formula Il is 4V, In another embodiment the compound of Formula Il is 5A. In another embodiment the compound of Formula Il is 5C. In another embodiment the compound of Formula H is 5D. In another embodiment the compound of Formula Ii is 5E. Sn another embodiment the compound of Formula Il is 5H. in another embodiment the compound of Formula I! is 5J. ϊn another embodiment the compound of Formula Il is 5L. In another embodiment the compound of Formula Il is 5P. In another embodiment the compound of Formula Ii is 5T. Jn another embodiment the compound of Formula Ii is 5V. In another embodiment the compound of Formula H is 5W. In another embodiment the compound of Formula Ii is 5X. In another embodiment the compound of Formula Il is 5Y. In another embodiment the compound of Formula il is 6. In another embodiment the compound of Formula Il is 6A. In another embodiment the compound of Formula il is 6D, In another embodiment the compound of Formula Il is 61. In another embodiment the compound of Formula Il is 6K. In another embodiment the compound of Formula II is 6L. In another embodiment the compound of Formula Il is 6M. In another embodiment the compound of Formula Il is 6N. In another embodiment the compound of Formula Il is 6O. In another embodiment the compound of Formula Il is 6P. In another embodiment the compound of Formula I! is 7. In another embodiment the compound of Formula Il is 7D. In another embodiment the compound of Formula Il is 12. In another embodiment the compound of Formula Il is 13U. in another embodiment the compound of Formula II is 2OA. In another embodiment the compound of Formula Il is 2OC. In another embodiment the compound of Formula Ii is 21 C. In another embodiment the compound of Formula Il is 21 E.
As used herein, the following terms are as defined below unless otherwise indicated;
Mammal means humans and other mammalian animals.
The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alky)" as well as the "alkyl" portions of "hydroxyalkyl", "haioalkyl", "alkoxy", etc.
Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyi groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyf groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more tower alky! groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
AIkylene means a difunctional alkyl group obtained by removal of a hydrogen atom from a C1-C3 alkyl group as defined above. Non-limiting examples of aikyiene include methylene, ethylene and propylene {i.e., -CH2-, -(CH2J2--, -(CH2)S-). When substituted, the R17a and R17b groups can be on the same or different carbon atoms. The proviso that when R5 is heterocycioaikyi-((R17a, R17b)-alky1ene)- and the heterocycloalkyt ring is joined to the alkylene group by a ring nitrogen, the R17b substttuent on the α-carbon is H5 alkyi, CN, -CH2OH, -CH2~O-alkyi, -CON(Raa)2, -CH2N(R6J2 Or -CO2R6 is intended to eliminate unstable compounds, e.g., compounds wherein the α-carbon (herein meaning the carbon adjacent to the ring nitrogen) is substituted by OH.
Hydroxyalkyl represents an alkyt group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alky! group.
Alkoxy means an alkyl-O- group in which the aikyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
Aminoalkyl means an amino-alkyl group in which the a!ky! group is as previously described. The bond to the parent moiety is through the alkyi.
Halogen represents fluoro, chloro, bromo and iodo.
"Hydroxyalky!" means a HO-aikyi- group in which alkyi is as previously defined. Preferred hydroxyalkyls contain lower alkyi. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Alkenyi" means means a straight or branced aliphatic hydrocarbon group containing at least one carbon-carbon double bond and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkeny! groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain, "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyj, propenyf, n-butenyi, 3-methy!but-2~enyf n-pentenyl, octenyi and decenyl.
"Hydroxyalkenyl refers to an aikenyl group substituted by one or more hydroxy! groups, preferably 1 or 2 hydroxy groups, provided that a hydroxy! group is not present on a carbon that is part of a double bond. "Alkynyr means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyi groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyi chain. "Lower aikynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyi groups include ethynyl, propynyl, 2-butyny! and 3-rnethylbutynyl.
"Aryi" means an aromatic monocyclic or multicyclic ring system comprising about 8 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryi group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryi groups include phenyl and naphthyl.
Ηeteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryis contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryis include pyridyl, pyrazinyl, furanyl, thienyL pyrimidinyi, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyi, thiazolyl, pyrazolyl, furazanyl, pyrroiyl, pyrazolyi, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxaiinyl, phthalazinyl, oxindoly!, imidazo[1 ,2-a]pyridinyI, imsdazo[2,1~blthiazoiyf, benzofurazanyl, indoiyl, azaϊπdolyl, benzimidazolyl, benzothienyl, quinoiinyl, imidazolyl, thϊenopyridyf, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyi, benzothiazoiyi and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl. tetrahydroquinolyl and the (ike.
"Aralky!" or "arylafky!" means an aryl-alkyl- group in which the aryi and alkyi are as previously described. Preferred araikyls comprise a lower alky! group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aikenyl, alkynyl, aryi, heteroaryl, aralkyi, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyiheteroaryl, -CH(Yi)(Y2), -O-Y1, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxy, -C(O)Y1, halo, nitro, cyano, -C(O)2-Yi, -S(O)2-Yi, -S-Y1, cycloalkyi, cycloalkylaikyi, heterocycloalkylalkyi, cycloalkenyl, -Cf=N-CN)-NH2, -C(=NH)~NH2, -C(=NH)-NH(alkyi), -NYiY2, -alkyl-N YiY2, -C(O)NYiY2, and -SO2NY1Y2, wherein Y1, Y2 and Y3 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryi, heteroaryl, cycloalkyi, heterocycioalkyl, aralkyi and heteroarylaikyl. "Ring system substituents" on aromatic rings can also be selected from the group consisting Of -SF5, -OSF6, -Si(Y4J3, -S(O)N(YO(Y2), -Ct=NOY1)Y2, -P(O)(OY1)(OY2), -N(Yi)C(O)Y2, -CH2-N(Yi)C(O)Y2, -CH2-N(Y1)C(O)N(Yi)(Y3), -N(Yi)S(O)Y2, -N(Yi)S(O)2Y2, -CH2-N(Y1)S(O)2Y2, -N(Y1)S(O)2N(Y2)(Y3), -N(Yi)S(O)N(Y2)(Y3), -N(Y1)C(O)N(Y2)(Y3), -CH2-N(Y1)C(O)N(Y2)(Y3), -N(Y1)C(O)2(Y2), -CH2-N(Yi)C(O)2(Y2), -S(O)Y1, =NOY1, and -N3, wherein Yi, Y2 and Y3 are as defined above and each Y4 is independently selected from alkyl, aryi, heteroaryl, cyciσalkyl, heterocycioalkyl, aralky! and heteroarylalkyl. Furthermore, the alkyl, cyciøafkyl, aryS, heteroaryl and heterocycioalkyl portions of Yi, Y2 or Y3 can be optionally substituted with 1 or 2 substttuents independently selected from the group consisting of halo, OH, -CF3, CN, aikoxy, -NH2, -NH-aikyl, -N(aikyl)2 and Si(alkyl)3. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CHa^- and the like which form moieties such as, for example:
Similarly, a single divalent moiety such as a divalent alkyi chain or a -O-(CH2)2-O~ group can simultaneously replace two available hydrogen atoms on one carbon atoms on a ring system. An example of such spiro moieties is:
" -Heterocyciyl" means a non-aromatic saturated monocyclic or multicyclϊc ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyi root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyi ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyi can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyi can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyi rings include piperidyf, pyrrolidinyl, piperazinyi, morpholinyl, thiomorpholinyl, thiazoϋdiπyl, 1.4-dioxanyL tetrahydrofuranyf, tetrahydrothϊophenyi, lactam, lactone, and the like.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxy! groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
are considered equivalent in certain embodiments of this invention,
"Heteroarylalkyl" means a heteroaryt-aikyl- group in which the heteroaryl and alky! are as previously described. Preferred heteroaralkyls contain a lower alky! group. Non-limiting examples of suitable heteroaralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
Similarly, cycloalkylalkyl and heterocycloalkylalkyl mean cycloaikyl-alkyl and heterocycloaikyl-alkyl groups wherein cycloalkyl, heterocycloalkyl and alky! are as previously described, wherein the alky! portion is preferably lower alkyl. The bond to the parent moiety is through the alkyl portion.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a usefui degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof, The term "purified" or 'in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
When phenyl, Formula I or Il has the structure
When "2 C I i?s heteroaryl, heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, pyrrolyl, thiazoiyl, imidazolyl and furanyl. Examples of such groups are shown in the following partial structures:
One skilled in the art will recognize that when er £ I is a five membered ring containing two heteroatoms, there is only one substitutabte carbon, hence R2 is absent. "Cycloaikyl" means a non-aromatic mono- or multϊcyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms. The cycfoaikyi can be optionally substituted with one or more "ring system subststuents" which may be the same or different, and are as defined above. Non-limiting examples of suitabfe monocyclic cydoalkyis include cyclopropyi cyclopenty), cyclohexyi, cycloheptyl and the like. Non-iimiting examples of suitable multicyclic cydoalkyis include 1- decalinyl, norbornyl, adamantly and the like. "Cycloalkenyl" means partially saturated species such as, for example, cyclopentene, cyclohexene, indanyl, tetrahydronaphthy! and the like.
As used herein, the term "bridged heterocycfoaϊkyt" means a piperidinyl, ptperazinyl, rnorpholinyl, tetrahydropyranyl or tetrahydrofuranyl ring wherein a carbon on one side of the ring is joined by a C1-C3 alkyl group, or a hydroxy substituted C1-C3 alkyl group, to a carbon on the opposite side of the ring, provide that when the bridge is a C1 bridge both carbon atoms to which the bridge is bound to are not adjacent to the same heteroatom, Non-limiting examples include:
— N O? /— OH and \2J
As used herein, the term "fused ring heterocycioalkyl" means a 5 or six- membered heterocycioalkyl ring joined to a cycloalky! or heterocycloalky! ring through two adjacent shared carbon ring members. Non-limiting examples include
Haloalkyl represents an afkyl group as defined substituted by one or more halo atoms. Examples wherein haio is fluoro are -CH2F, -CHF2. -CF3, -CH2CF3, -CF2CF3 and the like. ft should afso be noted that any carbon as we!! as heteroatom with unsatisfied valences in the text, schemes, examples and Tabtes herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene ef al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
When any variable (e.g., alkyl, halo, etc.) occurs more than one time in any constituent or in Formula I or II, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs, solvates and co-crystais of the compounds of the invention are also contemplated herein.
The term "prodrug", as employed herein, means a compound that is transformed in vivo to yield a compound of Formula (I) (or Formuia II) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference thereto.
For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-CsJalkyt (C2-Ci2)a!kanoyloxymethyf, 1-{alkanoyioxy)ethy! having from 4 to 9 carbon atoms, 1-methyi-1~(aikanoy!oxy)-ethy: having from 5 to 10 carbon atoms, alkoxycarbonyioxymethy! having from 3 to 6 carbon atoms, 1-(a!koxycarbonyioxy)ethyi having from 4 to 7 carbon atoms, 1-methyi-1- (alkoxycarbonyioxy)ethyl having from 5 to 8 carbon atoms, N- (aikoxycarboπyl)amiπomethy! having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyi)amino)ethyl having from 4 to 10 carbon atoms, 3-phthaϋdyl, 4- crotonolactonyi, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylam!no(C2-C3)alkyt (such as β-dimethyiaminoethyi), carbamoyl-(C1-C2)aiky!, N,N-di (Ci-C2)alkylcarbarnoy)-(C1- C2)afkyl and piperidino-, pyrrolidine- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-pCeJaikanoyloxymethyl, 1-((Ci- C6)alkanoyloxy)ethyl, 1-methyl-1-((Ci-C6)alkanoyfoxy)ethyl, (Cr Ce)alkoxycarbony!oxymethyi, N-(Ci -C6)a!koxycarbonylaminomethyl, succinoyf, (Ci- C6)alkanoy!, α-amino(Ci-C4)a!kanyl, arylacyi and α-aminoacyl, or α-aminoacyi-α- arninoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(CrC6)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 crystallimty to the combined form, Co-crystais are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I of this invention in different proportions depending on the nature of the co-crystal. (Rmenar, J. F. et. al. J Am. Chem, Soc. 2003, 125, 8456). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective as PDE 10 inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula i or El can form salts which are also within the scope of this invention. Reference to a compound of Formula I or M herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)'\ as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as we!! as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I or Il contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesujfonat.es, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesuSfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toiuenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stah! et al, Camille G, (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiiey-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1- 19; P, Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, atkafi metal salts such as sodium, lithium, and potassium salts, aikaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, f-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialky! sulfates (e.g. dimethyl, diethyl, and dibutyi sulfates), long chain haiides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of Formula I or II, and salts, solvates, co-crystais and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, co-crystals and prodrugs of the compounds as well as the salts and solvates, co-crystals of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents. including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemptated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with ail other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "satt" , "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautorners, positional isomers, racemates or prodrugs of the inventive compounds. Isomers can be prepared using conventional techniques, either by reacting optically pure or opticaliy enriched starting materials or by separating isomers of a compound of Formula I. isomers may aiso include geometric isomers, e.g., when a double bond is present
Those skilled in the art will appreciate that for some of the compounds of Formula I or II, one isomer will show greater pharmacological activity than other isomers.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2H, 3H1 11C, 13C, 14C5 15N, 180, 170, 31P, 32P. 35S, 18F, 36CI and 123I5 respectively.
Certain isotopically-labelled compounds of Formula (I) (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 (I) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like 11C or 18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123I can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., ^H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo haif-iife or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 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. 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 H1 and of the salts, solvates, co-crystals and prodrugs of the compounds of Formula I or II, are intended to be included in the present invention.
In this specification, the term "at least one compound of Formula I (or Formula II)" means that one to three different compounds of Formula ! or Il may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I or il is used.
Compounds of Formula I are prepared by methods known in the art. A typical reaction scheme for preparing the compounds of Formula I is shown in Scheme 1.
SCHEME 1
NHNH,
An amino-substituted ary! or heteroaryl, 1 , in absolute ethanol is treated with ammonium hydroxide and then carbon disulfide, followed by chloroacetic acid and then hydrazine to give compound 2, which is purified by column chromatograpy on silica gel. Compound 2 in ethanol is treated with ethyl 2-chIoroacetoacetate to give ester compound 3. Ester 3 in absolute ethanol is treated with KOH in water. The resulting mixture is heated at reflux and then cooled. On acidification, the acid 4 is isolated. The actd 4 is treated with POCI3 under reflux, followed by cooling and adjusting the pH with 20% NaOH to give the chϊoro compound 5. Chloro compounds 5 can be converted to the R5-susbtituted compounds of formula 6 using methods known in the art and described in the examples below. Compounds of Formula Il can be prepared by methods similar to those described for compounds of Formula I, and by methods known in the art, for example the procedures described in US 5,459,146, US 5,506,236, US 5,608,067, and US 2007/0253957, all incorporated herein by reference, and by Crenshaw et al, J, Med. Chem., 19(2), 262-275 (1976).
In the scheme above and in the following preparative examples, the following abbreviations are used: RT - room temperature; Ac - acetyl; Me - methyl; Et - ethyl; Ph - phenyl; iPr - isopropyl; t-Bu - t-butyl ; tBOC - N-tert-butoxycarbonyi; DCM - dichloromethane; DMSO - dimethylsulfoxide; DlBAL - diisobutyia!uminum hydride; DCE - dichloroethane; DMF - dimethylformamide; THF - tetrahydrofuran; SEM-CI - 2-(tπmethylsilyl)ethoxymethy! chloride; DAST - (diethylamino)suffur trifluoride; TBAF - tetrabutylammonium fluoride; sat. (or sat) is saturated; IBX - iodoxybenzoic acid; TFA - trifluoroacetic acid.
Where LC/MS data are presented, analyses were performed using an Applied Biosystems APi-150 mass spectrometer and Shimadzu SCL-10A LC system. Column: Phenomenex Gemini C18, 5 micron, 50 mm x 4.6 mm ID; Gradient: From 90% water, 10% 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 II.
Example 1
CS2 (4.5 mL) was added to a mixture of 4-methoxy-2-methyIaniiine (9.0 g), absolute EtOH (25 mL) and NH4OH (6 mL). After 1 hr; chioroacetic 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 DC to give a purple-white solid (11.52 g). This material was purified with a silica gel normal phase column (330 g) eluting with CH2CI;? with a slow ramp to 10%, then 50% MeOH over 60 min. The fractions containing compound JU2 were concentrated in vacuo to give compound 1^2 (10.71 g) as an orange-white solid. LCMS: M is 211. Found: M+1 is 212 at 2.27 min. Step 2:
Compound 1^2 (8.33 g) and absolute EtOH (50 mL) were stirred at RT for 10 min. Ethyl 2-chloroacetoacetate (6.7 mL) in absolute EtOH (5 mL) was added dropwise. After 2 hr., the mixture was refrigerated for 1 hr. The mixture was filtered to give a yellow solid that was washed with cold EtOH1 and dried in a vacuum oven at 50 0C.
The filtrate was evaporated to about 10 mL, refrigerated overnight and filtered. The precipitates were combined to give compound I^ as a yellow soSid (7.30 g). LCMS: M is 289. Found, M+1 is 290 at 3.88 min.
KOH (13.7 g) in water (80 mL) was slowly added to a mixture of compound 1N3 (7.63 g) and absolute EtOH (40 mL) over 4 min. The resulting mixture was heated under reflux for 5 hr, then cooled in an ice bath and water (50 mL) was added. Cone. HCI (-18 mL) was added until the pH was ~3 to give a yeiiow solid. The solid was washed with water and dried in vacuum oven at 50 0C to give compound %A as a fluffy tan solid (4.59 g) that was used in the next step without purification. Step 4:
A mixture of compound I^ (4.50 g) and POCI3 (5 mL) was purged with nitrogen and heated under reflux for 1 hr. The mixture was cooled to 70 0C and concentrated in vacuo (bath at 70 0C). The mixture was cooled to 0 0C, 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 0C to give compound I^ as a brown solid (3.90 g) which was used in Example 3 without purification.
The following compounds were prepared in a similar manner.
Example 2
Alternate Synthesis of Analogs of 1-2
Hydrazine monohydrate (2 g) was added to a solution of isothiocyanate ΪM (10 g) in DCM slowly. The mixture was stirred at RT for 3 hr and the resulting mixture was filtered. The precipitate was washed with DCM to yield 7Λ (10,54 g). LCMS: M is 235. Found: m/z 236 (MH+).
The following compounds were similarly prepared.
microwave
Compound JM5 (0.825 g), piperazine (2.0 g), trifluoromethyltoluene (3.5 mL) and dioxane (3.5 mL) were added to a microwave vial. The mixture was purged with nitrogen, sealed and placed in a microwave reactor. The mixture was heated at 165 0C for 2 hr. The reaction mixture was diluted with EtOAc5 DCM, and MeOH, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was dried (K2CO3) and concentrated in vacuo to give a residue (0.51 g). The residue was purified on silica gel piates (6, 1000 μ) eluting with DCM:MeOH (9:1) to give the title compound 3 as a yeliow solid (0.23 g). LCMS: M is 311. Found M+1 is 312 at 1.66 min.
The following compounds were prepared in a similar manner:

50
51
Example 4
microwave
A microwave vial charged with I^ (0.100 g), NaH (0.030 g), KI (0.060 g), and 4- methylpiperidine (0.44 mL) was purged with nitrogen, sealed and heated in a microwave reactor at high setting for 1 hr. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a residue (0.066 g). This residue was purified on silica gel plates (6, 1000 μ) eiuting with acetone:DCM (2.8) to give the compound 4 (0.012 g). LCMS: M is 324. Found M+1 is 325. Retention time: 2.84 min
The following compounds were prepared in a similar manner:
53
54
* Compound 4C is a byproduct of the genera! reaction of Example 4. The following compounds were prepared in a similar manner, using dioxane as the solvent and heating the reaction mixture at 160 0C overnight:
The following compounds were prepared in a similar manner, using dioxane as the solvent, without Kl, and heating the reaction mixture at 160 0C overnight: 
The following compound was prepared in a similar manner, using dioxane as the solvent without Kl:
Example 5
H2N /-Λ neat
±£ y0 125 0C
A mixture of compound VS (41 mg) and 4-amiπomethyltetrahydropyran (400 mg) was stirred at 125 0C overnight. The reaction mixture was cooled to room temperature and water was added. The mixture was filtered and the precipitate was purified by silica gel column chromatography (hexane-EtOAc) to give compound 5 (16 mg). The mono
HCi salt was prepared by adding -1 equivalent of HCI/ether to a solution of compound 5 in ether and then evaporating to dryness. LCMS: M is 340. m/z 341 [M+Hf. Rt is 2.23 min.
The following compounds were obtained in a similar manner:

60
61
Example 6
A mixture of compound 1^5 (50 mg), homαmorpholine hydrochloride (200 mg), iriethyiamine (-200 mg) in DMSO (1 mL) was stirred at 125 0C for two days The reaction mixture was cooled to room temperature and water was added. The mixture was filtered. The precipitate was purified on silica gel plates eluting with 2% DCM- MeOH to give the compound 6 (5 mg) The mono HCf salt was prepared by adding ~1 equivalent of HCI/ether to a solution of compound 6 in ether and then evaporating to dryness after 1 hr LCMS M is 326 Found m/z 327 (MH)+ R1 is 2 4 mm
The following compounds were prepared in a similar manner
64
The following compound was prepared in a similar manner, using NMP as the
The following compounds were prepared in a similar manner, using NMP as the solvent and (1-Pr)2NEt as the base
Example 7
A mixture of compound JM (92 mg), homomorphøline 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 1M NaOH (50 ml_) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gef chromatography, efuting with a gradient of 0 to 100% EtOAc in hexanes to afford 10 mg of compound 7 as yellow oil. LCMS: M is 342. Found: M+1 is 343.
The following compounds were obtained in a similar manner: 
Example 3
CH1JSO2Ci pyridine
CH2CI2
S
A mixture of compound 3 (0.15 g) and DCM (10 mL) was treated with pyridine (50 μL) and then CH3SO2CI (50 μL). After 24 hr, additional pyridine (25 μL) and CH3SOaCi (25 μL} were added. After 2 hr, the reaction mixture was concentrated and purified on silica gel plates (2, 1000 μL) eluting with DCM:MeOH (9:1) to give a yellow solid. This yellow solid was suspended in DCM and filtered to give compound 8 as a yellow solid (0.050 g). The filtrate was placed on silica gel plates (2, 1000 μ) and eiuted as above to give additional compound 8 as a yeilow solid (0.028 g). LCMS: M is 389, Found M+1 is 390 at 0.79, 2.04 min.
acid (0.33 ml). After 1.5 hr, the reaction mixture was concentrated in vacuo. DCM was added and concentrated in vacuo (twice), The residue was partitioned between DCM and 2.5N K2COa solution. The organic layer was dried (K2CO3), concentrated in vacuo, and the residue was purified on silica gel plates (2, 1000 μ) 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
Trimethylsilyl isocyanate (55 μl) was added to compound 9 (121 mg) in dry dioxane (15 mL) at 60 0C, The mixture was heated for 70 mirs. The reaction mixture was cooled to RT, MeOH (5 mL) was added, and the mixture was concentrated in vacuo to give a yellow solid (142 mg). This solid was purified on silica gel plates (4, 1000 μ) eluting with DCM:MeOH (9:1) to give a yellow foam (92 mg). This foam was purified on a reverse phase HPLC column (10 μ; 30 x 100 mm) eluting with 0.1% HCO2H in CH3CN / 0.1% HCO2H in water (10% to 95% over 20 min) (2 runs) to give W2 A as an orange solid (63 mg) and 10-B as a yellow solid (22 mg). LCMS for ICkA: M is 368. Found: M+1 is 369 at 2.26 min (uv). LCMS for 10-B: M is 411. Found: M+1 is 412 at 0.82, 1.87 min (uv).
The following compounds were prepared in a similar manner:
Example 11
Compound ^S was treated with N-Boc-pϊperazine in a similar manner as described in Example 3 to give compound 11-1 as a brown solid {104 mg), which was used in the next step without purification. LCMS: M is 411. Found: M+1 is 412 at 2.88 min.
Under a nitrogen atmosphere, a soiution of 11-1 (100 mg) in CH3CN (3 mL) was treated with freshly ground K2CO3 (168 mg) and then CH3! (90 μl_). After 1 hr, additional CH3I (100 mL) and CH3CN (1.5 mL) were added. After 2.5 hr., additional CH3I (100 μl_) was added. The mixture was heated at 60 0C for 18 h. The reaction mixture was purified on silica gel plates (4, 1000 μ) eluting with DCM: MeOH 9:1 to give an amber oil (70 mg). This oil was purified on silica gel plates (2, 1000 μ) eluting with DCM:MeOH (9:1) to give an amber film (39 mg). This amber film was placed on silica gel plates and eluted with EtOAc:hexane (1 :3) to give the title compound 11-2 as a yellow foam (21 mg) which was used in the next step. LCMS: M is 425. Found: 426 at 4.56 min. Step 3:
A mixture of compound 11-2 (19 mg) in dry DCM (750 μL) was treated with trifluoroacetic acid (250 μL). After 35 min, the reaction mixture was concentrated in vacuo. DCM was added and the mixture was concentrated in vacuo two times. The residue was partitioned between DCM and 2.5N K2CO3. The organic layer was dried (K2CO3) and concentrated in vacuo. The residue was purified on a silica gel plate (1000 μ) eluting with DCM:MeOH:NH4OH (90:10:1) to give compound H as a yellow solid (12 mg). LCfVIS: M is 325. Found: M+ 1 is 326 at 2.37 mϊn (uv).
The foilowing compounds were prepared in a similar manner:
12-1 Compound JMS (1 ,0 g) was treated with 48% HBr in water. The resulting mixture was heated at 110 °C for 18 hr. The reaction mixture was cooled and filtered to give compound 12-1 as a dark green sofid which was used in the next step without purification. LCIVtS: M is 229. Found: M+1 is 230 at 1.96 min. Step 2:
A mixture of compound 12-1 (1.10 g) in acetic anhydride (40 mL) was treated with p-toluenesulfonic acid (40 mg). The resulting mixture was heated at 125 0C for 2 hr. The reaction mixture was cooled and filtered to give the title compound 12-2 (0.22 g) as a white solid. The filtrate was concentrated in vacuo to ~5 mL and filtered to give additional title compound (0.31 g). LCMS: M is 313. Found: M+1 is 314 at 3.51 min. Step 3:
A mixture of compound 12-2 (0.52 g) in DCM (30 mL) was treated with oxalyl chloride (2.4 mL) and stirred at RT for 4 hr. The reaction mixture was concentrated in vacuo to give a light tan residue. This residue was triturated with diethyl ether, then filtered to yield compound 12-3 (0.46 g) as an off white solid. LCMS: M is 331. M+1 is
332 at 4.41 min. Step 4:
dioxarte A microwave vial was charged with compound 12.-3 (0.20 g), trifϊuoromethylfoluene (2 mL), dioxane (2 mL), and /V-methyihomopiperazine (0.6 mL). The vial was purged with nitrogen, sealed, and heated at 165 CC in a microwave reactor. The reaction mixture was purified on silica gel plates (4, 1000 μ) eluting with DCM:MeOH (9:1) to give a yellow solid (0.27 g). This residue was purified on silica gel plates (2, 1000 μ) using DCM;MeOH:NH4OH (90:10:1) as the solvent to give a yellow solid. The chromatography was repeated using silica gel plates (4. 1000 μ) to yield compound 12 (0.76 g) as a yellow solid. LCMS: IvI is 325. Found: M+1 is 326 at 0.91: 1.43 min.
13-1
A solution of compound U> (4.6 g) and KCN (12 g) in DMSO (120 mL) was stirred at 110 0C overnight. The reaction mixture was cooled, diluted with water and filtered. The precipitate was washed with water, ether and DCM to yield compound 13; i (-3 g). LCMS: M is 252. Found: m/z 253 (MH)+.
33a. DiBAL (42 mL, 1M in hexane) was slowly added to a solution of compound 13-1 (3 g) in toluene (150 mL) at -78 0C. The mixture was warmed to RT and stirred overnight. The mixture was quenched at -78 0C 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 (1.2 g), which was used in the next step without purification. LCMS: M is 326, m/z 256 [M+H]+. Step 3:
13-2 °wNH
12
NaBH(OAc)3 CH2Cl2
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-H2O, 0.1% formic acid) to yield compound 13. (110 mg). The mono HCI salt was prepared by adding -1 equivalent of HCI/ether to an ether solution of compound 13 and then evaporating to dryness after 1 hr. LCMS: M is 326. Found: m/z 327 (MH+). R1 is 2.20 min.
The following compounds were prep _ared in a sim _ila ^r m^anner:


80
Example 14
A mixture OfAICI3 (1.02 g) and DCE (30 mL) was cooled to 0 °C EtSH (760 μL) was added dropwise. The resulting solution was stirred at 0 °C for 10 min. then a mixture of 13S (351 mg) and DCE (30 mL) was added. The solution was warmed to RT and stirred 3 h, H2O (150 mL) and sat NaHCO3 (150 mL) were added. The mixture was extracted with EtOAc (3 x 200 mi_). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give compound 14, which was used without further purification.
Example 15
A mixture of 14 (32 mg), K2CO3 (31 mg), 2-bromoethyI methyl ether (10 μL) and DMF (2 rtiL) was heated at 80 0C 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 vacuo. The residue was purified by reverse phase HPLC, eluting with 0.1% HCOOH in CH3CN / 0.1% HCOOH in water (10% to 95% over 20 min). Fractions possessing the product were neutralized with sat. NaHCO3 and the product extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give 1 mg of compound IjS as a yellow oil. LCMS: M is 384. Found: M-M is 385, Rt = 2.07 min.
A mixture of I1S (5.45 g), 1M HCl (40 mL), and MeOH (180 mL) was heated at 90 "C for 18 h. The mixture was allowed to cool to RT and the MeOH was removed in vacuo. 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 coof 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 0C in a vacuum oven, affording 3.98 g of compound 16-2 as a brown solid, which was used without further purification.
NaH (393 mg, 60% dispersion in mineral oil, 9.83 mmol) was added to a mixture of 16-2 (2.65 g) and THF (50 mL). The resulting mixture was stirred at RT for 1 h. SEM-CI (2.3 mL) was added. The solution was stirred at RT for 2 h, whereupon sat NaHCO3 (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 THF (20 mL) was cooled to -78 °C. n-BuLi (1.7 mL, 1.04M in hexanes) was added dropwise. The resulting solution was stirred at - 78 "C for 20 rnin. 4-Pyridinecarboxaldehyde (220 μL) was added dropwise. The solution was stirred at -78 °C for 45 min, then allowed to slowly warm to RT over 1 h. The solution was stirred at RT for 12 h, whereupon H2O (20 mL) was added. The mixture was extracted with EtOAc (2 x 3OmL). 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), HCi (2 ml), H2O (4 mL), and EtOH (4 mL) 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 / 0.1% 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 vacuo to give 30 mg of compound 16 as a yellow solid, LCMS: M is 334. Found: M+1 is 335, Rt = 1.95 min.
IM
A solution of 16-4 (22 mg) and IBX (29 mg) in DMSO (2 mL) was stirred at RT for 30 min. EtOAc (20 mL) was added and the solution washed with 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, HCI (250 μL). H2O (500 μl_), and EtOH (500 μL) was stirred at RT for 1 h. The solution was then heated at 75 °C for 45 min. The solution was cooled to RT and sat. 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 HPLC5 elutϊng 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 5 mg of compound 17 as a yellow solid. LCMS: M is 332. Found: M+1 is 333, R1 - 3.57 min.
DAST (5 drops) was added via syringe to a solution of 16-4 (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, HCI (250 μL), H2O (500 μL), and EtOH (500 μL) was stirred at RT for 2 h, then at 75 "C for 30 min. Sat NaHCOs (2 mL) and 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. The residue was purified by reverse phase HPLC1 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. NaHCOs 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, Rt - 2.68 min. The following compounds were prepared in a similar manner^
A mixture of compound 13-1 (7 mg) in cone H2SO4 (-400 μl_) was heated at 60 C for 3 days The mixture was cooled and added to ice water The resulting solution was neutralized with 15% NaOH solution and filtered. The precipitate was washed with DCM and then recrystatized from MeOH to afford compound IJt (1 mg).
Example 20
20-1 20-2 20-3
A mixture of 1-iodo-3-methylbenzoic acid, 20-1 , (5 g), 1-benzyl-3~methyl-1 H- pyrazof-5-amine, 20-2, (3.93 g), K2CO3 (2.64 g) and copper powder (0,61 g) in water (20 mL) was heated at reflux overnight. The resulting mixture was cooled to RT. The pH was adjusted to 14 with 1N aqueous NaOH and the mixture was extracted with CH2CI2. Concentrated HCI was added to the aqueous solution to adjust the pH to 3 and the mixture was filtered. The white solid was dried in a vacuum oven at 50 0C to give 20-3 (3.05 g). LCMS: M is 321. Found: MH+ is 322. The solid was used without further purification. The following compound was prepared in a similar manner.
Step 2:
A mixture of 20-3 (3.05 g) and POCl3 (5 mL) in a 50 mi round bottom flask was purged with nitrogen and heated at 1000C for 2 h. The mixture was concentrated in vacuo at 700C . ice was added to the mixture and the pH was adjusted to ~8 with 20% NaOH. The mixture was extracted with CH2CI2, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on SiO2, eluting with a gradient of 0 to 10% EtOAc in hexanes to afford 184 mg of 20-4. LCMS: MW is 321. Found: MH+ is 322,
The following compound was prepared in a similar manner.
Step 3:
A mixture of compound 20-4 {184 mg) and 4-amiπotetrahyd ropy ran (462 mg) was heated at 1500C overnight. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with CH2CS2, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on SiO2, 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.
: M isN 4H32. 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 0C 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 0C for 36 h. The mixture was filtered and concentrated in vacuo. Aqueous NaHCOa solution was added to the residue. The resulting mixture was extracted with 10% MeOH in CH2CI2, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on SiO2, 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:
LCMS: M is 342, Found: MH+ is 343. Retention time: 2.03 min. Example 21
Step 1:
Compound 21-3 was prepared using procedures simitar to those described in earlier examples.
/T-BuLi (0.31 mL, 1.6 M in hexane) was added to a solution of 21-3 (199 mg) at - 78 0C, The mixture was stirred at -78 0C for 1 hr. DMF (0.32 mL) was added. The mixture was sfowfy warmed to RT over a 2~hr period. Additional DMF (1 mL) was added to the mixture at RT and the resulting mixture was stirred for 1 hr. The reaction was quenched with water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on SiO25 eiuting with a gradient of 0 to 10% hexane in EtOAc to afford 2.4 mg of 21 -A (LCMS: M is 351 Found: MH+ is 352) and 78 mg of a mixture of 21 -A and 21-4 (LCMS: M is 379. Found: MH+ is 380) with a ratio of 1 :2.
Step 2:
A mixture of 21-4 (500 mg), 2-methy!morphoIine (266 mg)r Et3N (0.74 mL) and NaBH(0Ac)3 in CH2Cb (30 mL) was stirred at RT overnight. The reaction was quenched with 1N NaOH, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The residue was treated with TFA (13 mL) and the resulting mixture was heated at 73 0C for 40 h. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 extracted with CH2CI2, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on SiO2. eluting with a gradient of 0 to 2% MeOH in CH2Cl2 followed by HPLC to afford 129 mg of 21B. LCMS: M is 344. Found: MH* is 345, Retention time: 2.87 min.
The following compounds were prepared in a similar manner:
Example 22
Cyclopropyi magnesium b THF) was added to a suspension of 2Λ-A (93 mg) in THF at -40 0C and stirred for 1 hr The mixture was warmed to RT, treated with saturated aqueous NaHCO3 solution, extracted with EtOAc5 dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on SiO2, 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 0C overnight. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3, extracted with CH2Ci2, dried (MgSO4) and concentrated in vacuo. The residue was purified by HPLC to afford 10 mg of 22. LCMS: M is 301 , Found MH+ is 302, Retention time: 3.43 min. Example 23
LAH (0.46 mL, 2M in THF) was added to a solution of 7F (117 mg) in dioxane (1 mL) at 0 0C dropwise. The reaction mixture was warmed to RT, stirred for 10 min, and heated at 1000C 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 CH2Cb, stirred for 90 min, filtered and concentrated. The residue was purified by column chromatography on SiO2, eiuting with a gradient of 0 % to 10% MeOH in CH2CI2 to afford 9.5 mg of 23. LCMS: MW is 359. Found: MH+ is 360. Retention time: 1.97 min.
Example 24
TEA (0.23 mL), DMAP (27 mg), and Boc2O (0.36 mg) were added to 16^2 in THF (20 mL) and stirred at RT overnight. The reaction was quenched with 10% aqueous Na2COa solution, extracted with EtOAc, washed with 10% aqueous NH4CI solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on SiCb eluting with a gradient of 0 to 30% EtOAc in hexane to give 24-1.
Compound 24 was prepared from 24-1 according the procedure for the synthesis of 16-4 using π-BuLi (0.51 ml, 1.6 M ), and tetrahydro-2H-pyran~4~carba!dehyde (93 mg) in THF (8 mL). LCMS: MW is 441. Found: MH+: 442. Retention time: 4.65 min.
Example 25
A mixture of compound 24 (28 mg) and TFA (1 mL) was stirred at RT for 2 hr. The mixture was concentrated in vacuo, and partitioned between CH2CI2 and aqueous NaHCOs. 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 342S retention time: 2.92 min.
Example 26
Step 1:
rt-8uLi in hexane (1 ml, 1.6 M) was added to a solution of 16-2 (50 mg) in anhydrous THF at -78 0C dropwise. After stirring for 1 hs a solution of 26-1 (175 mg) in THF was added to the mixture slowly. The solution was stirred at -78 0C for at least 1 h, slowly warmed to RT and stirred overnight. The reaction was cooled to -78 0C and quenched with H2O. The solution was warmed to RT, extracted with EtOAc, dried (Na2SO^, and concentrated. The residue was purified by silica gel chromatography eluttng with EtOAc-Hexane (0-100%) to afford 26^2 (17 mg). LCMS: M is 440. Found: M+1 is 441, retention time: 3.78 min. Step 2:
A mixture of 26-2 (15 mg) and 20% TFA in 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: IV! is 340. Found: M-M is 341 , retention time: 2.12 min.
Example 27
/7-BuLi in hexane (2 mL, 1.6 M) was added to a mixture of 16-2 (200 mg) in anhydrous THF at -780C dropwise. After stirring for -40 rnin, p-fluorobenzylaldehyde (200 mg) was added slowly. The mixture was stirred at -78 0C for ~1 h, slowly warmed to RT (~1 hr) and stirred at RT for 1 hr. The reaction was cooled to -78 0C. 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 elυting with EtOAc-Hexane (0-100%) to afford 27 (18 mg). LCMS: M is 351 Found: M+1 is 352, retention time: 3.66 min.
The following compounds were prepared in a similar manner:
97
A mixture of 27A (12.7 m inane (19.4 mg) in CH2Cl2 was stirred at RT for 2 h. The mixture was treated with saturated aqueous NaHCOs. 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:
28A
Example 29
Step i:
A mixture of 16-2 (100 mg), 2-ethynyipyridine (41 mg), PdCI2(PPh3)2 (19.4 mg), CuI (5.3 mg), diisopropylamine (1.5 ml_) in toluene (-3 mL) was degassed and charged with N2. The mixture was heated at ~9G 0C 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-H2O, 0.01 % HCOOH, 10% to 100% gradient) to yield 29B (9 mg), LCMS: M is 332, Found. M+1 is 333, retention time: 2.25 min.
The following compounds were prepared in a simiiar manner:
Ex. No. Structure i ftΛW ! ES-MS ! Rt 100
101
To a mixture of 16-2 {500 mg) in anhydrous THF (10 mL) in a microwave vial was sequentially added 4-(aminomethy[)pyridine (540 mg), DBU (760 mg), Herrmann's catalyst (40 mg), f-Bu3P'HBF4 (30 mg), and Mo(CO)6 (440 mg). The mixture was sealed, purged with N2, and placed in a microwave reactor. The mixture was heated at 150 0C (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 CH2CI2- MeOH, and followed by HPLC (CH3CN-H2O, 0.1 % HCO2H) to yield 30 (206 mg). LCMS; M is 361. Found: M-M is 362, retention time: 2.14 min.
The following compound was prepared in a similar manner:
Example 31
To a solution of 4-hydroxy-tetrahydropyran (~5 mL) in Λ/~methyl-2~pyrroiidinone (-5 mL) was added NaH (764 mg of 60% in oil) at 0 0C. After stirring for 0.5 h, compound JUS (500 mg) was added to the reaction mixture. The mixture was heated at 1 10 0C overnight. The mixture was cooled and quenched with ice water, and filtered. The residue was purified by silica gel column chromatography eluting with DCM-MeOH to afford compound 3J. (-76 mg). LCMS: M is 327. Found: m/z 328 (MH+), retention time: 2.79 min.
Example 32
Step 1 :
To a solution of KI (60 mg) in Λ/-methyl-2-pyrroitdinone (-1 mL) in a microwave vial was added NaH (60 mg of 60% in oil) and then compound jM5 (100 mg). The mixture was sealed, purged with N2, and placed in a microwave reactor. The mixture was heated at 150 0C (high absorption) for 1 hr. The reaction mixture was cooled, treated with ice water and filtered. The precipitate was washed with ether to yield 32A (-50 mg). LCMS: M is 324. Found: m/z 325 (MH+), retention time: 2.47 min Step 2:
To a solution of compound 32A (35 mg) in THF at -78 0C was added DIBAL (323 uL, 1M in hexane). The mixture was warmed to RT and stirred for 2 h. The mixture was cooled -78 0C, treated with IVIeOH (140 uL), sat, NH4Cl (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: m/z 309 (IvIH+), retention time: 2,22 min. A mixture of 16-2 (133 m d (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 0C 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 get chromatography, eluting with a gradient of 0 to 70% EtOAc in hexanes. The resultant residue was further purified by reverse phase HPLC1 equipped with a silica gel column 6 μm; 25 x 100 mm eluting with 0.1% HCOOH in CH3CN / 0.1 % HCOOH in water (10% to 95% over 20 mm). 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, LCIVIS: M is 304. Found: M+1 is 305, Rt = 2.46 min.
Example 34
Preparation of 34A:
A mixture of 1^2 (124 mg), 4-vinyipyrfdine (110 μL), Pd(OAc)2 (20 mg), P(o-tol)3 (20 mg), TEA (1 mL) and DMF (1 mL) was heated for 30 min at 120 6C 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 rnL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0 to 100% EtOAc in hexanes. The residue so obtained was further purified by reverse phase HPLC, eluting with 0.1% HCOOH in 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 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 rnL) 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 HPLC1 eiuting 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 11 mg of 34B as a yellow oil. LCMS: M is 332. Found: M+1 is 333, Rt = 2.17 min.
A solution of 35-1 (TIPS is triisopropylsilyl) (1.35 g) in THF (25 mL) was cooled to -78 "C. /1-BuLi (2.30 mL, 1.04 M in hexanes) was added dropwise. The resulting solution was stirred at -78 °C for 20 min, whereupon B(OMe)3 (500 μL) was added. The mixture was stirred at -78 "C for 1 h, whereupon a 1 :1 solution of MeOH and H2O (4 mL) was added. The mixture was warmed to RT and H2O (20 mL) was added. The mixture was extracted with Et2© (3 x 40 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to obtain 35-2. Step 2:
35-3
A mixture of 16-2 (300 mg), the crude 35-2, Pd(PPh3J4 (96 mg), Na2CO3 (40 mg), toluene (8 mL), EtOH (2 mL), and HaO (2 mL) was heated in a microwave reactor at 120 6C 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 THF (10 mL) and TBAF (1 M solution in THF, 450 μLs 0.45 rnmol) was added. The mixture was stirred at RT for 30 min. H2O (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 gef chromatography, eluting with a gradient of 0 to 35% EtOAc ϊn hexanes. The residue was purified by reverse phase HPLC, efuting with 0.1% HCOOH in 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 14 mg of 35 as a yellow solid. LCMS: M is 292. Found: M+1 is 293, Rt - 2.89 min.
To a cold (0 0C), stirred solution of dtisopropyl amine (135 mg) in anhydrous THF (5 rnL) was added /i-BuLi (0.81 mL of 1.6 M solution in hexane) dropwise via syringe. After being stirred at 0 0C for 20 min, the solution was cooled to -78 0C and 4- methylpyrimidine (118 mg) was added dropwise via syringe. The resulting solution was stirred at -78 0C for 1 h. in a separate flask, 3.6-1 (150 mg) (prepared in a manner similar to compound 16-2) was dissolved in anhydrous THF (5 mL). To this solution was added NaH (33 mg of 60% in oil) in portions at RT. The resulting mixture was stirred at RT for 1 h before being added dropwise via syringe at -78 0C 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 CH2Cb (3 x 20 mL). The combined organic iayer was dried over MgSO4, filtered and concentrated to give a residue which was purified by column chromatography on silica eluting with 30: 1 CH2CI2:Me0H to afford 36 (118 mg) as a light yellow solid. LCMS: M is 373. Found M+1 is 374. Retention time: 3.75 min.
The following compounds were prepared in a similar manner: 108
109
The amount and frequency of administration of the active compound employed and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient. A typical recommended dosage regimen can range from about 10 mg/dose to about 100 mg/dose, preferably about 10 to about 50 mg/dose, and more preferably about 20 to about 25 mg/dose.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A Genπaro (ed.), The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wiikins, Baltimore, MD.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral Injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered In portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
The activity of the compounds of Formula I or I! can be determined by the following procedures. In Vitro PPE10 assay
PDE10A1 activity was measured in white opaque 384-weil Opti-Piates (Perkin Elmer Life Sciences) using a scintillation proximity assay (GE Healthcare). Human recombinant PDE10A1 was purchased from BPS Bioscience, Inc. The reaction mixture contained PDE10A1 ( 0.02 nM), 10 nM [3H]cAMP ((5\8-3H]Adenosine 3\5"-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in 50 mM Tris-HCI, pH 7.5S 8.3 mM MgCI2, 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 μl. The assay was initiated with the addition of substrate and was allowed to proceed for 30 minutes at room temperature before being stopped by the addition of 300 μg yttrium SPA PDE beads. The reaction mixtures were thoroughly mixed, and the beads were allowed to settle for 30 minutes. The plates were then counted in a TopCount scintillation counter. Under these conditions, less than 30% of the substrate was hydroiyzed in the absence of compound. Ki values were determined as described by Cheng and Prusoff (1973).
Using the test procedures described above, the following compounds of Formula I were found to have Ki values of less than 500 nM: Examples 3E, 3F, 3S1 3V, 38B1 4, 4A, 4B, 4F1 4H, 41, 4K1 4L, 5, 5F1 5G, 5K1 5IVI5 50, 5Q, 5R, 5S, 6H, 7A, 7B, 7E, 8, 8A1 8BS 8C, 9, 10A, 10C, 10D, 10E, 10F1 10G, 10H, 13, 13-1 , 13A, 13B, 13C, 13D, 13F, 13G1 131, 13J. 13K5 13LS 13N, 130, 13P. 13Q, 13R5 13S1 13T1 13V, 14, 15, 16, 17, 18, 21B, 21 D, 21F, 22S 23, 24, 26, 27, 27A, 27B1 27C, 28, 29A, 29B. 29D, 29E, 2SF, 32B. 33, 34A5 348, 35, 36C, 36E, 38F and 38G2. Compounds of Formula I having a Ki of less than 100 nM are Examples 3E, 3F1 3S5 3V1 4, 4B, 4F, 4H, 41, 4K1 5, 5F5 5K, 5M1 5O1 5Q1 5R1 5S, 6H, 7E, 8B, 8C1 9, 10A1 10C, 10D, 10E, 10F, 10G, 10H, 13, 13A1 13C, 13F1 13G1 131, 13J, 13K, 13L1 13N1 13Or 13P, 13Q, 13R, 13S, 13V, 14, 15, 16, 17, 18, 21 B, 21 D, 21 F, 22, 26, 27, 27A, 27B, 27C, 29B1 29F, 32B, 34B, 35, 36C, 36E, 36F and 36G2.
Using the test procedures described above, the following compounds of Formula II were found to have Ki values of !ess than 500 nM: Examples 3, 3D, 3G, 31, 3M, 3N, 3O1 3R, 3T1 3W1 3Y, 3AA, 3CC, 4C, 40, 4P1 4Q, 4R, 4S, 4U, 4V, 5A, 5C1 5D, 5E1 5H. 5J, 5L, 5P, 5T, 5V, 5W, 5X, 5Y, 6, 6A1 6D, 61, 6K, 6L, 6M, 6N, 6Oη 6P, 7, 7D, 12, 13U, 2OA, 20C5 21C1 and 21 E. Compounds of Formula tl having a Ki of less than 100 nM are those in Exampfes 3, 3D, 3GS 3I1 3O, 3R, 3T1 3W1 3Y, 3AA; 3CC1 4C, 40, 4P1 4G, 4R, 4S, 4V, 5H1 5P1 5TS 5V1 5W, 5Y, 6, 6A5 61, 6K, 6LS 6M, 6N, 6P, 7, 7D, and 12.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. AN such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1 , A compound of Formula I:
Formula I or a pharmaceutically acceptable salt thereof, wherein and the carbon atoms to which it is attached form a phenyl ring, a heteroaryi ring of 6 ring members wherein 1 or 2 ring members are nitrogen atoms, or a heteroaryl ring of 5 ring members wherein 1 or 2 ring members are heteroatoms selected from the group consisting of N, S and O, provided that when it is a 5- membered heteroaryl containing two heteroatoms, R2 is absent;
R1 is H, alkyl, alkoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-COaH, -C(O)N(R6A)2, -N{R6β)2, -alkylN(R6B)2r -NR6-C(O)N(R6A)2, -N<Re)C(O)Oalkyi, -N(R6)SO2-alkyl, phenyl, CN,
-SO2R6, -SR6, trimethylsilyh -SF5, -OSF5, or
-(CH2)n-X-(CH2)m-R >1 δ , wherein X is -0-, -S-, or -NRb~, n is O1 1 or 2, m is 1 , 2 or 3, and
R ) 18 is selected from the group consisting of
and n^y<^ R2 is H, alkyl, aikoxy, alkoxyafkoxy, OH, hydroxys Ikyl, -CF3, -OCF3, halo, -O-cyciσaikyl, benzyloxy, -C(O)Oalkyl, -O-alkyi-CO2H, -C{O)N<R6A)2, -N(R6B)2! -aIkyIlsi{R6B)2, -NR6~C(O)N(R6A)2, -N(R6)C(O)OaIkyl, ~N(R6)SO2-a!kyl, phenyl or CN; or R1 and R2 on adjacent ring carbon atoms together form -0-CH2-O- or ~O-(CH2)2-O-;
R3 is H, aikyi, halo, fluoroalkyl, aJkoxyaikyl, hydroxyalkyl, cycloalkyl, -N(R6B)2, -OCF3, -CF3, -SF5, -OSF5 or -CN;
R4 is H, alkyl, alkoxyalkyl-, benzyl, -C(O)alkyi, -C(O)Oalkyl, -alkyi-OCfOJ-alkyi, - SO2-alkyl, -C(O)N(R6A)2 or -C{O)O-benzyis wherein benzyl is optionally substituted by halo or aikoxy;
R5 is alkyl, -CN, -C(O)OR6A, -C(O)N(R6A)2, aryl-((R17a, Rm)-alkyleneh heteroaryl-((R17a, R17b)-alkyiene)-; heterocycloalkyl-((R17a, R17b)-aikyiene)-, hydroxyalkenyl, heteroaryiaikenyh arylalkynyl-, heteroaryfalkynyl-, bridged heterocycloalkyl, fused ring heterocycloatkyl, -alkyl-O-aryl, -alkyl-O-heteroaryi, -afkyl-O-cycioaikyl, -alkyl-O-heterocycloalkyl, -alkyl-N(R6)-aryl, -alkyf-NfR^-heteroaryl. -alkyl-NCR^-cycloalkyl. -alkyl-NCR^-heterocycioalky!, -alkyl-heterocycloafkyf, heterocycioalkenyl, heteroaryl, heterocycloalkyl-heteroaryi-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 aikyl; each R6A is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycioalkyl, arylaikyl- and heteroaryialkyl-; 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 ptperazϊnyt, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl or homothiomorpholinyf ring; each RδB is independently selected from the group consisting of H, alkyl, ary!t heteroaryl, cycioalkyl, arylaikyl-, heteroaryialkyl-, -SO2aikyl, -SO2-aryi, ~S02-heteroaryl, -C(O)alkyl, -C(O)aryt, -C(O)-heteroary!, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-heteroaryl! -C(O)N(R6J2, -C(O)NR6-aryl, and -C(O)NR6-heteroaryl; or two ReB 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, thiomorpholinyi or homothiomorphoϋnyl ring;
R9 is H, alkyl, or two hydrogen atoms on a carbon ring member are replaced by =0;
R11 is alkyl, phenyl or two hydrogen atoms on a single carbon ring member are replaced by a sptrαcycfϊc group is formed by replacing two hydrogen atoms on a single carbon ring member with -(CH2)^6- or ~O-(CH2)2-O-;
R'2 is 1 or 2 substituents independently selected from the group consisting of alkyl, hydroxyalkyl and fluoroaϊkyl;
R13 is hydroxyafkyi, cycioalkyl, -C(O)-cyc!oalkyl, -C(O)-aikyl-cycloalkyf, aryl. arylaikyl-, -C(O)alkyl, -C(O)Oalkyl. -C{O)ary!s ~C(O)~aikyiaryf, -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-alky[1 -C(O)-alkyl~NR6-C(O)O- benzyl, -SOzalkyl; -302-aryi, -SO2-alkyIaryl, -SO2-heteroaryi or diphenyfmethyf optionally substituted on a phenyl ring with halo;
R14 is H, alkyl, hydroxyalkyl, cycloalkyl, -C(O)-cycloaikyli -C(O)-alkyI-cycIoalkyI, aryl, arylalkyh -C(O)alkyl, -C(O)Oalkyl, -C(O)aryl, -C(O)-alkylaryl, -C(O)O-aryl, -C(O)O-alkylaryI, heteroaryl, heteroarylalkyl-, -C(O)-heteroaryl, ~C(O)N(R6A)2, -C(O)-a!kyl-NR6-C(O)~ary!f -C(O)~alkyi-NR6~C(O)O- alkyl, -C(O)-alkyJ-NR6-C(O)O-benzyl, -SO2aikyl, ~SO2-aryl, ~SO2-alkylaryi, -SO2- heteroaryl or diphenylmethyl, optionafiy 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, aminoalkyh -N(R6B)2, -NR6-C(O)N(R6A)2> -NR6-C(O)-aikyl! -NRe-C(O)Oalkyi, -NR6-SO2-alkyl, -alkyl-imidazolyl, wherein the imidazoiyl is optionally substituted with aikyi, and phenyl, or two hydrogen atoms on a carbon ring member are replaced by -(C H2^e- or -O- (CH2J2-O-; and
R17a is H or alkyl and R17b is H, alky!, OH1 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 =0, =NORδ or -(CH2)^6; provided that when R5 is heterocycloa!kyl-((R17a, R17b)-alkylene)- and the heterocycloaJky! ring is joined to the alkyfene group by a ring nitrogen, the R17b substituent on the α-carbon is H, alky!, CN, -CH2OH, -CH2-O-alkyl, -CON(R6a)2l -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, alky!, alkoxy, atkoxyalkoxy, -CFs, -OCF3 and halo.
4. The compound of claim 1 wherein: R1 is alky!, and R2 is alkoxy; or
R1 is alkyl and R2 is -OCF3; or
R1 is alkyl and R2 is H, OH1 halo or alkoxyaikoxy ; or
R1 is alkoxy and R2 is aikoxy or H; or
R1 is alkoxyaikoxy 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 aikyl or H, and R4 is H, -C(O)O-alkyi, or -S02alkyl.
6. The compound of claim 1 wherein R5 is selected from the group consisting of -CN5 -C(O)N(R6A)2, aryl-((R17a, R17b)-alkylene}-, heteroaryl-((R17a. R17b)-alkylene)-, heterocycioaikyl-((R17a, R17b)-alkylene)-, hydroxyalkenyl, heteroaryialkenyi-, heteroaryialkynyh heterocycloalkenyl-, heteroaryi,
7, The compound of claim 1 wherein Rδ is -CN; -C(O)NH-alkyl-pyridyl; -CH(OH)-phenyϊ; -alkylene-phenyi: -alkylene-pyridyl, -C{O)-pyridyl, -CH(F)-pyridyl;
-CH(OH)-pyridyl; -CH=CH-pyridyl; -C≡C-pyrrdyl;
R14 wherein R14 is H1 alkyl or hydroxyalkyi;
wherein R14 is heterocyctoalkyl-((R )1?a , D R117/bB)-alkylene)- selected from the group consisting of heterocycloalkyi-((R17a, R17b)-afky)ene)-, wherein R17a and Rπb are independently H or alkyl, selected from the group consisting of
Rio; wherein b is 1 , 2 or 3; r is 1 or 2; R7 is H, alkyl or -SO2~afkyl; R8 is 1 or 2 substituents independently selected from the group consisting of H1 alkyl, OH, hydroxyaikyl, halo. and -CF3; R9 is H, aikyl, or two hydrogen atoms on a carbon ring member are replaced by =0; and R10 is H, aikyl or hydroxyalkyl;
_ wherein r is 1 , Rs is H or aikyl, and R13 is -SO2alkyl, -CONH2, »C(O)heteroaryI or -C(O)cycloalkyl;
herein r is 2, R9 is H and R13 is -SO2alkyl or -CONH2: wherein r is 2, and R15 is aikyl, allkoxy, -CF3, OH, hydroxyalkyl, halo, - NH2, -C(O)NH2, -CH2NH2, -C(O)O-alkyl, ~NHSO2aiky! Or -NHC(O)NH2; wherein r is 2, and R ,15 is hydroxyalkyl; or
8, The compound of claim 1 selected from the group consisting of Examples 3E, 3F5 3S, 3V1 3BB, 4, 4A, 4B, 4F, 4H, 41, 4K, 4L, 5, 5F, 5G1 5K, 5OS 5QS 5R, 5St 6H, 7A,
7B, 7CS 7F, 8, 8A, 8B, 8CS 9, 1OA, 10C1 1OD, 1OE, 1OF, 1OG, 1OH, 13, 13-1 , 13A1 13B5 13C1 13D1 13F, 13G1 131, 13J1 13K, 13L, 13N1 130, 13P, 13Q, 13R1 13S, 13T, 13V, 14, 15, 18, 17, 18, 21B1 21D, 21F1 22, 23, 24, 26, 27, 27A, 27B5 27CS 28, 29A. 298, 29Dt 29E, 29F1 32B, 33; 34A, 34B1 35, 36C1 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 Il for the manufacture of a medicament for treating phosphodiesterase 10 modulated disorders wherein said compound of Formula fl has the formula:
Formula M or a pharmaceutically acceptable salt thereof, wherein
.y
\ 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, alky!, aikoxy, alkoxyalkoxy, OH, hydroxyalkyl, -CF3, -OCF3, halo, -O-cycloalkyl, benzyloxy, -C{O)Oalkyl, -O-alkyl-CO2H, -C(O)N(R5A)2, -N(R68J2, -alkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oa!kyl, ~N{R6)SO2-aIkyJ, phenyl, CN,
-SO2R6. -SR6, trimethylsityl-, -SF5, »OSF5i -C(=NOR6)-R6, , w r Qf
-(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, hydroxyaikyl, -CF3, -OCF3, halo, -O-cycioaiky!, benzyloxy, -C(O)OaIkyi, ~O-alkyl-CO2H, ~C(O)N(R6A)2, -N(R6B)2t -aIkylN(R6B)2, -NR6-C(O)N(R6A)2, -N(R6)C(O)Oaikyl, -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-; r is 1 or 2;
R3 is H, alkyl, halo, fluoroalkyi, alkoxyalkyi, hydroxyaikyi, cycloalkyl, -N(R6β)2, -OCF3, -SF5, -OSF5 or -CN;
R4 is H1 alkyl, alkoxyaiky!-, benzyl, -C(O)alkyl, -C(O)Oalkyl, -alkyl-OC(0)-alkyl, - SO2-alkyi, ~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)2l -O-heterocycloalkyl, -O-aikyl-heterocycloalkyi, aryloxy-, arylalkoxy-, heteroaryloxy-, -N(R6A)2, -NR6-alkyl-N(alkyI)2, -NR6~alkyl~O-alkyl-OH, -NR6-hydroxyaϊkyl, -S-alkyl, -S-hydroxyalkyl, -S-aryl, -S-alkylaryi, -S-heteroaryi, -S-alkyl-heteroaryl, -S-heterocycloalkenyl, -SC(O)-alkyi, -SO2-alkyl, -S-alkyl~C{O)OH, -S-alkyl-N(alkyl)2,
/ — \ — N N-alkyl
-S-alkyi-NHCfOJH.-S-alkyl-CfOJNH-alkyl-pyrrolidinone, each R6 is independently H or alkyl; each R6A is independently selected from the group consisting of H, alkyf, aryl, heteroary!, cycloalkyi, aryϊaϊkyi- and heteroarylalkyS-; or two R6A groups are aiky! 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, morphofinyl, homomorphofiπyl, thiomorpholinyl or homothiornorpholinyl ring; and each R6B is independently selected from the group consisting of H, alkyi, aryi, heteroaryl, cycloalkyl, aryialkyh heteroarylatkyl-, -SO2aikyl, -SO2-aryf, -S02-heteroaryl, -C(O)aikyi, -C(O)aryl, -C(0)-heteroaryl, -C(O)O-alkyl, -C(O)O-aryl, -CCOJO-heteroaryl, -C(O)N(R6)2, -C(O)NR6-aryl, and -C(O)NR6-heteroaryi; or two R68 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 piperazinyi, homopiperazinyi, morpholiπyl, hornomorphoϋnyi, thiomorphoϊinyl or homothiomorpholinyl ring.
13. The use of claim 12 where iinn forms a phenyϊ ring.
14. The use of claim 12 wherein R1 and R2 are independently selected from the group consisting of H, alkyi, alkoxy, alkoxyalkoxy, -CF3, -OCF3 and halo.
15. The use of claim 12 wherein: R1 is alkyi, and R2 is aikoxy; or R1 is alkyl and R2 is -OCF3; or
R1 is alkyl and R2 is H, OH, halo or alkoxyalkoxy : or
R1 is aikoxy and R2 is afkoxy or H; or
R1 is afkoxyalkoxy and R2 is H; or
R1 is hafo 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-alky!, or -SO2alkyL
17. The use of claim 12 wherein R5A is H, halo, -O-alkyl-N(atkyl)2l -O-heterocycloalkyl, -O-alkyf-heterocycioalkyi, -N(R6A)2l -NR6-aϊkyl-O~alkyI-OH. -NR6-hydroxyalkyl, -S-hydroxyalkyl, -SO2-alky!f or -S-alkyl-NHC(O)H.
18. The use of claim 17 wherein R5A is is H; Ci; ~O-(CH2)2-N(CH3)2; ; -N(CH3)2; -NH(CHa)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, cyclopentyi, cyclohexyl or cycloheptyl, and wherein the cycloalkyl potion is optionally substituted by 1 or 2 ring system substituents;
-N(R ϊ6\ )-{heterocycIoalkyl), wherein heterocycloalkyl is or wherein R19 is H, alkyl or -S02alkyl;
-NR6-alkyl-aryl, optionally substituted by 1 or 2 ring system substituents, wherein the optional substituents are independently selected from the group consisting of OH5 alkoxy or -OCF3, or two hydrogen atoms on adjacent carbon ring members are replaced by -0-(CH2J2-O-;
-NRβ~afkyf~heteroalkyl; or
-N(RSA)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 Il is selected from Examples 3, 3D, 3G, 3lr 3M, 3N, 30, 3R, 3T, 3W5 3Y, 3AA, 3CC, 4CS 4O5 4P1 4Q1 4R, 4S1 4U5 4V, 5A, 5CS 5D, 5E, 5H, 5J, 5LS 5P, 5T1 5V, 5W, 5X1 5Y, 6, 6A, 6D, 61, 6K1 6L, 6M1 6N, 6OS 6P1 7, 7D: 12, 13U, 2OA, 2OC, 21C1 and 21E.
EP09748190A 2008-10-28 2009-10-26 Substituted pyrazoloquinolines and derivatives thereof Withdrawn EP2350072A1 (en)

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