WO2007103554A1 - Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors - Google Patents

Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors Download PDF

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Publication number
WO2007103554A1
WO2007103554A1 PCT/US2007/006036 US2007006036W WO2007103554A1 WO 2007103554 A1 WO2007103554 A1 WO 2007103554A1 US 2007006036 W US2007006036 W US 2007006036W WO 2007103554 A1 WO2007103554 A1 WO 2007103554A1
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Prior art keywords
hydrogen
alkyl
alkoxy
compound
optionally substituted
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PCT/US2007/006036
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French (fr)
Inventor
Ruiping Liu
Mark P. Arrington
Allen T. Hopper
Richard D. Conticello
Stephen A. Hitchcock
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Amgen Inc.
Memory Pharmaceuticals Corporation
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Priority to MX2008011257A priority Critical patent/MX2008011257A/en
Priority to JP2008558419A priority patent/JP2009529060A/en
Priority to CA002644850A priority patent/CA2644850A1/en
Priority to AU2007223801A priority patent/AU2007223801A1/en
Priority to EP07752718A priority patent/EP1996574A1/en
Publication of WO2007103554A1 publication Critical patent/WO2007103554A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • PDElO inhibitors pharmaceutical compositions containing such compounds, and processes for preparing such compounds.
  • Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDElO enzyme, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
  • cAMP and cGMP cyclic nucleotide monophosphates
  • PKA cAMP-dependent protein kinase
  • Downstream mediators of cGMP signaling also include kinases and ion channels. In addition to actions mediated by kinases, cAMP and cGMP bind directly to some cell proteins and directly regulate their activities.
  • Cyclic nucleotides are produced from the actions of adenylyl cyclase and guanylyl cyclase, which convert ATP to cAMP and GTP to cGMP. Extracellular signals, often through the actions of G protein-coupled receptors, regulate the activities of the cyclases. Alternatively, the amount of cAMP and cGMP may be altered by regulating the activities of the enzymes that degrade cyclic nucleotides. Cell homeostasis is maintained by the rapid degradation of cyclic nucleotides after stimulus-induced increases. The enzymes that degrade cyclic nucleotides are called 3',5'-cyclic nucleotide-specific phosphodiesterases (PDEs).
  • PDEs 3',5'-cyclic nucleotide-specific phosphodiesterases
  • PDE-PDEl 1 Eleven PDE gene families (PDEl-PDEl 1) have been identified based on their distinct amino acid sequences, catalytic and regulatory characteristics, and sensitivity to small molecule inhibitors. These families are coded for by 21 genes; and further multiple splice variants are transcribed from many of these genes. Expression patterns of each of the gene families are distinct. PDEs differ with respect to their affinity for cAMP and cGMP. Activities of different PDEs are regulated by different signals. For example, PDEl is stimulated by Ca 2+ /calmodulin. PDE2 activity is stimulated by cGMP. PDE3 is inhibited by cGMP. PDE4 is cAMP specific and is specifically inhibited by rolipram. PDE5 is cGMP- specific. PDE6 is expressed in retina.
  • PDEl 0 sequences were identified by using bioinformatics and sequence information from other PDE gene families (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999; Loughney et al., Gene 234:109-117, 1999; Soderling et al., Proc. Natl. Acad. Set USA 96:7071-7076, 1999).
  • the PDElO gene family is distinguished based on its amino acid sequence, functional properties and tissue distribution.
  • the human PDElO gene is large, over 200 kb s with up to 24 exons coding for each of the splice variants.
  • the amino acid sequence is characterized by two GAF domains (which bind cGMP), a catalytic region, and alternatively spliced N and C termini. Numerous splice variants are possible because at least three alternative exons encode N termini and two exons encode C-termini.
  • PDElOAl is a 779 amino acid protein that hydrolyzes both cAMP and cGMP.
  • the K n , values for cAMP and cGMP are 0.05 and 3.0 micromolar, respectively.
  • several variants with high homology have been isolated from both rat and mouse tissues and sequence banks.
  • [0007J PDElO RNA transcripts were initially detected in human testis and brain.
  • tissue distribution of PDEl 0 indicates that PDEl 0 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDElO enzyme, for example, in neurons that comprise the basal ganglia and therefore would be useful in treating a variety of neuropsychiatric conditions involving the basal ganglia such as obesity, non- insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like.
  • R 4 where R 4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, or -X 1 R 7 (where X !
  • R 8 , R 9 , R 10 , R n , and R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
  • R 5 and R 6 where R s and R 6 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl, and provided that at least one of R 4 , R 5 , and R 6 is not hydrogen; wherein the aromatic or alicyclic ring in R 4 , R 5 .
  • R 6 , and R 7 is optionally substituted with one to three substitutents independently selected from R a , R b , and R c , which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; and additionally substituted with one or two substitutents
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, and:
  • R 3a is pyrrolidin-1-yl, then R 4 is not -X 1 R 7 , where X 1 is -0-, and R 7 is substituted or unsubstituted, aryl or heteroaryl;
  • R 3a is piperidin-1-yl, where one of R 4 , R 5 and R 6 is hydrogen and another of R 4 , R 5 and R 6 is substituted or unsubstituted aryl or heteroaryl, then the remaining member of R 4 , R 5 and R 6 is not hydrogen; alkyl; carboxy; cyano; hydroxyl; alkoxy; -COR', -CONR'R" or -NR'R" (where R' and R" are independently hydrogen, alkyl, or unsubstituted aryl); or -NHCOR' (where R' is alkyl or unsubstituted aryl); or (iii) R 3a is piperidin-1-yl, where two of R 4 , R 5 and R 6 are hydrogen, then remaining of R 4 , R 5 and R is not —COR' (where R' is alkyl or unsubstituted aryl), -COOR' (where R' is alkyl or unsub
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, then:
  • R 3a is not substituted or unsubstituted 1,2,3,4-tetrahydroisoquinolin- 3-yl or l,2,3,4-tetrahydroisoquinolin-2-yl;
  • R 3a is not monosubstituted or disubstituted pyrrolidinyl where the one or two substituents are alkyl;
  • R when R is hydrogen, alkyl, or alkoxy, R 1 , R 2 , and R 3 are independently hydrogen, halo, haloalkyl, alkyl, alkoxy, carboxy, hydroxymethyl or hydroxy, and R 3a is aryl, then one of R 4 , R 5 , and R 6 is an aromatic or alicyclic ring or a group that contains an aromatic or alicyclic ring provided that the aromatic or alicyclic ring is not phenyl (optionally substituted with one, two, or three substitutents, independently selected from cyano, halo, -CONH 2 and haloalkyl), benzyl, benzyloxy,
  • R when R is hydrogen, R 1 , R 2 , and R 3 are independently hydrogen, halo, alkoxy, or hydroxy, and R 3a is heteroaryl, then the heteroaryl ring is not phthalazin-1-yl optionally substituted with R 4 , R 5 and R 6 , where R 4 is alkyl, and R 5 and R 6 are alkoxy; isoquinolinyl optionally substituted with one or two substituents selected from alkoxy and hydroxy; lH-indoIyl optionally substituted with R 4 , R 5 , and R 6 where R 4 is hydrogen, one of R 5 and R 6 is hydrogen, alkyl, or alkoxy, and other of R 5 and R 6 is alkyl, alkoxy, haloalkyl, dialkylaminoalkyl, or hydroxyalkyl; benzo[c]isoxazolyl optionally substituted with R 4 , R 5 , and R 6 where one of R 4 , R 5 , and R 6 where
  • R 3a is not: monosubstituted piperazinyl [wherein the substitutent on the piperazinyl ring is alkyl, alkoxycarbonyl, phenyl, -COR' (where R' is alkyl; or piperidinyl or pyrrolidinyl each optionally substituted with one or two substituents each independently selected from alkyl or hydroxyl), hydroxyalkyl, -CONHR' (where R' is phenyl substituted with fluoro or phenoxy), lH-benzo[d]imidazol-2(3H)-one optionally substituted with alkyl, or 3,4-dihydroquinolinyl-2(lH)-one]; substituted or unsubstit
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable expicient.
  • this invention is directed to a method of treating a disorder treatable by inhibition of PDElO in a patient which method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disease is obesity, non-insulin dependent diabetes, Huntington's disease, schizophrenia, bipolar disorder, or obsessive- compulsive disorder.
  • this invention is directed the use of a compound of
  • Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder treatable by inhibition of PDElO in a patient is obesity, non- insulin dependent diabetes, Huntington's disease, schizophrenia, bipolar disorder, or obsessive- compulsive disorder.
  • the pharmaceutical composition could contain one or more compounds of Formula (I) (including individual stereoisomer, mixtures of stereoisomers where the compound of Formula (I) has at least a stereochemical centre), a pharmaceutically acceptable salt thereof, or mixtures thereof.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alicyclic means a non-aromatic ring, e.g., cycloalkyl or heterocyclyl ring.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like.
  • Alkylthio means a -SR radical, where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.
  • Alkylsulfinyl means a -SOR radical where R is alkyl as defined above, e.g., methylsulf ⁇ nyl, ethylsulf ⁇ nyl, and the like.
  • Alkylsulfonyl means a -SO 2 R radical, where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Amino means an -NH 2 .
  • Alkylamino means an -NHR radical, where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
  • Alkoxy means an —OR radical, where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, «-, iso-, or tert-butoxy, and the like.
  • Alkoxycarbonyl means a -C(O)OR radical, where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3 -methoxy propyl, 2-ethoxyethyl, and the like.
  • Alkoxyalkyloxy means an -OR radical, where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two -NRR', where R is hydrogen, alkyl, or -COR a , where R a is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, each as defined herein, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like.
  • aminoalkoxy means an -OR radical, where R is aminoalkyl as defined above, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.
  • Aminocarbonyl means a -CONRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., -CONH2, methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
  • Aminosulfinyl means a -SONRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., — CONH2, methylaminosulf ⁇ nyl. 2-dimethylaminosulfinyl, and the like.
  • Aminosulfonyl means a -SO2NRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., — SO 2 NH 2 , methylaminosulfonyl, 2-dimethylaminosulfonyl, and the like.
  • Acyl means a -COR radical, where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., acetyl, propionyl, benzoyl, pyridinylcarbonyl, and the like.
  • R in a -COR radical is alkyl, the radical is also referred to herein as "alkylcarbonyl.”
  • Acylamino means an -NHCOR radical, where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., acetylamino, propionylamino, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, e.g., phenyl or naphthyl.
  • Alkyl means an -(alkylene)-R radical, where R is aryl as defined above.
  • Cycloalkyl means a cyclic saturated monovalent bridged or non-bridged hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. Additionally, one or two ring carbon atoms may optionally be replaced with a —CO— group.
  • Cycloalkenyl means a cyclic nonaromatic monovalent bridged or non- bridged hydrocarbon radical of five to ten carbon atoms, which contains at least one carbon- carbon double bond, e.g., cyclopentenyl or cyclohexenyl. Additionally, one or two ring carbon atoms may optionally be replaced by a —CO- group.
  • Cycloalkylalkyl means an -(alkylene)— R radical, where R is cycloalkyl as defined aoove; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
  • Cycloalkyloxy means an —OR radical, where R is cycloalkyl as defined, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cycloalkylalkyloxy means an -OR radical, where R is cycloalkylalkyl as defined, e.g., cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylethyloxy, cyclohexylmethyloxy, and the like.
  • Carboxy means -COOH.
  • Disubstituted amino means an -NRR' radical, where R and R' are independently alkyl, cycloalkyl, cycloalkylalkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., dimethylamino, phenylmethylamino, and the like.
  • Halo means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Haloalkoxy means an -OR radical, where R is haloalkyl as defined above, e.g., -OCF 35 -OCHF 2 , and the like.
  • Hydrocarbon radical means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that, if two hydroxy groups are present, they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
  • Hydroxalkoxy or "hydroxyalkyloxy” means an —OR radical, where R is hydroxyalkyl as defined above.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, in which one or two ring atoms are heteroatom(s), independently selected from N, O, and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms are C. Additionally, one or two ring carbon atoms can optionally be replaced by a — CO— group, and the heterocyclic ring may be fused to phenyl or heteroaryl ring, provided that the entire heterocyclyl ring is not completely aromatic. Unless stated otherwise, the fused heterocyclyl ring can be attached at any ring atom.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like.
  • heterocyclyl ring When the heterocyclyl ring has five, six or seven ring atoms, and is not fused to phenyl or heteroaryl ring, it is referred to herein as "monocyclic five-, six-, or seven-membered heterocyclyl ring, or five-, six-, or seven-membered heterocyclyl ring.”
  • heterocyclyl ring When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic.
  • Heterocyclylalkyl means an -(alkylene)-R radical, where R is heterocyclyl ring as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, where one or more, preferably one, two, or three, ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon, e.g., benzofuranyl, benzo[d]thiazolyl, isoquinolinyl, quinolinyl, thiophenyl, imidazolyl, oxazolyl, quinolinyl, furanyl, thazolyl, pyridinyl, and the like.
  • Heteroaralkyl means an -(alkylene)-R radical, where R is heteroaryl as defined above.
  • “Monosubstituted amino” means an -NHR radical, where R is alkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., methylamino, 2-phenylamino, hydroxyethylamino, and the like.
  • the present invention also includes prodrugs of compounds of Formula (I).
  • prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups, however, regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N.N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N.N-dimethylaminocarbonyl
  • amides e.g., trifluoroacetylamino, acetylamino, and the like
  • Prodrugs of compounds of Formula (I) are also within the scope of this invention.
  • the present invention also includes protected derivatives of compounds of
  • Formula (I) For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol, or any group containing a nitrogen atom, these groups can be protected with a suitable protecting groups.
  • suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis; John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include, for instance, acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene
  • pharmaceutically acceptable salt also refers to salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.
  • the compounds of the present invention may have one or more asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in an optically active, racemic, or diastereomeric form. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
  • Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this invention.
  • alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when a cyclic group, such as aryl, heteroaryl, and heterocyclyl, is substituted, it includes all the positional isomers albeit only a few examples are set forth.
  • heterocyclyl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is mono- or disubstituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.
  • Optionally substituted phenyl means a phenyl ring optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each as defined herein.
  • Optionally substituted heteroaryl means a monovalent monocyclic or bi cyclic aromatic radical of 5 to 10 ring atoms, where one or more, preferably one, two, or three ring atoms are heteroatoms, each independently selected from N, O, and S, and the remaining ring atoms are carbon that is optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each independently selected from al
  • optionally substituted heteroaryl includes, but is not limited to, optionally substituted pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, each optionally substituted as indicated above.
  • Optionally substituted heterocyclyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms, each independently selected from N, O, and S(O) n , where n is an integer from 0 to 2, and the remaining ring atoms are carbon.
  • One or two ring carbon atoms can optionally be replaced by a -CO- group and is optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each as defined herein.
  • a "pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Sulfinyl means a -SOR radical, where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., methylsulfinyl, phenylsulfinyl, benzylsulfinyl, and the like.
  • Sulfonyl means a -SO 2 R radical, where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., methylsulfonyl, phenylsulfonyl, benzylsulfonyl, pyridinylsulfonyl, and the like.
  • Treating" or “treatment” of a disease includes:
  • a "therapeutically effective amount” means the amount of a compound of
  • Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.
  • X is nitrogen
  • Y and Z are -CK-.
  • Y is nitrogen
  • Z is nitrogen
  • Y is nitrogen
  • Y is nitrogen
  • Z is nitrogen
  • Z is nitrogen
  • Z is nitrogen
  • one group of compounds of Formula (I) is that wherein R is fluoro or chloro.
  • (A) Within the above embodiments 1-9, and subgroups contained therein, one group of compounds of Formula (I) is that wherein R 1 is hydrogen.
  • R 2 is methoxy
  • R 3 is cycloproplmethyloxy, cyclopropylethoxy, cyclobutylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyl, or cyclohexylethyloxy.
  • Formula (I) is that wherein R 1 is hydrogen, and R 2 and R 3 are alkoxy, preferably, methoxy or ethoxy.
  • Formula (I) is that wherein R 1 is hydrogen, R 2 is alkoxy, and R 3 is alkyl.
  • one group of compounds of Formula (I) is that wherein R 1 is hydrogen, R 2 is methoxy or ethoxy, and R 3 is methyl, ethyl, or propyl.
  • Formula (I) is that wherein R 1 is hydrogen, R 2 is alkoxy, and R 3 is cycloalkyl, preferably cyclopropyl.
  • R 1 is hydrogen, R 2 is methoxy or ethoxy, and R 3 is cyclopropyl.
  • Formula (I) is that wherein R 1 is hydrogen, R 2 is fluoro, trifluoromethoxy, methylamino, or dimethylamino, and R 3 is alkyl, alkoxy, haloalkyl, halo, alkoxycarbonyl or cycloalkyl.
  • Formula (I) is that wherein R 1 is hydrogen, R 3 is alkoxy, and R 2 is alkyl.
  • one group of compounds of Formula (I) is that wherein R 1 is hydrogen, R 3 is methoxy or ethoxy, and R 2 is methyl, ethyl, or propyl.
  • Formula (I) is that wherein R 1 is hydrogen, R 3 is alkoxy, and R 2 is cycloalkyl, preferably cyclopropyl.
  • R 1 is hydrogen, R 3 is methoxy or ethoxy and R 2 is cyclopropyl.
  • (P) Within the above embodiments 1-9, one group of compounds of
  • Formula (I) is that wherein R 1 is hydrogen, one of R 2 and R 3 is alkoxy and the other of R 2 and R 3 is halo or haloalkoxy.
  • A is a monocyclic five-, six-, or seven-membered heterocyclyl ring substituted with R 4 , R 5 and R 6 , as defined in the Summary of the Invention.
  • R 4 is as defined in the Summary of the invention.
  • R 4 is as defined in the Summary of the invention.
  • R 4 is phenyl optionally substituted, as defined in the Summary of the Invention.
  • R 3a rings in subgroups (ii)-(iv) above, the subgroups contained therein, including the hydrogen in -NH- groups in the rings, can also be optionally substituted with R 5 and R 6 , where R 5 and R 6 are as defined in the Summary of the Invention.
  • R 5 and R 6 are as defined in the Summary of the Invention.
  • one of R 5 and R 6 is hydrogen.
  • one group of compounds is that wherein the above rings are substituted with R 4 as defined in the Summary of the Invention, and substituted with R and R 6 , where one of R 5 and R 6 is hydrogen.
  • the -NH- groups in the rings are substituted with alkyl, cycloalkyl, or cycloalkylalkyl.
  • the -NH- groups in the rings are unsubstituted.
  • one group of compounds is that wherein R 3a is morpholin-4-yl, piperazin-1-yl, or homopiperazin- 1-yl, substituted as defined above.
  • R 3a is piperidin-1-yl or homopiperidin-1-yl, substituted as defined above.
  • another group of compounds is that wherein R 3a is mor ⁇ holin-4-yl substituted as defined above.
  • one group of compounds is that wherein the. above rings are substituted with R 4 as defined in the Summary of the Invention, preferably cycloalkyl, aryl, heteroaryl, or six-membered saturated heterocyclyl optionally substituted with R a , R b and R c ; and substituted with R 5 and R 6 , where at least one of R 5 and R 6 is hydrogen.
  • the -NH- groups in the rings are substituted with alkyl, cycloalkyl, or cycloalkylalkyl.
  • the -NH- groups in the rings are unsubstituted.
  • R 4 is as defined in the Summary of the Invention.
  • one group of compounds is that wherein R 4 is cycloalkyl, phenyl, heteroaryl, or six-membered saturated heterocyclyl, preferably cycloalkyl, aryl, heteroaryl, or six membered saturated heterocyclyl, optionally substituted with R a , R b and R c .
  • the rings of the formulas shown above are optionally substituted, including the hydrogen atom on the -NH- group within the rings, with R 5 and R 6 , as defined in the Summary of the Invention; preferably, R s is hydrogen ,and R 6 is attached to the carbon adjacent to the nitrogen attached to the quinoline or isoquinoline ring.
  • one group of compounds is that where R 4 is phenyl substituted with R a and R b that are meta to each other.
  • one group of compounds is that wherein R 3a is morpholin-4-yl, piperazin-1-yl, 2-oxopiperidinyl, 2,4-dioxo ⁇ iperazinyI, or 2-oxopiperazinyl, substituted as defined in (vi) above.
  • another group of compounds is that wherein R 3a is piperidin-1-yl, substituted as defined in (vi) above.
  • another group of compounds is that wherein R 3a is morpholin-4-yl substituted as defined in (vi) above.
  • R 4 is phenyl or heteroaryl, substituted at the para position with R a , and optionally substituted with R b and R c , wherein R a , R b , R c , and R 5 are as defined in the Summary of the Invention.
  • the -NH- groups in the above rings can optionally be substitituted with R 6 as defined in the Summary of the Invention.
  • R 6 is cycloalkyl, alkyl, or cycloalkylalkyl.
  • R 3a is other than piperidin-1-yl substituted as described above.
  • R 3a is piperidin-1-yl substituted as described above.
  • R 3a is morpholin-4-yl substituted as described above. In yet another group of compounds within this embodiment R 3a is morpholin-4-yl where R 4 is phenyl is substituted with R a and R b where R a and R b are meta to each other. In yet another group of compounds within this embodiment R 3a is piperazin-1-yl where R 4 is phenyl is substituted with R a and R b where R a and R b are meta to each other.
  • R 4 is -CONR 7 R 8 where R 7 and R 8 are as defined in the Summary of the Invention, preferably R 7 is phenyl optionally substituted with R b and R c wherein R a , R b , and R c are as defined in the Summary of the Invention.
  • the -NH- groups in the above rings can optionally be substitituted with R 6 as defined in the Summary of the Invention.
  • R 6 is cycloalkyl, alkyl, or cycloalkylalkyl.
  • R 3a is other than piperidin-1-yl substituted as described above.
  • R 3a is piperidin-1-yl substituted as described above.
  • R 4 is cycloalkyl substituted at the para position with R a and optionally substituted with R b and R c wherein R a , R b and R c are as defined in the Summary of the Invention and R 5 is as defined in the Summary of the Invention.
  • the -NH- groups in the above rings can optionally be substitituted with R 6 as defined in the Summary of the Invention.
  • R 6 is cycloalkyl, alkyl, or cycloalkylalkyl.
  • R 4 is cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, Or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl).
  • R 4 is phenyl, heteroaryl or heterocyclyl.
  • the rings shown in the formulas above are also optionally substituted, including the hydrogen in -NH- groups in the rings, with R 5 and R 6 where R 5 and R 6 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulf ⁇ nyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino.
  • R 4 , R s , R 6 , and R 7 is optionally substituted with one to three substitutents independently selected from R a , R b , and R c which are alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy,' aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino; and additionally substituted with one or two substitutents independently selected from R d and R e where R d and R c are hydrogen or fiuoro.
  • R 3a is: where R 4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c , as defined in the Summary of the Invention.
  • R 3a is:
  • R 4 is morpholin-4-yl, piperazin-1-yl, or pyridinyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c , as defined in the Summary of the Invention.
  • R 3a is:
  • R 4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c , as defined in the Summary of the Invention and where the hydrogen in -NH- groups in the ring is optionally substituted with R 5 and R 6 .
  • one group of compounds is that wherein R 3a is
  • R 4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c , as defined in the Summary of the Invention and where the hydrogen in -NH- groups in the ring is optionally substituted with R 5 and R 6 .
  • R 4 is cyclopentyl, cyclohexyl, phenyl, heteroaryl, or monocyclic saturated f ⁇ ve-or six- membered heterocyclyl ring
  • R 5 is hydrogen, alkyl, phenyl, heteroaryl, or monocyclic five- or six-membered heterocyclyl ring
  • R 6 is alkyl, preferably methyl; and wherein the aromatic or alicyclic ring in R 4 and R 5 is optionally substituted with R a , R b and R c , as defined in the Summary of the Invention.
  • R 4 is phenyl, heteroaryl, or monocyclic five- or six-membered heterocyclyl ring and R 5 is hydrogen or alkyl.
  • R 4 and R s are independently phenyl, heteroaryl, or monocyclic saturated five- or six-membered heterocyclyl ring.
  • the aromatic or alicyclic ring is optionally substituted with R a selected from alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and R b and R c , independently selected from alkyl, alkoxy, halo,
  • A is a monocyclic five-, six-, or seven-membered heterocyclyl ring, and ring (a) is substituted with:
  • R 4 where R 4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R l2 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl and
  • R 5 where R 5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl, or heterocyclyl; and
  • R 6 where R 6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino, preferably hydrogen; wherein the aromatic or alicyclic ring in R 4 , R 5 , R 6 , and R 7 is optionally substituted with one to three substitutents independently selected from R a , R b , and R c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalk ⁇ xy, hydroxyl, hydroxyalkyl, alky
  • A is a saturated five or six membered heterocyclyl ring and substituted as described above.
  • X 2 , X 3 , and X 4 are independently carbon, nitrogen, oxygen, or sulfur; provided that at least two of X 2 , X 3 , and X 4 are other than carbon; and
  • B is phenyl, a six-membered heteroaryl ring (wherein the six-membered heteroaryl ring contains one or two nitrogen atoms, the rest of the ring atoms being carbon), or a monocyclic five-, six-, or seven-membered heterocyclyl ring; wherein ring (b) is substituted with:
  • R 4 where R 4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
  • R 5 where R 5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
  • R 6 where R 6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R 4 , R 5 , R ⁇ , and R 7 is optionally substituted with one to three substituents independently selected from R a , R b , and R c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alk
  • R 4 where R 4 is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, - NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
  • R 5 where R s is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
  • R 6 where R 6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R 4 , R 5 , R 6 , and R 7 is optionally substituted with one to three substituents independently selected from R a , R b , and R c which .
  • R 3a is other than piperidin
  • R 4 where R 4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
  • R 5 where R 5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
  • R 6 where R 6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R 4 , R 5 , R 6 , and R 7 is optionally substituted with one to three substituents independently selected from R a , R b , and R c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxy
  • R 4 where R 4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl. aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
  • R 5 where R 5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulf ⁇ nyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
  • R 6 where R 6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R 4 , R 5 , R 6 , and R 7 is optionally substituted with one to three substituents independently selected from R a , R b , and R c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxy
  • R 3a is a group of formula:
  • R 4 and R 5 is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, monsubstituted or disubstituted amino, or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -S-, -SO-, -SO 2 -, -NR 1 1 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl,
  • R 4 is aryl, heteroaryl, or heterocyclyl optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 3a is a group of formula: where R 4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -.
  • R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); R 5 is cycloalkyl, aryl, heteroaryl, or heterocyclyl; and R 6 is alkoxy cyano, monsubstituted amino or disubstituted amino, wherein the aromatic or alicyclic ring in R 5 and R 7 is optionally substituted with one to three substitutents independently
  • R 4 and R 5 are as defined in (xvii) above.
  • R 4 and R 5 are as defined in (xxi) above.
  • R 3a is a group of formula:
  • R 4 and R s are as defined in (xxi) above.
  • R 4 is heteroaryl optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is heterocyclyl, preferably piperazinyl, piperidinyl, or morpholinyl, each optionally substituted with one to three substitutents, independently selected from R a , R b , and R c .
  • R 4 is mono or disubstituted amino and R 5 is hydrogen, alkyl, or halo.
  • R 4 is as defined in the Summary of the Invention.
  • the isoquinoline ring can optionally be substituted with R » 5 as defined in the Summary of the Invention.
  • R 4 is heteroaryl optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is heterocyclyl, preferably piperazinyl, piperidinyl. or morpholinyl, each optionally substituted with one to three substitutents, independently selected from R a , R b , and R c .
  • R 4 is as defined in the Summary of the Invention.
  • the isoquinoline ring can optionally be substituted with R 5 as defined in the Summary of the Invention.
  • R 4 is heteroaryl optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is heterocyclyl, preferably piperazinyl, piperidinyl, or morpholinyl, each optionally substituted with one to three substitutents, independently selected from R a , R b , and R c .
  • R 3a is a group of formula: where one of R 4 and R 5 is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, monsubstituted or disubstituted amino, Or-X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -S-, -SO-, -SO 2 -, -NR 10 SO 2 -, or -SO 2 NR 11 - where R 8 -R ⁇ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloal
  • R 3a is a group of formula:
  • R 5 is hydrogen or alkyl
  • R 4 is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substitute
  • R 4 is aralkyl (preferably benzyl) optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is heteroaryl optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is heterocyclyl optionally substituted with optionally substituted phenyl or optionally substituted heteroaryl.
  • R 3a is a group of formula:
  • R s is hydrogen or alkyl, preferably hydrogen; n is 1, 2, or 3; Z is -O-, -NH-, or - N(alkyl)— ; and R a is phenyl or heteroaryl each optionally substituted with R a , R b , and R c , preferably phenyl optionally substituted with R a , R b , and R c .
  • R 4 is hydrogen, alkyl, h , haloalkyl, h o a r loalkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, or -X 1 R 7 (where X 1 is -O-, -CO-, -C(O)O-, -OC(O)-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 - R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, ary
  • one group of compounds is that wherein R 4 is phenyl, heteroaryl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is alkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or -X 1 R 7 (where X 1 is -O-, -CO-, -NR 8 CO-, -CONR 9 -, -NR 10 -, -S-, -SO-, -SO 2 -, -NR 11 SO 2 -, or -SO 2 NR 12 - where R 8 -R 12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R 7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl), wherein the aromatic or alicyclic ring in R 4 is optionally substituted with one to three substitute
  • R 4 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from R a , R b , and R c .
  • R 4 is aralkyl, preferably benzyl, optionally substituted with R a , R b and R c , as defined in the Summary of the Invention.
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, from about 0 0 C to about 125 0 C, or at about room (or ambient) temperature, e.g., about 23 0 C.
  • R H, alkyl, alkoxy, or halo i.
  • Compound 2, where R is alkyl or halo, such as chloro or bromo can be prepared by treating compound 2, where R is H, with a halogenating agent, such as N- chlorosuccinimide or N-bromosuccinimide, in N,N-dimethylformamide (see, Journal of Heterocyclic Chemistry, 38:597-600, 2001). Treatment of the resulting halo compound 2 with an alkyl Grignard reagent provides compound 2, where R is alkyl. 2H-Isoquinolin-1- one 2 is then converted to compound 3, where X is chloro or bromo, by treatment with phosphorus oxychloride or phosphorous oxybromide, respectivley.
  • a halogenating agent such as N- chlorosuccinimide or N-bromosuccinimide
  • Compound 3 is converted into the corresponding compound of Formula (I) via a variety of methods.
  • compounds of Formula (I), wherein R 3a is an aryl or heteroaryl ring can be prepared by standard synthetic methods known to one of ordinary skill in the art, e.g., Suzuki-type coupling of the corresponding aryl or heteroaryl boronic acid with compound 3 where X is halo (see, Miyaura and Suzuki, Chem. Rev., 95:2457-2483, 1995).
  • Such boronic acids are either commercially available, e.g., Aldrich Chemical Co.
  • Compounds of Formula (I), where R 3a is a heterocyclic ring (e.g., pyrrolidin-1- yl, piperidin-1-yl, or mor ⁇ olin-4-yl) attached via a nitrogen atom can be prepared by reacting compound 3 with a heterocyclic ring in the presence of a base, such as triethylamine or pyridine.
  • a base such as triethylamine or pyridine.
  • Suitable solvents include, but are not limited to, polar aprotic solvents, such as tetrahydrofuran and N,N-dimethylforamide (DMF).
  • heterocyclic rings pyrrolidines, piperidines, homopiperidines, piperazines, homopiperazines, morpholines, and the like
  • pyrrolidines, piperidines, homopiperidines, piperazines, homopiperazines, morpholines, and the like are either commercially available, or can be readily prepared by standard methods known within the art (see, Louie and Hartwig, Tetrahedron Letters, 36:3609, 1995; Guram et al., Angew Chem. Int. Ed., 34:1348, 1995).
  • a compound of Formula (I) can be prepared by heating compound 3 with a heterocyclic ring in a suitable organic solvent, such as tetrahydrofuran (THF), benzene, dioxane, toluene, alcohol, or a mixture thereof, under catalytic conditions, using, for example, a palladium or copper catalyst, such as, but not limited to, tris(dibenzylidene-acetone) dipalladium(O) or copper (I) iodide, in the presence of a suitable base, such as potassium carbonate, sodium ⁇ -butoxide, lithium hexamethyldisilizane, and the like.
  • a suitable organic solvent such as tetrahydrofuran (THF), benzene, dioxane, toluene, alcohol, or a mixture thereof.
  • a palladium or copper catalyst such as, but not limited to, tris(dibenzylidene-acetone) dipalladium(O) or
  • Substituted indazoles useful to make compounds of Formula (I) are either commercially available, e.g., Aldrich Chemical Co. (Milwaukee, WI) 5 , Sinova, Inc. (Bethesda, MA), J & W PharmLab, LLC (Morrisville, PA), or can be prepared by methods commonly known within the art (see, Lebedev et al, J. Org. Chem. 70:596-602, 2005; and the references cited therein).
  • indazoles wherein R 4 is heterocyclyl, e.g., morpholine or N-methylpiperazine may be synthesized by Buchwald-type coupling of the corresponding bromoindazole with the desired heterocyclic compound.
  • the bromoindazoles may be prepared as described in International Publication No. WO 2004/029050, the disclosure of which is incorporated herein by reference in its entirety. Copper catalyzed reaction of the appropriately substituted indazole with compound 3, where X is halo, provides the desired compounds of Formula (I).
  • the bromoindazole undergoes palladium catalyzed reaction with compound 3 (X is halo) to provide a 4-(bromo-lH-indazol-l-yl) substituted compound of Formula (I).
  • N-arylation reaction with, for example, morpholine or N-methylpiperazine, provides a desired compound of Formula (I).
  • Suzuki-type reaction of the 4-(bromo-lH-indazol-l-yl)-substituted compound with an aryl or heteroaryl boronic acid e.g., phenylboronic acid or 4-pyridine boronic acid
  • compound 5 can be converted to the corresponding 1 ,4- dichloroisoquinoline derivative by treating it with phosphorus pentachloride at elevated temperatures (see, Barber et al., Bioorg. Med. Chem. Lett., 14:3227-3230, 2004).
  • Compound 7 is then converted to a compound of Formula (I) as described in Scheme 1 above.
  • R 2 , R 3 and R 3a are as defined in the Summary of the Invention, can be prepared as described in Scheme 3 below (see, J. Med Chem., 42:5369, 1999).
  • R 1 is hydrogen
  • R 2 and R 3 are the same and are selected from alkoxy, haloalkoxy, hydroxy, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, or -O ⁇ (aIkylene)-NR 15 R 16 , for example, methoxy, can be synthesized by methods common to the art.
  • a base such as cesium carbonate, triethylamine, sodium hydride, potassium carbonate, potassium hydride, or the like
  • Suitable organic solvents include acetone, acetonitrile, DMF, THF, and the like. Reduction of the nitro group under known reaction conditions, e.g., hydrogenation with palladium on carbon, iron powder in acetic acid, or nickel boride, provides the amino compound 9 (see, Castle et al. J.
  • PDElO enzyme comprises the step of administering a therapeutically effective amount of a compound of Formula (I), or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat the disorder or disease.
  • this invention provides a use of a compound as described herein in the manufacture of a medicament for treating a disorder or disease treatable by inhibition of PDElO.
  • the compounds of the present invention inhibit PDEl 0 enzyme activity, and hence raise the levels of cAMP or cGMP within cells that express PDElO. Accordingly, inhibition of PDEl 0 enzyme activity would be useful in the treatment of diseases caused by deficient amounts of cAMP or cGMP in cells. PDElO inhibitors would also be of benefit in cases wherein raising the amount of cAMP or cGMP above normal levels results in a therapeutic effect. Inhibitors of PDElO may be used to treat disorders of the peripheral and central nervous system, cardiovascular diseases, cancer, gastro-enterological diseases, endocrinological diseases and urological diseases.
  • Indications that may be treated with PDElO inhibitors include, but are not limited to, those diseases thought to be mediated in part by the basal ganglia, prefrontal cortex, and hippocampus. These indications include psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
  • ADHD attention deficit/hyperactivity disorder
  • Psychoses are characterized by delusions and hallucinations.
  • the compounds of the present invention are suitable for use in treating patients suffering from all forms of psychoses, including, but not limited to, schizophrenia, late-onset schizophrenia, schizoaffective disorders, prodromal schizophrenia, and bipolar disorders. Treatment can be for the positive symptoms of schizophrenia as well as for the cognitive deficits and negative symptoms.
  • Other indications for PDElO inhibitors include psychoses resulting from drug abuse (including amphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus, sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewy bodies, or hypoglycemia.
  • OCD Obsessive-compulsive disorder
  • OCD may result, in some cases, from streptococcal infections that cause autoimmune reactions in the basal ganglia (Giedd et n ⁇ ., Am J Psychiatry. 157:281-283, 2000). Because PDElO inhibitors may serve a neuroprotective role, administration of PDElO inhibitors may prevent the damage to the basal ganglia after repeated streptococcal infections and thereby prevent the development of OCD.
  • cAMP or cGMP In the brain, the level of cAMP or cGMP within neurons is believed to be related to the quality of memory, especially long term memory. Without wishing to be bound to any particular mechanism, it is proposed that, since PDElO degrades cAMP or cGMP, the level of this enzyme affects memory in animals, for example, in humans.
  • a compound that inhibits cAMP phosphodiesterase (PDE) can thereby increase intracellular levels of cAMP, which in turn activate a protein kinase that phosphorylates a transcription factor (cAMP response binding protein).
  • the phosphoylated transcription factor then binds to a DNA promoter sequence to activate genes that are important in long term memory. The more active such genes are, the better is long-term memory. Thus, by inhibiting a phosphodiesterase, long term memory can be enhanced.
  • Dementias are diseases that include memory loss and additional intellectual impairment separate from memory.
  • the compounds of the present invention are suitable for use in treating patients suffering from memory impairment in all forms of dementia.
  • Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld- Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.
  • neurodegenerative dementias e.g.
  • the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
  • the present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline.
  • MCI mild cognitive impairment
  • the present invention includes methods of treatment for memory impairment as a result of disease.
  • Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntingdon's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
  • the compounds of the present invention are suitable for use in the treatment of memory impairment due to, for example, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, depression, aging, head trauma, stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetes associated cognitive impairment, memory deficits from early exposure of anesthetic agents, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases.
  • Alzheimer's disease multiple sclerosis
  • ALS amylolaterosclerosis
  • MSA multiple systems atrophy
  • schizophrenia Parkinson's disease
  • Huntington's disease Huntington's disease
  • Pick's disease Creutzfeld- Jakob disease
  • depression head trauma
  • stroke spinal cord injury
  • CNS hypoxia CNS hypoxia
  • cerebral senility diabetes associated cognitive impairment
  • the compounds of the present invention are also suitable for use in the treatment of a class of disorders known as polyglutamine-repeat diseases. These diseases share a common pathogenic mutation.
  • the expansion of a CAG repeat, which encodes the amino acid glutamine, within the genome leads to production of a mutant protein having an expanded polyglutamine region.
  • Huntington's disease has been linked to a mutation of the protein huntingtin. In individuals who do not have Huntington's disease, huntingtin has a polyglutamine region containing about 8 to 31 glutamine residues. For individuals who have Huntington's disease, huntingtin has a polyglutamine region with over 37 glutamine residues.
  • DRPLA dentatorubral-pallidoluysian atrophy
  • DRPLA dentatorubral-pallidoluysian atrophy
  • ataxin-1 spinocerebellar ataxia type-1
  • ataxin-2 spinocerebellar ataxia ty ⁇ e-2
  • ataxin-3 also called Machado-Joseph disease or MJD
  • ataxin-3 also called Machado-Joseph disease or MJD
  • spinocerebellar ataxia type-6 alpha Ia- voltage dependent calcium channel
  • spinocerebellar ataxia type-7 ataxin-7
  • SBMA spinal and bulbar muscular atrophy
  • the basal ganglia are important for regulating the function of motor neurons; disorders of the basal ganglia result in movement disorders. Most prominent among the movement disorders related to basal ganglia function is Parkinson's disease (Obeso et al., Neurology. 62(1 Suppl l):S17-30, 2004). Other movement disorders related to dysfunction of the basal ganglia include tardive dyskinesia, progressive supranuclear palsy and cerebral palsy, corticobasal degeneration, multiple system atrophy, Wilson disease, dystonia, tics, and chorea. The compounds of the invention are also suitable for use to treat movement disorders related to dysfunction of basal ganglia neurons.
  • PDElO inhibitors are useful in raising cAMP or cGMP levels and prevent neurons from undergoing apoptosis.
  • PDElO inhibitors may be anti-inflammatory by raising cAMP in glial cells.
  • any insult to the brain can potentially damage the basal ganglia including strokes, metabolic abnormalities, liver disease, multiple sclerosis, infections, tumors, drug overdoses or side effects, and head trauma.
  • the compounds of the invention can be used to stop disease progression or restore damaged circuits in the brain by a combination of effects including increased synaptic plasticity, neurogenesis, anti-inflammatory, nerve cell regeneration and decreased apoptosis.
  • c AMP and cGMP The growth of some cancer cells is inhibited by c AMP and cGMP.
  • cells may become cancerous by expressing PDElO and reducing the amount of c AMP or cGMP within cells.
  • inhibition of PDElO activity inhibits cell growth by raising cAMP.
  • PDElO may be expressed in the transformed, cancerous cell but not in the parent cell line.
  • PDElO is expressed and PDElO inhibitors reduce the growth rate of the cells in culture.
  • breast cancer cells are inhibited by administration of PDElO inhibitors.
  • Many other types of cancer cells may also be sensitive to growth arrest by inhibition of PDElO. Therefore, compounds disclosed in this invention can be used to stop the growth of cancer cells that express PDElO.
  • the compounds of the invention are also suitable for use in the treatment of diabetes and related disorders such as obesity, by focusing on regulation of the cAMP signaling system.
  • PDE-10 especially PDE-IOA
  • intracellular levels of c AMP are increased, thereby increasing the release of insulin-containing secretory granules and, therefore, increasing insulin secretion.
  • WO 2005/012485 which is hereby incorporated by reference in its entirety.
  • the compounds of Formula (I) can also be used to treat diseases disclosed in US Patent application publication No. 2006/019975, the disclosure of which is incorporated herein by reference in its entirety.
  • the PDEl 0 inhibitory activities of the compounds of the present invention can be tested, for example, using the in vitro and in vivo assays described in the Biological Examples below.
  • the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of a compound of this invention, i.e., the active ingredient depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of formula (I) may range from approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day, more preferably 3.5 mg to 70 mg per day.
  • compounds of this invention can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • the preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations depend on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 ran in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of formula (I).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • the compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of psychoses, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss, e.g., nicotinic ⁇ -7 agonists, PDE4 inhibitors, other PDElO inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and galanthanamine).
  • each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range, and can be administered either simultaneously or sequentially.
  • Drugs suitable in combination with the compounds of the present invention include, but are not limited to, other suitable schizophrenia drugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolar disorder drugs, including, but not limted to, Lithium, Zyprexa, and Depakote; Parkinson's disease drugs, including, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin; agents used in the treatment of Alzheimer's disease, including, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used in the treatment of dementia, including, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon; agents used in the treatment of epilepsy, including, but not limited to,
  • agonists, antagonists such as Rosiglitazone, Troglitazone and Pioglitazone
  • insulin secretagogues e.g., sulfonylurea drugs, such as Glyburide, Glimepiride, Chlorpropamide, Tolbutamide, and Glipizide, and non-sulfonyl secretagogues
  • oc-glucosidase inhibitors such as Acarbose, Miglitol, and Voglibose
  • insulin sensitizers such as the PPAR- ⁇ agonists, e.g., the glitazones; biguanides, PTP-IB inhibitors, DPP-IV inhibitors, and 1 lbeta-HSD inhibitors
  • hepatic glucose output lowering compounds such as glucagon antagonists and metaformin, e.g., Glucophage and Glucophage XR
  • insulin and insulin derivatives both long and short acting forms and formulations of insulin
  • Step 1 A mixture of 3,4-dimethoxybenzaldehyde (30 g, 180.72 mmol), malonic acid (28.4 g, 273.08 nimol), and piperidine (3 mL) in pyridine (90 mL) was stirred at 120 0 C for 6 hr. The reaction mixture was monitored by TLC (EtOAc/PE (1 :1, v/v)). Upon completion, the reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 by the addition of concentrated HCl. The product was isolated by filtration, and the filter cake was washed with water. The solid was dried in an oven under reduced pressure to provide 30 g (80%) of (E)-3-(3,4-dimethoxyphenyl)acrylic acid as a light yellow solid.
  • Step 2 To a solution of (E)-3-(3,4-dimethoxyphenyl) acrylic acid (10 g, 48.08 mmol) in THF (500 mL) was added a solution of DPPA (13.3 g, 48.36 mmol) in THF (20 mL) dropwise with stirring at 0 to 5 0 C. TEA (5 g, 49.50 mmol) was then added dropwise with stirring over a time period of 1.5 hr, and the resulting mixture was stirred for additional 12 hr at room temperature. The reaction mixture was concentrated, followed by the dropwise addition of CH 3 OH (300 mL) with stirring. The resulting solution was refluxed for additional 48 hr.
  • Step 3 A solution of (E)-methyl-3,4-dimethoxystyrylcarbamate (15 g, 63.29 mmol) and Bu 3 N (7.5 g) in 1-phenoxybenzene (150 mL) was refluxed for 12 hr. The reaction was monitored by TLC (EtOAc/PE (1:1. v/v)). Upon completion, PE (2 L) was added, and the product was isolated by filtration to provide 6,7-dimethoxy-isoquinolin-l(2H)-one as a light yellow solid (2.0 g).
  • Step 4 A solution of 6,7-dimethoxyisoquinolin-l(2H)-one (2 g, 8.29 mmol) and phosphorus oxybromide (14 g, 48.78 mmol) in dry acetonitrile (200 mL) was reflexed for 4 hr. The reaction mixture was monitored by TLC(EtO Ac:PE (1 :1, v/v)). Upon completion, the reaction was quenched with ice. The reaction mixture was neutralized with solid potassium carbonate. The resulting aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated.
  • Step 1 Acetic anhydride (150 mL) was added to a mixture of 2-(3 ,4- dimethoxyphenyl)ethanamine (40 g, 220.99 mmol), DMAP (2 g, 16.39 mmol), and Et 3 N (40 g, 396.04 mmol) in a 500 mL 3-necked round bottom flask. The resulting solution was stirried for 5 hr at room temperature. The reaction was monitored by TLC (EtOAc:PE, (1 :1, v/v)). A filtration was performed to provide N- (3,4-dimethoxy-phenethyl)acetamide as a white solid (32 g).
  • Step 2 A mixture of N-(3 s 4-dimethoxyphenethyl)acetamide (25 g, 112.11 mmol) and POCl 3 (37 mL) in toluene (187 mL) was stirred at 120 0 C for 3.5 hr. The reaction was monitored by TLC (EtOAc: PE (1 :1, v/v)). Upon completion, the reaction mixture was cooled to room temperature and the pH was adjusted to 12 by the addition of NaOH (4N). The resulting mixture was washed with EtOAc and filtration was performed to yield 6,7- dimethoxy-l-methyl-3,4-dihydroisoquinoline as a yellow solid (20 g).
  • Step 3 Into a 1000 mL 3-necked round bottom flask' purged and maintained with an inert atmosphere of nitrogen while cooling in an ice bath at 0 0 C was added 6,7- dimethoxy-l-methyl-3,4-dihydroisoquinoline (8 g, 39.02 mmol), 1,2,3,4- tetrahydronaphthalene (650 mL) and Pd/C (8 g). The reaction mixture was then refluxed for 3 hr. The reaction was monitored by TLC (EtOAc/MeOH (10:1, v/v)). Upon completion, the reaction mixture was cooled to room temperature, and filtered. The pH was adjusted to 2 by the addition of 10% aqueous HCl.
  • Step 4 A solution of 6,7-dimethoxy-l-methylisoquinoline (3.3 g, 16.26 mmol) and m-CPBA (3.7 g, 21.45 mmol) in DCM (80 mL) was refluxed overnight. The mixture was cooled to room temperature, the pH was adjusted to 8 by the addition of NaOH (4N), and then extracted one time with EtOAc. The organic fraction was dried over anhydrous Na 2 SO 4 and concentrated to provide 6,7-dimethoxy-l-methyl-isoquinoline-N-oxide as a yellow solid (3-3 g).
  • Step 5 A solution of 6,7-dimethoxy-l-methylisoquinoline-N-oxide (500 mg, .
  • Stepl To a solution of ethyl 2-aminoacetate hydrochloride (20 g, 143.37 mmol) in MeOH (300 mL) was added Et 3 N (14.6 g, 144.27 mmol) dropwise at 0 °C. The reaction mixture was stirred for 10-20 min and then 3,4-dimethoxybenzaldehyde (24 g) was added in several batches. The resulting solution was stirred for 2 hr, and then NaBH 4 (11 g, 297.30 mmol) was added in several batches. The resulting solution was stirred overnight at room temperature. The reaction was monitored by TLC (EtOAc/PE, (1 :2, v/v)).
  • ethyl 2-(3,4-dimethoxybenzylamino)acetate was also prepared as following.
  • 3,4-dimethoxy benzaldehyde 25g, 150.5 mmol
  • dichloroethane 250ml
  • glycine ethyl ester 25.2g, 180.6 mmol
  • magnesium sulfate 4Og
  • Triethyl amine 42.23ml, 301 mmol
  • the crude product was purified by silica gel chromatography using 1 :5 (v/v) EtOAc :PE as an eluant to provide ethyl 2-(N-(3,4- dimethoxybenzyl)-4-methylphenylsulfonamido)acetate as a white solid (55 g).
  • Step 4 To a solution of 2 ⁇ (N-(3,4-dimethoxybenzyl)-4-methylphenyl- sulfonamido)acetic acid (47 g, 124.01 mmol) in dichloromethane (300 mL) was added oxalyl chloride (78 g, 655.46 mmol) at 0 0 C. The resulting solution was refluxed for 5 hr. The reaction mixture was concentrated to provide 2-(N-(3,4-dimethoxybenzyl)-4-methylphenyl- sulfonamido)acetyl chloride as a yellow solid (50 g).
  • Step 5 Into a 500 mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen and maintained at -78 0 C in a bath of liquid N 2 was added 2-(N-(3,4-dimethoxybenzyl)-4-methylphenylsulfonamido)acetyl chloride (50 g, 100.55 mmol), DCM (300 mL) and AlCl 3 (53 g, 398.50 mmol). The resulting solution was stirred for 4 hr at -78 0 C and then for 4 hr at -10 0 C, followed by the dropwise addition of 10% aqueous HCl/ice at -10 0 C with stirring over 30 min.
  • 2-(N-(3,4-dimethoxybenzyl)-4-methylphenylsulfonamido)acetyl chloride 50 g, 100.55 mmol
  • DCM 300 mL
  • AlCl 3 53 g, 3
  • Step 7 Into a 250 mL 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen and maintained at 0 0 C was added 6,7- dimethoxyisoquinolin-4-ol (1.35 g, 5.27 mmol), DCM (200 mL), Et 3 N (3.4 g, 33.66 mmol) and TfjO (2.4 g, 8.51 mmol). The resulting solution was stirred for 30 min at 0 0 C and reaction was monitored by TLC (EtOAc/PE (1:1, v/v)). The resulting mixture was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , and concentrated.
  • the reaction mixture was then filtered through a plug of celite. After concentration, the crude product was purified by column chromatography using a gradient from 0 to 5 v% MeOH in 1:1 (v/v) EtOAc/hexane and DMEA 0.3 v%, followed by preparative HPLC over a Cl 8 reverse phase column using a gradient from 5 v% to 60 v% acetonitrile in water with 0.1 v% formic acid over 8 min with a flow rate of 40 mL/min to provide 6,7-dimethoxy-4-[2-(4- methoxyphenyl)morphoIin-4-yl]quinoIine as a yellow gum (28 mg, 34%).
  • the reaction mixture was filtered through celite, rinsed with ⁇ 30 mL of 10 v% MeOH in DCM, and concentrated (rotovap).
  • the compound was purified on a C18 preparative HPLC column (30x100 mm) using acetonitrile: water (with 0.1 v% formic acid) in a gradient from 20 v% CH 3 CN to 80 v% CH 3 CN at a flow rate of 45 mL/min.
  • the fractions were monitored at a wavelength of 352 nm and the product had a retention time of 2 to 3 min.
  • the material was loaded onto an SCX column, rinsed with one column volume of MeOH, and eluted with 2.0 M ammonia in methanol (8 mL).
  • the yellow suspension was stirred at 60 0 C for 65 hr, filtered through DCite, rinsed with ⁇ 30 mL of 10 v% MeOH in DCM, and concentrated (rotovap).
  • the crude product was purified on a Cl 8 preparative HPLC column (30x100 mm) using 15 v% CH 3 CN in water (with 0.1 v% formic acid) for 5 min, and then using a gradient from 15 v% CH 3 CN to 80 v% CH3CN over 2 min at a flow rate of 45 mL/min. Fractions were monitored at a wavelength of 357 run and the product was collected from 3.25 to 5.25 min.
  • reaction Upon completion, the reaction was allowed to cool to room temperature. The solution was moved to a seperatory funnel, and water and ethyl acetate was added. The aqueous layer was extracted ethyl acetate three times. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated.
  • the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10 v% to 60 v% ethyl acetate in hexane, to provide l-(6-fluoropyridin-3-yl)-6 5 7-dimethoxyisoquinoline (0.5 g).
  • the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1 v% to 5 v% MeOH in CH 2 CI 2 , to provide 5-(6,7-dimethoxyisoquinolin-l-yl)-N- iso ⁇ ropylpyridin-2-amine (0.0356 g, 0.110 mmol).
  • the aqueous layer was extracted with EtOAc.
  • the combined organic layers were washed with water, brine, dried with MgSO 4 , filtered, and concentrated.
  • the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in CH 2 CI 2 , to provide 5-(6,7-dimethoxyisoquinolin-l-yl)-N-ethyl-N-propylpyridin-2- amine (0.0700 g, 0.20 mmol).
  • the mixture was cooled to room temperature, diluted with ethyl acetate and H 2 O, the layers were separated and the aqueous was extracted with ethyl acetate three times. The combined organics were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by Biotage, 25 m column, 20-100% EA/DCM to yield the title compound.
  • Enzyme Activity To analyze the enzyme activity, 5 ⁇ L of serial diluted mPDE10A7 containing lysate were incubated with equal volumes of diluted (100-fold) fluorescein labeled cAMP or cGMP for 30 min in MDC HE 96-well assay plates (Molecular Devices Corp., Sunnyvale CA) at room temperature. Both the enzyme and the substrates were diluted in the following assay buffer: Tris/HCl (pH 8.0) 50 mM, MgCl 2 5 mM, 2- mercaptoethanol 4 mM, and BSA 0.33 mg/mL.
  • Enzyme Inhibition To check the inhibition profile, 10 ⁇ L of serial diluted compounds were incubated with 30 ⁇ l of diluted PDE enzymes in a 96-well polystyrene assay plate for 30 min at room temperature. After incubation, 5 ⁇ L of the compound-enzyme mixture were ali quoted into a MDC HE black plate, mixed with 5 ⁇ L of 100-fold diluted fluorescein labeled substrates (cAMP or cGMP), and incubated for 30 min at room temperature. The reaction was stopped by adding 20 ⁇ L of diluted binding reagents and counted in an Analyst GT for fluorescence polarization. The data were analyzed with SoftMax Pro.
  • the thought disorders that are characteristic of schizophrenia may result from an inability to filter, or gate, sensorimotor information.
  • the ability to gate sensorimotor information can be tested in many animals as well as in humans.
  • a test that is commonly used is the reversal of apomorphine-induced deficits in the prepulse inhibition of the startle response.
  • the startle response is a reflex to a sudden intense stimulus such as a burst of noise.
  • rats are exposed to a sudden burst of noise, at a level of 120 db for 40 msec, e.g., the reflex activity of the rats is measured.
  • the reflex of the rats to the burst of noise may be attenuated by preceding the startle stimulus with a stimulus of lower intensity, at 3 to 12 db above background (65 db), which attenuates the startle reflex by 20 to 80%.
  • the prepulse inhibition of the startle reflex may be attenuated by drugs that affect receptor signaling pathways in the CNS.
  • drugs that affect receptor signaling pathways in the CNS One commonly used drug is the dopamine receptor agonist apomorphine.
  • Administration of apomorphine reduces the inhibition of the startle reflex produced by the prepulse.
  • Antipsychotic drugs such as haloperidol prevents apomorphine from reducing the prepulse inhibition of the startle reflex.
  • This assay can be used to test the antipsychotic efficacy of PDElO inhibitors, as they reduce the apomorphine-induced deficit in the prepulse inhibition of startle.

Abstract

The present invention is directed to certain quinoline and isoquinoline compounds that are PDElO inhibitors, pharmaceutical compositions containing such compounds and processes for preparing such compounds. The invention is also directed to methods of treating diseases mediated by PDElO enzyme, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

Description

OUINOLINE AND ISOOUINOLINE DERIVATIVES AS PHOSPHODIESTERASE 10 INHIBITORS
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application
No. 60/780,611, filed March 8, 2006, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided herein are certain quinoline and isoquinoline compounds that are
PDElO inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDElO enzyme, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
BACKGROUND
[00031 Neurotransmitters and hormones, as well as other types of extracellular signals such as light and odors, create intracellular signals by altering the amounts of cyclic nucleotide monophosphates (cAMP and cGMP) within cells. These intracellular messengers alter the functions of many intracellular proteins. Cyclic AMP regulates the activity of cAMP-dependent protein kinase (PKA). PKA phosphorylates and regulates the function of many types of proteins, including ion channels, enzymes, and transcription factors. Downstream mediators of cGMP signaling also include kinases and ion channels. In addition to actions mediated by kinases, cAMP and cGMP bind directly to some cell proteins and directly regulate their activities.
[0004] Cyclic nucleotides are produced from the actions of adenylyl cyclase and guanylyl cyclase, which convert ATP to cAMP and GTP to cGMP. Extracellular signals, often through the actions of G protein-coupled receptors, regulate the activities of the cyclases. Alternatively, the amount of cAMP and cGMP may be altered by regulating the activities of the enzymes that degrade cyclic nucleotides. Cell homeostasis is maintained by the rapid degradation of cyclic nucleotides after stimulus-induced increases. The enzymes that degrade cyclic nucleotides are called 3',5'-cyclic nucleotide-specific phosphodiesterases (PDEs).
[0005] Eleven PDE gene families (PDEl-PDEl 1) have been identified based on their distinct amino acid sequences, catalytic and regulatory characteristics, and sensitivity to small molecule inhibitors. These families are coded for by 21 genes; and further multiple splice variants are transcribed from many of these genes. Expression patterns of each of the gene families are distinct. PDEs differ with respect to their affinity for cAMP and cGMP. Activities of different PDEs are regulated by different signals. For example, PDEl is stimulated by Ca2+/calmodulin. PDE2 activity is stimulated by cGMP. PDE3 is inhibited by cGMP. PDE4 is cAMP specific and is specifically inhibited by rolipram. PDE5 is cGMP- specific. PDE6 is expressed in retina.
[0006] PDEl 0 sequences were identified by using bioinformatics and sequence information from other PDE gene families (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999; Loughney et al., Gene 234:109-117, 1999; Soderling et al., Proc. Natl. Acad. Set USA 96:7071-7076, 1999). The PDElO gene family is distinguished based on its amino acid sequence, functional properties and tissue distribution. The human PDElO gene is large, over 200 kbs with up to 24 exons coding for each of the splice variants. The amino acid sequence is characterized by two GAF domains (which bind cGMP), a catalytic region, and alternatively spliced N and C termini. Numerous splice variants are possible because at least three alternative exons encode N termini and two exons encode C-termini. PDElOAl is a 779 amino acid protein that hydrolyzes both cAMP and cGMP. The Kn, values for cAMP and cGMP are 0.05 and 3.0 micromolar, respectively. In addition to human variants, several variants with high homology have been isolated from both rat and mouse tissues and sequence banks.
[0007J PDElO RNA transcripts were initially detected in human testis and brain.
Subsequent immunohistochemical analysis revealed that the highest levels of PDElO are expressed in the basal ganglia. Specifically, striatal neurons in the olfactory tubercle, caudate nucleus and nucleus accumbens are enriched in PDElO. Western blots did not reveal the expression of PDElO in other brain tissues, although immunoprecipitation of the PDElO complex was possible in hippocampal and cortical tissues. This suggests that the expression level of PDElO in these other tissues is 100-fold less than in striatal neurons. Expression in hippocampus is limited to the cell bodies, whereas PDElO is expressed in terminals, dendrites and axons of striatal neurons.
10008] The tissue distribution of PDEl 0 indicates that PDEl 0 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDElO enzyme, for example, in neurons that comprise the basal ganglia and therefore would be useful in treating a variety of neuropsychiatric conditions involving the basal ganglia such as obesity, non- insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like.
SUMMARY OF THE INVENTION
[0009] In one aspect, provided herein is a compound of Formula (I):
Figure imgf000004_0001
(I) or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, wherein:
X is nitrogen and Y and Z are each -CH= or one of Y and Z is nitrogen and the other is -CH= and X is -CR= (where R is hydrogen, alkyl, halo, or cyano); R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino,dialkyl amino, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)-NR13R14 and -O-(alkylene>-NRI5R16 (where R13, R14, R15, and R16 are independently hydrogen or alkyl), wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)-NR13R14 or— O-(alkylene)-NR13R16 are optionally replaced by one to two oxygen or nitrogen atom(s), and provided that at least one of R1, R2, and R3 is not hydrogen; and R3a is aryl, heteroaryl, or heterocyclyl ring substituted with:
R4, where R4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, or -X1R7 (where X! is -O-, -CO-, -C(O)O-, -OC(O)-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8, R9, R10, Rn, and R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
R5 and R6, where Rs and R6 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl, and provided that at least one of R4, R5, and R6 is not hydrogen; wherein the aromatic or alicyclic ring in R4, R5. R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; and additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro; provided that:
(a) when R is hydrogen, R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, and:
(i) R3a is pyrrolidin-1-yl, then R4 is not -X1R7, where X1 is -0-, and R7 is substituted or unsubstituted, aryl or heteroaryl;
(ii) R3a is piperidin-1-yl, where one of R4, R5 and R6 is hydrogen and another of R4, R5 and R6 is substituted or unsubstituted aryl or heteroaryl, then the remaining member of R4, R5 and R6 is not hydrogen; alkyl; carboxy; cyano; hydroxyl; alkoxy; -COR', -CONR'R" or -NR'R" (where R' and R" are independently hydrogen, alkyl, or unsubstituted aryl); or -NHCOR' (where R' is alkyl or unsubstituted aryl); or (iii) R3a is piperidin-1-yl, where two of R4, R5 and R6 are hydrogen, then remaining of R4, R5 and R is not —COR' (where R' is alkyl or unsubstituted aryl), -COOR' (where R' is alkyl or unsubstituted aryl), -CONR5R", -NR'R" or -NHCOR' (where each R" is hydrogen, alkyl, or unsubstituted aryl, and each R' is unsubstituted aryl);
(b) when R is hydrogen, R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, then:
(i) R3a is not substituted or unsubstituted 1,2,3,4-tetrahydroisoquinolin- 3-yl or l,2,3,4-tetrahydroisoquinolin-2-yl; and
(ii) R3a is not monosubstituted or disubstituted pyrrolidinyl where the one or two substituents are alkyl;
(c) when R is hydrogen, alkyl, or alkoxy, R1, R2, and R3 are independently hydrogen, halo, haloalkyl, alkyl, alkoxy, carboxy, hydroxymethyl or hydroxy, and R3a is aryl, then one of R4, R5, and R6 is an aromatic or alicyclic ring or a group that contains an aromatic or alicyclic ring provided that the aromatic or alicyclic ring is not phenyl (optionally substituted with one, two, or three substitutents, independently selected from cyano, halo, -CONH2 and haloalkyl), benzyl, benzyloxy,
1 H-benzimidazol-2-ylthio, lH-benzimidazol-2-ylsulfinyl, pyridinyl (optionally substituted with halo or — CONH2), pyrimidinyl, or morpholin-4-yl-carbonyl;
(d) when R is hydrogen, R1, R2, and R3 are independently hydrogen, halo, alkoxy, or hydroxy, and R3a is heteroaryl, then the heteroaryl ring is not phthalazin-1-yl optionally substituted with R4, R5 and R6, where R4 is alkyl, and R5 and R6 are alkoxy; isoquinolinyl optionally substituted with one or two substituents selected from alkoxy and hydroxy; lH-indoIyl optionally substituted with R4, R5, and R6 where R4 is hydrogen, one of R5 and R6 is hydrogen, alkyl, or alkoxy, and other of R5 and R6 is alkyl, alkoxy, haloalkyl, dialkylaminoalkyl, or hydroxyalkyl; benzo[c]isoxazolyl optionally substituted with R4, R5, and R6 where one of R4, R5, and R6 is hydrogen and the other two of R4, R5, and R6 are independently selected from alkoxy, aryl, and benzyloxy; lH-indazolyl optionally substituted with one or two of alkoxy or hydroxy; pyrrolyl substituted with R4, R5, and R6 where one of R4, R5, and R6 is hydrogen or alkyl and the other two of R4, R5, and R6 are phenyl optionally substituted with one or two alkoxy; thienyl optionally substituted with halo; or pyrazolyl optionally substituted with R4, R5, and R6 where R4 is hydrogen, one of R5 and R6 is alkoxycarbonyl and the other of R5 and R6 is alkoxyalkyl;
(e) when R is hydrogen or alkoxy, R1, R2, and R3 are independently hydrogen, halo, alkyl, haloalkyl, haloalkoxy, alkoxy, carboxy, hydroxymethyl or hydroxy, then R3a is not: monosubstituted piperazinyl [wherein the substitutent on the piperazinyl ring is alkyl, alkoxycarbonyl, phenyl, -COR' (where R' is alkyl; or piperidinyl or pyrrolidinyl each optionally substituted with one or two substituents each independently selected from alkyl or hydroxyl), hydroxyalkyl, -CONHR' (where R' is phenyl substituted with fluoro or phenoxy), lH-benzo[d]imidazol-2(3H)-one optionally substituted with alkyl, or 3,4-dihydroquinolinyl-2(lH)-one]; substituted or unsubstituted benzimidazolyl, 1,2,3,4- tetrahydroisoquinolinyl, isoquinolinyl, isobenzofuranyl-l(3H)-one, 1,2,3- oxadiazolyl-5(2H)-one, l,3,4-oxadiazolyl-2(3H)-one, 2,3- dihydrobenzo [b] [ 1 ,4]dioxinyl, benzo[d] [ 1 ,3]dioxolyl, 1 ,2,4,5 ,6,7- hexahydropyrazolo[l ,5-a]pyridinyl, 1 ,2-dihydropyrazolo[l ,5-a]pyridinyl, H- pyrazolo[l,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, benzisoxazolyl, 1 , 1 -dioxo-3H-benzo[c] [1 ,2]oxathiolyl, benzoruranyl-2(3H)- one, (Z)-I H-benzo[e][l ,4]diazepinyl-2(3H)-one, 1 ,3a-dihydropyrazolo[l ,5- αjpyridinyl, oxazolyl-2(3H)-one, naphthyl, or imidazo[5,l -a]isoquinolinyl; mono or disubstituted piperidinyl (where one substituent is hydrogen or hydroxy, and the other substitutent is alkoxy, hydroxyl, carboxy, or IH- benzo[d]imidazol-2(3H)-one optionally substituted with alkyl); or pyrrolidinyl optionally substuted with alkyl or alkoxy; and
(f) when X is N, then at least two of R1, R2 and R3 are not simultaneously hydrogen; and
(g) the compound is not a salt of (a)-(f). [0010] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable expicient.
[0011] In a third aspect, this invention is directed to a method of treating a disorder treatable by inhibition of PDElO in a patient which method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Within this aspect, the disease is obesity, non-insulin dependent diabetes, Huntington's disease, schizophrenia, bipolar disorder, or obsessive- compulsive disorder.
[0012] In a fourth aspect, this invention is directed the use of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder treatable by inhibition of PDElO in a patient. Within this aspect, in one embodiment the disorder is obesity, non- insulin dependent diabetes, Huntington's disease, schizophrenia, bipolar disorder, or obsessive- compulsive disorder.
[0013] It will be readily apparent to a person skilled in the art that the pharmaceutical composition could contain one or more compounds of Formula (I) (including individual stereoisomer, mixtures of stereoisomers where the compound of Formula (I) has at least a stereochemical centre), a pharmaceutically acceptable salt thereof, or mixtures thereof.
DETAILED DESCRIPTION
Definitions
[0014] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.
[0015] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
[0016] "Alicyclic" means a non-aromatic ring, e.g., cycloalkyl or heterocyclyl ring. [0017] "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like.
[0018] "Alkylthio" means a -SR radical, where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.
[0019] "Alkylsulfinyl" means a -SOR radical where R is alkyl as defined above, e.g., methylsulfϊnyl, ethylsulfϊnyl, and the like.
[0020] "Alkylsulfonyl" means a -SO2R radical, where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
[0021] "Amino" means an -NH2.
[0022] "Alkylamino" means an -NHR radical, where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
[0023] " Alkoxy" means an —OR radical, where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, «-, iso-, or tert-butoxy, and the like.
[0024] "Alkoxycarbonyl" means a -C(O)OR radical, where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
[0025] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3 -methoxy propyl, 2-ethoxyethyl, and the like.
[0026] "Alkoxyalkyloxy" means an -OR radical, where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.
[0027] "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two -NRR', where R is hydrogen, alkyl, or -CORa, where Ra is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, each as defined herein, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like.
[0028] "Aminoalkoxy" means an -OR radical, where R is aminoalkyl as defined above, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.
[0029] " Aminocarbonyl" means a -CONRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., -CONH2, methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
[0030] "Aminosulfinyl" means a -SONRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., — CONH2, methylaminosulfϊnyl. 2-dimethylaminosulfinyl, and the like.
[0031] "Aminosulfonyl" means a -SO2NRR' radical, where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., — SO2NH2, methylaminosulfonyl, 2-dimethylaminosulfonyl, and the like.
[0032] "Acyl" means a -COR radical, where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., acetyl, propionyl, benzoyl, pyridinylcarbonyl, and the like. When R in a -COR radical is alkyl, the radical is also referred to herein as "alkylcarbonyl."
[0033] "Acylamino" means an -NHCOR radical, where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., acetylamino, propionylamino, and the like.
[0034] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, e.g., phenyl or naphthyl.
[0035] "Aralkyl" means an -(alkylene)-R radical, where R is aryl as defined above. [0036] "Cycloalkyl" means a cyclic saturated monovalent bridged or non-bridged hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. Additionally, one or two ring carbon atoms may optionally be replaced with a —CO— group.
[0037] "Cycloalkenyl" means a cyclic nonaromatic monovalent bridged or non- bridged hydrocarbon radical of five to ten carbon atoms, which contains at least one carbon- carbon double bond, e.g., cyclopentenyl or cyclohexenyl. Additionally, one or two ring carbon atoms may optionally be replaced by a —CO- group.
[0038] Cycloalkylalkyl" means an -(alkylene)— R radical, where R is cycloalkyl as defined aoove; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
[0039] "Cycloalkyloxy" means an —OR radical, where R is cycloalkyl as defined, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[0040] "Cycloalkylalkyloxy" means an -OR radical, where R is cycloalkylalkyl as defined, e.g., cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylethyloxy, cyclohexylmethyloxy, and the like.
[0041] "Carboxy" means -COOH.
[0042] "Disubstituted amino" means an -NRR' radical, where R and R' are independently alkyl, cycloalkyl, cycloalkylalkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., dimethylamino, phenylmethylamino, and the like.
[0043] "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
[0044] "Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CF2CF3, -CF(CH3)3, and the like.
[0045] "Haloalkoxy" means an -OR radical, where R is haloalkyl as defined above, e.g., -OCF35 -OCHF2, and the like. [0046] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that, if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
{0047] "Hydroxyalkoxy" or "hydroxyalkyloxy" means an —OR radical, where R is hydroxyalkyl as defined above.
[0048] "Heterocyclyl" means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, in which one or two ring atoms are heteroatom(s), independently selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms are C. Additionally, one or two ring carbon atoms can optionally be replaced by a — CO— group, and the heterocyclic ring may be fused to phenyl or heteroaryl ring, provided that the entire heterocyclyl ring is not completely aromatic. Unless stated otherwise, the fused heterocyclyl ring can be attached at any ring atom. More specifically, the term "heterocyclyl" includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring has five, six or seven ring atoms, and is not fused to phenyl or heteroaryl ring, it is referred to herein as "monocyclic five-, six-, or seven-membered heterocyclyl ring, or five-, six-, or seven-membered heterocyclyl ring." When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic.
[0049] Heterocyclylalkyl" means an -(alkylene)-R radical, where R is heterocyclyl ring as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
[0050] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, where one or more, preferably one, two, or three, ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon, e.g., benzofuranyl, benzo[d]thiazolyl, isoquinolinyl, quinolinyl, thiophenyl, imidazolyl, oxazolyl, quinolinyl, furanyl, thazolyl, pyridinyl, and the like.
[0051] "Heteroaralkyl" means an -(alkylene)-R radical, where R is heteroaryl as defined above.
[0052] "Monosubstituted amino" means an -NHR radical, where R is alkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined above, e.g., methylamino, 2-phenylamino, hydroxyethylamino, and the like.
[0053] The present invention also includes prodrugs of compounds of Formula (I).
The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups, however, regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N.N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) are also within the scope of this invention.
[0054] The present invention also includes protected derivatives of compounds of
Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol, or any group containing a nitrogen atom, these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis; John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
[0055] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include, for instance, acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3- hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
[0056] The term "pharmaceutically acceptable salt" also refers to salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.
[0057J It is understood that the pharmaceutically acceptable salts are non-toxic.
Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995), which is incorporated herein by reference.
[0058] The compounds of the present invention may have one or more asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in an optically active, racemic, or diastereomeric form. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
[0059] Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this invention.
[0060] Additionally, as used herein, the term "alkyl" includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when a cyclic group, such as aryl, heteroaryl, and heterocyclyl, is substituted, it includes all the positional isomers albeit only a few examples are set forth.
[0061] All polymorphic forms and solvates, including hydrates, of a compound of
Formula (I) are also within the scope of this invention.
[0062] "Oxo" means the =(O) group.
[0063] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is mono- or disubstituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.
[0064] Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each as defined herein.
[0065] Optionally substituted heteroaryl" means a monovalent monocyclic or bi cyclic aromatic radical of 5 to 10 ring atoms, where one or more, preferably one, two, or three ring atoms are heteroatoms, each independently selected from N, O, and S, and the remaining ring atoms are carbon that is optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each as defined herein. More specifically, the term optionally substituted heteroaryl includes, but is not limited to, optionally substituted pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, each optionally substituted as indicated above. [0066] Optionally substituted heterocyclyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms, each independently selected from N, O, and S(O)n, where n is an integer from 0 to 2, and the remaining ring atoms are carbon. One or two ring carbon atoms can optionally be replaced by a -CO- group and is optionally substituted with one, two, or three substituents, each independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, acylamino, sulfonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkoxycarbonyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, sulfinyl, and sulfonyl, each as defined herein.
[0067] A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.
[0068] "Sulfinyl" means a -SOR radical, where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., methylsulfinyl, phenylsulfinyl, benzylsulfinyl, and the like.
[0069] "Sulfonyl" means a -SO2R radical, where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined above, e.g., methylsulfonyl, phenylsulfonyl, benzylsulfonyl, pyridinylsulfonyl, and the like.
[0070] "Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. [0071] A "therapeutically effective amount" means the amount of a compound of
Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.
Embodiments
[0072] In one aspect, provided herein is a compound of Formula (I), an individual stereoisomer, a mixture of stereoisomers, or pharmaceutically acceptable solvate or salt thereof, as defined in the Summary of the Invention.
[0073] (1) In one embodiment, X is nitrogen, and Y and Z are -CK-.
[0074] (2) In another embodiment, Y is nitrogen, and X and Z are =CH— .
[0075] (3) In yet another embodiment, Z is nitrogen, and X and Y are =CH-.
[0076] (4) In yet another embodiment, Y is nitrogen, Z is -CH=, and X is -CR=, where R is alkyl.
[0077] (5) In another embodiment, Y is nitrogen, Z is -CH=, and X is -CR=, where R is methyl, ethyl, n-propyl, or isopropyl.
[0078] (6) In another embodiment, provided herein are compounds of Formula
(I), wherein Y is nitrogen, Z is -CH=, and X is -CR=, where R is halo. Within this embodiment, one group of compounds of Formula (I) is that wherein R is fluoro or chloro..
[0079] (7) In yet another embodiment, Z is nitrogen, Y is -CH=, and X is -CR= where R is alkyl.
[0080] (8) In another embodiment, Z is nitrogen, Y is -CH=, and X is -CR= where R is methyl, ethyl, n- or wo-propyl.
[0081] (9) In yet another embodiment, Z is nitrogen, Y is -CH=, and X is -CR= where R is halo. Within this embodiment, one group of compounds of Formula (I) is that wherein R is fluoro or chloro. [0082] (A) Within the above embodiments 1-9, and subgroups contained therein, one group of compounds of Formula (I) is that wherein R1 is hydrogen.
[0083] (B) Within the above embodiment 1-9, and subgroups contained therein, another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, and R3 is cycloalkoxy or cycloalkylalkyloxy. Within this embodiment, one group of compounds is that wherein R2 is methoxy, and R3 is cyclopropoxy, cyclobutyoxy, cyclopentoxy. or cyclohexyloxy. Within this embodiment, another group of compounds is that wherein R2 is methoxy, and R3 is cycloproplmethyloxy, cyclopropylethoxy, cyclobutylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyl, or cyclohexylethyloxy.
[0084] (C) Within the above embodiments 1-9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, preferably methoxy or ethoxy, and R3 is hydroxyalkyl.
[0085] (D) Within the above embodiments 1-9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R is hydrogen, R is alkoxy, preferably methoxy or ethoxy, and R3 is hydroxyalkyloxy.
[0086] (E) Within the above embodiments 1 -9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, preferably methoxy or ethoxy, and R3 is alkoxyalkyl.
[0087] (F) Within the above embodiments 1 -9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, preferably methoxy or ethoxy, and R3 is alkoxyalkyloxy.
[0088] (G) Within the above embodiments 1-9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, preferably methoxy or ethoxy, and R3 is -(alkylene)-NRI3R14, where R13 and R14 are as defined in the Summary of the Invention.
[0089] (H) Within the above embodiments 1 -9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, preferably methoxy or ethoxy, and R3 is -O-(alkylene)-NR15R16, where R15 and R16 are as defined in the Summary of the Invention [0090] (I) Within the above embodiments 1-9, and subgroups contained therein, yet another group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is alkylamino, dialkylamino, fluoro, or trifluoromethoxy, and R3 is cycloalkoxy, cycloalkylalkyloxy, hydroxyalkoxy, alkoxylalkyloxy, or-O(alkylene)-NR15R16, where R15 and R16 are as defined in the Summary of the Invention
[0091] (J) Within the above embodiment 1-9, another group of compounds of
Formula (I) is that wherein R1 is hydrogen, and R2 and R3 are alkoxy, preferably, methoxy or ethoxy.
[0092] (K) Within the above embodiments 1-9, another group of compounds of
Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, and R3 is alkyl. Within this embodiment, one group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is methoxy or ethoxy, and R3 is methyl, ethyl, or propyl.
[0093] (L) Within the above embodiments 1-9, one group of compounds of
Formula (I) is that wherein R1 is hydrogen, R2 is alkoxy, and R3 is cycloalkyl, preferably cyclopropyl. Within this embodiment, one group of compounds of Formula (I) is that wherein R1 is hydrogen, R2 is methoxy or ethoxy, and R3 is cyclopropyl.
[0094] (M) Within the above embodiments 1-9, one group of compounds of
Formula (I) is that wherein R1 is hydrogen, R2 is fluoro, trifluoromethoxy, methylamino, or dimethylamino, and R3 is alkyl, alkoxy, haloalkyl, halo, alkoxycarbonyl or cycloalkyl.
[0095] (N) Within the above embodiments 1-9, another group of compounds of
Formula (I) is that wherein R1 is hydrogen, R3 is alkoxy, and R2 is alkyl. Within this embodiment, one group of compounds of Formula (I) is that wherein R1 is hydrogen, R3 is methoxy or ethoxy, and R2 is methyl, ethyl, or propyl.
[0096] (O) Within the above embodiments 1-9, one group of compounds of
Formula (I) is that wherein R1 is hydrogen, R3 is alkoxy, and R2 is cycloalkyl, preferably cyclopropyl. Within this embodiment, one group of compounds of Formula (I) is that wherein R1 is hydrogen, R3 is methoxy or ethoxy and R2 is cyclopropyl. [0097] (P) Within the above embodiments 1-9, one group of compounds of
Formula (I) is that wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other of R2 and R3 is halo or haloalkoxy.
[0098] (i) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, one group of compounds of Formula (I) is that wherein R3a is a ring of formula (a):
(a) where A is a monocyclic five-, six-, or seven-membered heterocyclyl ring substituted with R4, R5 and R6, as defined in the Summary of the Invention.
[0099] (ii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), O)(A-P), (4)(A-P), (5)(A-P)S (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000020_0002
wherein R4 is as defined in the Summary of the invention.
[00100] (iii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (S)(A-P), (6)(A-P), (T)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000021_0001
wherein R4 is as defined in the Summary of the invention.
[00101] (iv) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000021_0002
wherein R4 is as defined in the Summary of the invention.
[00102] Within the subgroups (ii)-(iv) above, one group of compounds is that wherein
R4 is phenyl optionally substituted, as defined in the Summary of the Invention.
[00103] Within the subgroups (ii)-(iv) above, another group of compounds is that wherein R4 is heteroaryl optionally substituted, as defined in the Summary of the Invention.
[00104] Within the subgroups (ii)-(iv) above, yet another group of compounds is that wherein R4 is saturated monocyclic heterocyclyl optionally substituted, as defined in the Summary of the Invention.
[00105] Within the subgroups (ii)-(iv) above, another group of compounds is that wherein R4 is saturated fused heterocyclyl optionally substituted, as defined in the Summary of the Invention.
[00106] The R3a rings in subgroups (ii)-(iv) above, the subgroups contained therein, including the hydrogen in -NH- groups in the rings, can also be optionally substituted with R5 and R6, where R5 and R6 are as defined in the Summary of the Invention. Preferably, one of R5 and R6 is hydrogen.
[00107] (v) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000022_0001
wherein the ring is substituted with R4, R5 and R6, as defined in the Summary of the Invention.
[00108] Within this subgroup, one group of compounds is that wherein the above rings are substituted with R4 as defined in the Summary of the Invention, and substituted with R and R6, where one of R5 and R6 is hydrogen. In one group of compounds, the -NH- groups in the rings are substituted with alkyl, cycloalkyl, or cycloalkylalkyl. In another group of compounds, the -NH- groups in the rings are unsubstituted. Within this embodiment, one group of compounds is that wherein R3a is morpholin-4-yl, piperazin-1-yl, or homopiperazin- 1-yl, substituted as defined above. Within this embodiment, another group of compounds is that wherein R3a is piperidin-1-yl or homopiperidin-1-yl, substituted as defined above. Within this embodiment, another group of compounds is that wherein R3a is morρholin-4-yl substituted as defined above.
[00109] (vi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000022_0002
wherein the ring is substituted with R4 , R5 and R6, as defined in the Summary of the Invention. [00110] Within this subgroup, one group of compounds is that wherein the. above rings are substituted with R4 as defined in the Summary of the Invention, preferably cycloalkyl, aryl, heteroaryl, or six-membered saturated heterocyclyl optionally substituted with Ra, Rb and Rc; and substituted with R5 and R6, where at least one of R5 and R6 is hydrogen. In one group of compounds, the -NH- groups in the rings are substituted with alkyl, cycloalkyl, or cycloalkylalkyl. In another group of compounds, the -NH- groups in the rings are unsubstituted.
[00111] (vii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P)3 (2)(A-P), (3)(A-P), (4)(A-P), (S)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000023_0001
preferably,
Figure imgf000023_0002
where R4 is as defined in the Summary of the Invention.
[00112] Within this embodiment, one group of compounds is that wherein R4 is cycloalkyl, phenyl, heteroaryl, or six-membered saturated heterocyclyl, preferably cycloalkyl, aryl, heteroaryl, or six membered saturated heterocyclyl, optionally substituted with Ra, Rb and Rc. The rings of the formulas shown above are optionally substituted, including the hydrogen atom on the -NH- group within the rings, with R5 and R6, as defined in the Summary of the Invention; preferably, Rs is hydrogen ,and R6 is attached to the carbon adjacent to the nitrogen attached to the quinoline or isoquinoline ring. Within this embodiment, one group of compounds is that where R4 is phenyl substituted with Ra and Rb that are meta to each other.
[00113] Within this embodiment, one group of compounds is that wherein R3a is morpholin-4-yl, piperazin-1-yl, 2-oxopiperidinyl, 2,4-dioxoρiperazinyI, or 2-oxopiperazinyl, substituted as defined in (vi) above. Within this embodiment, another group of compounds is that wherein R3a is piperidin-1-yl, substituted as defined in (vi) above. Within this embodiment, another group of compounds is that wherein R3a is morpholin-4-yl substituted as defined in (vi) above.
[00114] (viϋ) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), <2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)( A-P)3 and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
R ■55γ-γRR44 OO^^NN^RR44 RVYR4
Figure imgf000024_0001
where R4 is phenyl or heteroaryl, substituted at the para position with Ra, and optionally substituted with Rband Rc, wherein Ra, Rb, Rc, and R5 are as defined in the Summary of the Invention. The -NH- groups in the above rings can optionally be substitituted with R6 as defined in the Summary of the Invention. In one group of compounds within this embodiment, R6 is cycloalkyl, alkyl, or cycloalkylalkyl. In another group of compounds within this embodiment, R3a is other than piperidin-1-yl substituted as described above. In another group of compounds within this embodiment, R3a is piperidin-1-yl substituted as described above. In yet another group of compounds within this embodiment R3a is morpholin-4-yl substituted as described above. In yet another group of compounds within this embodiment R3a is morpholin-4-yl where R4 is phenyl is substituted with Ra and Rb where Ra and Rb are meta to each other. In yet another group of compounds within this embodiment R3a is piperazin-1-yl where R4 is phenyl is substituted with Ra and Rb where Ra and Rb are meta to each other. In yet another group of compounds within this embodiment R4 is -CONR7R8 where R7 and R8 are as defined in the Summary of the Invention, preferably R7 is phenyl optionally substituted with Rb and Rc wherein Ra, Rb, and Rc are as defined in the Summary of the Invention.
[00115] (ix) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P). (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000025_0001
where R4 is heterocyclyl, preferably heterocyclyl containing at least a -C=O group wherein the heterocyclyl ring is optionally substituted at the para position with Ra and optionally substituted with Rb and Rc wherein Ra, Rb, and Rc are as defined in the Summary of the Invention and R5 is as defined in the Summary of the Invention. Within this group, in one embodiment, R4 is monocyclic saturated six membered ring containing at least a -C=O group and optionally substituted at the para position with Ra and optionally substituted with Rb and Rc wherein Ra, Rb, and Rc are as defined in the Summary of the Invention. The -NH- groups in the above rings can optionally be substitituted with R6 as defined in the Summary of the Invention. Preferably, R6 is cycloalkyl, alkyl, or cycloalkylalkyl. In one group of compounds within this embodiment R3a is other than piperidin-1-yl substituted as described above. In one group of compounds within this embodiment, R3a is piperidin-1-yl substituted as described above.
[00116] ' (x) Within the above embodiments (l)-(9), and embodiments contained therein i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000025_0002
where R4 is cycloalkyl substituted at the para position with Ra and optionally substituted with Rb and Rc wherein Ra, Rb and Rc are as defined in the Summary of the Invention and R5 is as defined in the Summary of the Invention. The -NH- groups in the above rings can optionally be substitituted with R6 as defined in the Summary of the Invention. In one group of compounds within this embodiment R6 is cycloalkyl, alkyl, or cycloalkylalkyl.
[00117] (xi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), P)(A-P), (4)(A-P), (S)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000026_0001
where r R>5 are as defined in the Summary of the Invention.
[00118] (xii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (O)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula (a) or (b), as defined in embodiments (xv) or (xvi), respectively. In one group of compounds is that wherein R3a is a ring of formula:
Figure imgf000026_0002
where R4 is cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, Or -SO2NR12- where R8-R12are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl). In certain subgroups, R4 is phenyl, heteroaryl or heterocyclyl. The rings shown in the formulas above are also optionally substituted, including the hydrogen in -NH- groups in the rings, with R5 and R6 where R5 and R6 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfϊnyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino. The aromatic or alicyclic ring in R4, Rs, R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy,' aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino; and additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Rc are hydrogen or fiuoro. [00119] Within this embodiment, one group of compounds is that wherein R3a is:
Figure imgf000027_0001
where R4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, as defined in the Summary of the Invention.
[00120] Within this embodiment, another group of compounds is that wherein R3a is:
Figure imgf000027_0002
where R4 is morpholin-4-yl, piperazin-1-yl, or pyridinyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, as defined in the Summary of the Invention.
[00121] Within this embodiment, one group of compounds is that wherein R3a is:
Figure imgf000027_0003
where R4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, as defined in the Summary of the Invention and where the hydrogen in -NH- groups in the ring is optionally substituted with R5 and R6.
[00122] Within this embodiment, one group of compounds is that wherein R3a is
Figure imgf000027_0004
where R4 is phenyl, heteroaryl, or five- or six-membered heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, as defined in the Summary of the Invention and where the hydrogen in -NH- groups in the ring is optionally substituted with R5 and R6. [00123] (xϋi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P)3 (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (O)(A-P)5 (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000028_0001
where R4 is cyclopentyl, cyclohexyl, phenyl, heteroaryl, or monocyclic saturated fϊve-or six- membered heterocyclyl ring; R5 is hydrogen, alkyl, phenyl, heteroaryl, or monocyclic five- or six-membered heterocyclyl ring; and R6 is alkyl, preferably methyl; and wherein the aromatic or alicyclic ring in R4 and R5 is optionally substituted with Ra, Rb and Rc, as defined in the Summary of the Invention.
[00124] Within this subgroup, in one embodiment, R4 is phenyl, heteroaryl, or monocyclic five- or six-membered heterocyclyl ring and R5 is hydrogen or alkyl. In another embodiment, R4 and Rs are independently phenyl, heteroaryl, or monocyclic saturated five- or six-membered heterocyclyl ring. In each of the above embodiments, the aromatic or alicyclic ring is optionally substituted with Ra selected from alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and Rb and Rc, independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, and disubstituted amino.
[00125] (xiv) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), Q)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula:
Figure imgf000029_0001
where R4 is aralkyl, preferably benzyl, optionally substituted with Ra, Rband Rc, as defined in the Summary of the Invention; and R5 is as defined in the Summary of the Invention, preferably hydrogen or alkyl.
[00126] (xv) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula (a):
Figure imgf000029_0002
(a) where A is a monocyclic five-, six-, or seven-membered heterocyclyl ring, and ring (a) is substituted with:
R4, where R4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-Rl2 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
R5, where R5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl, or heterocyclyl; and
R6, where R6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino, preferably hydrogen; wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkαxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Rc are hydrogen or fluoro.
[00127] In one embodiment, A is a saturated five or six membered heterocyclyl ring and substituted as described above.
[00128] (xvi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a ring of formula (b):
X4-
.? ψ,
X2
(b) where:
X2, X3, and X4 are independently carbon, nitrogen, oxygen, or sulfur; provided that at least two of X2, X3, and X4 are other than carbon; and
B is phenyl, a six-membered heteroaryl ring (wherein the six-membered heteroaryl ring contains one or two nitrogen atoms, the rest of the ring atoms being carbon), or a monocyclic five-, six-, or seven-membered heterocyclyl ring; wherein ring (b) is substituted with:
R4, where R4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
R5, where R5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
R6, where R6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R4, R5, Rδ, and R7 is optionally substituted with one to three substituents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and additionally substituted with one or two substituents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro.
[00129] (xvii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a monocyclic six- or seven-membered heterocyclyl ring substituted with:
R4, where R4 is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, - NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
R5, where Rs is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
R6, where R6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substituents independently selected from Ra, Rb, and Rc which . are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and additionally substituted with one or two substituents independently selected from Rd and Re where Rdand Reare hydrogen or fluoro. In one group within this embodiment, R3a is other than piperidinyl substituted as described above. In one group within this embodiment, R3a is piperidinyl substituted as described above.
[00130] (xviii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is pyrrolidin-1-yl substituted with:
R4, where R4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
R5, where R5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
R6, where R6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substituents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, arninosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and additionally substituted with one or two substituents independently selected from Rd and Re where Rd and Rc are hydrogen or fluoro.
100131] (xix) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), O)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is 2-oxopyrrolidinyl or 2,4-dioxoimidazolidinyl substituted with:
R4, where R4 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, Or-X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl. aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);
R5, where R5 is hydrogen alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfϊnyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl; and
R6, where R6 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, or monosubstituted amino, disubstituted amino, preferably hydrogen; and wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substituents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfmyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and additionally substituted with one or two substituents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro.
[00132] (xx) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P)5 (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is phenyl optionally substituted as defined in the Summary of the Invention.
[00133] Within this embodiment, one group of compounds is that wherein R3a is a group of formula:
Figure imgf000034_0001
where one of R4 and R5 is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, monsubstituted or disubstituted amino, or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -S-, -SO-, -SO2-, -NR1 1SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and the other of R4 and R5 is cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein the aromatic or alicycUc ring in R4 and R5 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulflnyl, sulfonyl, aminocarbonyl. aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
[00134] Preferably, R4 is aryl, heteroaryl, or heterocyclyl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc.
[00135] Within this embodiment, one group of compounds is that wherein R3a is a group of formula:
Figure imgf000035_0001
where R4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-. -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); R5 is cycloalkyl, aryl, heteroaryl, or heterocyclyl; and R6 is alkoxy cyano, monsubstituted amino or disubstituted amino, wherein the aromatic or alicyclic ring in R5 and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
[00136] (xxi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (S)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000035_0002
where R4 and R5 are as defined in (xvii) above.
[00137] (xxii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000036_0001
where R4 and R5 are as defined in (xxi) above.
[00138] One class of compounds is that where R3a is a group of formula:
Figure imgf000036_0002
where R4 and Rs are as defined in (xxi) above.
[001391 Within this subgroup (xxii), another class of compounds is that where R4 is heteroaryl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc.
[00140] Within this subgroup (xxii), another class of compounds is that where R4 is heterocyclyl, preferably piperazinyl, piperidinyl, or morpholinyl, each optionally substituted with one to three substitutents, independently selected from Ra, Rb, and Rc.
[00141] Within this subgroup (xxii), another class of compounds is that where R4 is mono or disubstituted amino and R5 is hydrogen, alkyl, or halo.
[00142] (xxiii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000036_0003
where R4 is as defined in the Summary of the Invention. The isoquinoline ring can optionally be substituted with R » 5 as defined in the Summary of the Invention.
[00143] Within this subgroup (xxiii), another class of compounds is that where R4 is heteroaryl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc. Within this subgroup (xxiii), another class of compounds is that where R4 is heterocyclyl, preferably piperazinyl, piperidinyl. or morpholinyl, each optionally substituted with one to three substitutents, independently selected from Ra, Rb, and Rc.
[00144] (xxiv) Within the above embodiments (l)-(9), and embodiments contained • therein, i.e., (I)(A-P)5 (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000037_0001
where R4 is as defined in the Summary of the Invention. The isoquinoline ring can optionally be substituted with R5 as defined in the Summary of the Invention.
[00145] Within this subgroup (xxiv), another class of compounds is that where R4 is heteroaryl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc. Within this subgroup (xxiv), another class of compounds is that where R4 is heterocyclyl, preferably piperazinyl, piperidinyl, or morpholinyl, each optionally substituted with one to three substitutents, independently selected from Ra, Rb, and Rc.
[00146] (xxv) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000037_0002
where " — " represents a single bond or a double bond, and R4, Rs, and R6 are as defined in the Summary of the Invention.
[00147] Within this embodiment, one class of compounds is that wherein R3a is a group of formula:
Figure imgf000038_0001
where one of R4 and R5 is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, monsubstituted or disubstituted amino, Or-X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -S-, -SO-, -SO2-, -NR10SO2-, or -SO2NR11- where R8-Rπ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and the other one of R4 and R5 is cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein the aromatic or alicyclic ring in R4 and R5 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alky], cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. Preferably, R4 is aryl, heteroaryl, or heterocyclyl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc.
[00148] Within this embodiment, another class of compounds is that wherein R3a is a group of formula:
Figure imgf000038_0002
where R4 and R5 are as described immediately above.
[00149] (xxvi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another class of compounds is that wherein R3a is a group of formula:
Figure imgf000039_0001
where R >4 a Λn_dJ R r>5 a, re as described in (xxv) above.
[00150] (xxvii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
R4 N-N Li >R«
where R5 is hydrogen or alkyl, and R4 is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
[00151] In one embodiment, R4 is aralkyl (preferably benzyl) optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc. In another embodiment, R4 is heteroaryl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc. In one embodiment, R4 is heterocyclyl optionally substituted with optionally substituted phenyl or optionally substituted heteroaryl. In one class of compounds, R3a is a group of formula:
Figure imgf000039_0002
where Rs is hydrogen or alkyl, preferably hydrogen; n is 1, 2, or 3; Z is -O-, -NH-, or - N(alkyl)— ; and Ra is phenyl or heteroaryl each optionally substituted with Ra, Rb, and Rc, preferably phenyl optionally substituted with Ra, Rb, and Rc. [00152] (xxviii) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), P)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)( A-P)5 and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000040_0001
where R4 is hydrogen, alkyl, h , haloalkyl, h oarloalkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, or -X1R7 (where X1 is -O-, -CO-, -C(O)O-, -OC(O)-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8- R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and R5 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl provided that at least one of R4and R5 is not hydrogen; and wherein the aromatic or alicyclic ring in R4 and R5 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy. alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
[00153] Within this embodiment, one group of compounds is that wherein R4 is phenyl, heteroaryl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc.
[00154] (xxix) Within the above embodiments (1)~(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), P)(A-P), (4)(A-P), (S)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000041_0001
where R4 is alkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or -X1R7 (where X1 is -O-, -CO-, -NR8CO-, -CONR9-, -NR10-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl), wherein the aromatic or alicyclic ring in R4 is optionally substituted with one to three substitutents independently selected from Rα, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
[00155] Preferably, R4 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc.
[00156] (xxx) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is a group of formula:
Figure imgf000041_0002
where R4 is aralkyl, preferably benzyl, optionally substituted with Ra, Rband Rc, as defined in the Summary of the Invention.
[00157] (xxxi) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is pyridinyl, pyrimidinyl, benzoisothiazoly, or 5-, 6-, 7-, or 8-azaindolyl, each substituted as defined in the Summary of the Invention.
[00158J (xxxii) Within the above embodiments (l)-(9)5 and embodiments contained therein, i.e., (I)(A-P)5 (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is morpholin-4-yl or piperazin-1-yl, each substituted as defined in the Summary of the Invention.
[00159] (xxxiii)Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P)5 (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P)5 (O)(A-P)5 (7)(A-P). (S)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is piperidinyl, piperazinyl, or morpholinyl, each optionally substituted as defined in the Summary of the Invention.
[00160] (xxxiv) Within the above embodiments (l)-(9), and embodiments contained therein, i.e., (I)(A-P), (2)(A-P), (3)(A-P), (4)(A-P), (5)(A-P), (6)(A-P), (7)(A-P), (8)(A-P) and (9)(A-P), and groups contained therein, yet another group of compounds of Formula (I) is that wherein R3a is pyridinyl, pyrimidinyl, or isothiazolyl, each optionally substituted as defined in the Summary of the Invention.
[00161] Representative compounds of Formula (I) are provided in Table 1 below:
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000043_0001
General Synthetic Schemes
[00162] Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
[00163] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, WI), Bachem (Torrance, CA), or Sigma (St. Louis, MO), or are prepared by methods known to those skilled in the art, following procedures set forth in references, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplernentals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
[00164] The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. [00165] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -780C to about 1500C, from about 00C to about 1250C, or at about room (or ambient) temperature, e.g., about 230C.
[00166] Compounds of Formula (I), where Z is nitrogen; and X is -CR= (where R is hydrogen, alkyl, alkoxy, or halo), Y is carbon, and R1, R2, R3, and R3a are as defined in the Summary of the Invention, can be prepared as described in Scheme 1.
Scheme 1
Figure imgf000044_0001
R = H, alkyl, alkoxy, or halo i. R33B(OH)2 ii. Nitrogen containing heterocycles
Figure imgf000044_0002
[00167] Treatment of acrylic acid derivative 1 with a halogenating agent, such as thionyl chloride, followed by treatment with sodium azide, provides acryloyl azide, which upon heating at approximately 2700C in a suitable high boiling solvent, such as diphenylether, cyclizes to form the corresponding 2H-isoquinolin-l-one 2. Compounds of formula 1 are either commercially available or can be synthesized by methods common to the art.
[00168] Compound 2, where R is alkyl or halo, such as chloro or bromo, can be prepared by treating compound 2, where R is H, with a halogenating agent, such as N- chlorosuccinimide or N-bromosuccinimide, in N,N-dimethylformamide (see, Journal of Heterocyclic Chemistry, 38:597-600, 2001). Treatment of the resulting halo compound 2 with an alkyl Grignard reagent provides compound 2, where R is alkyl. 2H-Isoquinolin-1- one 2 is then converted to compound 3, where X is chloro or bromo, by treatment with phosphorus oxychloride or phosphorous oxybromide, respectivley.
{00169] Compound 3 is converted into the corresponding compound of Formula (I) via a variety of methods. For example, compounds of Formula (I), wherein R3a is an aryl or heteroaryl ring, can be prepared by standard synthetic methods known to one of ordinary skill in the art, e.g., Suzuki-type coupling of the corresponding aryl or heteroaryl boronic acid with compound 3 where X is halo (see, Miyaura and Suzuki, Chem. Rev., 95:2457-2483, 1995). Such boronic acids are either commercially available, e.g., Aldrich Chemical Co. (Milwaukee, WI), Lancaster Synthesis (Ward Hill, MA), or Maybridge (Cornwall, UK), or can readily be prepared from the corresponding bromides by methods described in the literature (see, Miyaura et al, Tetrahedron Letters, 1979, 3437; Miyaura and Suzuki, Chem. Commun. 1979, 866).
[00170] Compounds of Formula (I), where R3a is a heterocyclic ring (e.g., pyrrolidin-1- yl, piperidin-1-yl, or morρolin-4-yl) attached via a nitrogen atom, can be prepared by reacting compound 3 with a heterocyclic ring in the presence of a base, such as triethylamine or pyridine. Suitable solvents include, but are not limited to, polar aprotic solvents, such as tetrahydrofuran and N,N-dimethylforamide (DMF). Such heterocyclic rings (pyrrolidines, piperidines, homopiperidines, piperazines, homopiperazines, morpholines, and the like) are either commercially available, or can be readily prepared by standard methods known within the art (see, Louie and Hartwig, Tetrahedron Letters, 36:3609, 1995; Guram et al., Angew Chem. Int. Ed., 34:1348, 1995).
[00171] Alternatively, a compound of Formula (I) can be prepared by heating compound 3 with a heterocyclic ring in a suitable organic solvent, such as tetrahydrofuran (THF), benzene, dioxane, toluene, alcohol, or a mixture thereof, under catalytic conditions, using, for example, a palladium or copper catalyst, such as, but not limited to, tris(dibenzylidene-acetone) dipalladium(O) or copper (I) iodide, in the presence of a suitable base, such as potassium carbonate, sodium Λ-butoxide, lithium hexamethyldisilizane, and the like.
100172] Substituted indazoles useful to make compounds of Formula (I) are either commercially available, e.g., Aldrich Chemical Co. (Milwaukee, WI)5, Sinova, Inc. (Bethesda, MA), J & W PharmLab, LLC (Morrisville, PA), or can be prepared by methods commonly known within the art (see, Lebedev et al, J. Org. Chem. 70:596-602, 2005; and the references cited therein). For example, indazoles wherein R4 is heterocyclyl, e.g., morpholine or N-methylpiperazine, may be synthesized by Buchwald-type coupling of the corresponding bromoindazole with the desired heterocyclic compound. The bromoindazoles may be prepared as described in International Publication No. WO 2004/029050, the disclosure of which is incorporated herein by reference in its entirety. Copper catalyzed reaction of the appropriately substituted indazole with compound 3, where X is halo, provides the desired compounds of Formula (I). Alternatively, the bromoindazole undergoes palladium catalyzed reaction with compound 3 (X is halo) to provide a 4-(bromo-lH-indazol-l-yl) substituted compound of Formula (I). Subsequent N-arylation reaction with, for example, morpholine or N-methylpiperazine, provides a desired compound of Formula (I). Alternatively, Suzuki-type reaction of the 4-(bromo-lH-indazol-l-yl)-substituted compound with an aryl or heteroaryl boronic acid (e.g., phenylboronic acid or 4-pyridine boronic acid) gives the corresponding 4- aryl or heteroaryl substituted indazole compound of Formula (I).
[00173] Compounds of Formula (I), where Y is nitrogen, X is -CR= (R = alkyl), Z is carbon, and R1, R2, R3 and R3a are as defined in the Summary of the Invention, can be prepared as described in Scheme 2 below.
Scheme 2
Figure imgf000046_0001
[00174] An acrylic acid derivative 4 is converted to the corresponding 2H-isoquinolin-
1-one 5 under reaction conditions described in Scheme 1. Treatment of isoquinolin-1-one S with N-bromosuccinimide in N,B-diniethylformamide (see, Journal of Heterocyclic Chemistry, 38:597-600, 2001), followed by phosphorus oxybromide, provides 1,4- dibromoisoquinoline 6. Treatment of compound 6 with a suitable Grignard reagent, catalyzed by a palladium or copper catalyst, provides l-alkyl-4-bromo-isoquinoline 7. Compounds of formula 4 are either commercially available or can be synthesized by methods common to the art. Alternatively, compound 5 can be converted to the corresponding 1 ,4- dichloroisoquinoline derivative by treating it with phosphorus pentachloride at elevated temperatures (see, Barber et al., Bioorg. Med. Chem. Lett., 14:3227-3230, 2004). Compound 7 is then converted to a compound of Formula (I) as described in Scheme 1 above.
[00175] Compounds of Formula (I), where X is nitrogen, Y and Z are -CH=, and R1,
R2, R3 and R3a are as defined in the Summary of the Invention, can be prepared as described in Scheme 3 below (see, J. Med Chem., 42:5369, 1999).
Scheme 3
Figure imgf000047_0001
[00176] Compounds 9, where R1 is hydrogen, and R2 and R3 are the same and are selected from alkoxy, haloalkoxy, hydroxy, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, or -O~(aIkylene)-NR15R16, for example, methoxy, can be synthesized by methods common to the art. For example, 3,4-dihydroxy-nitrobenzene 8 (R1 = H, R2 = R3 = OH) can be treated with a desired R3LG, where R3 is as defined above and LG is a suitable leaving group, in the presence of a base, such as cesium carbonate, triethylamine, sodium hydride, potassium carbonate, potassium hydride, or the like, to provide the corresponding dialkoxy product. Suitable organic solvents include acetone, acetonitrile, DMF, THF, and the like. Reduction of the nitro group under known reaction conditions, e.g., hydrogenation with palladium on carbon, iron powder in acetic acid, or nickel boride, provides the amino compound 9 (see, Castle et al. J. Org. Chem. 19:1117, 1954). [00177] Compounds 9, where R1 is hydrogen, R2 is haloalkoxy, hydroxy, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, or — O-{alkylene)- NR1SR16, and R3 is methoxy, can be prepared from 2-methoxy-5-nitrophenol as a starting material. Simple etherification, as described above, can be utilized to provide the required R2 substitution, which, when followed by the reduction step as described above, provides the desired amino compound 9. Treatment of intermediate phenols with haloacetic acid, e.g., chlorodifluoroacetic acid, under basic conditions provides difluoromethyl ethers. Heating compound 9 with diethyl 2-(ethoxymethylene)malonate in the presence of diphenylether provides 4-hydroxyquinoline 10, which is then converted to 4-halo compound 11. Compound 11 is converted to a compound of Formula (I) as described in Scheme 1 above.
[00178] 4-Chloroquinoline 11, where R1 is hydrogen, and R2 and R3 are halo, can be prepared as shown Scheme 4 below, which exemplifies the synthesis of 4-chloro-6,7- difluoroquinoline 16 (see, Bioorg. Med. Chem., 13:2021, 2005; and PCT Application Publication No. WO 95/23787).
Scheme 4
PhOPh, 2500C
Figure imgf000048_0001
Figure imgf000048_0002
12 13 14
Figure imgf000048_0003
15 16
Utility and Methods of Use
[00179] Provided herein are methods for treating a disorder or disease by inhibiting
PDElO enzyme. The methods, in general, comprises the step of administering a therapeutically effective amount of a compound of Formula (I), or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat the disorder or disease. [00180] In certain embodiments, this invention provides a use of a compound as described herein in the manufacture of a medicament for treating a disorder or disease treatable by inhibition of PDElO.
[00181] The compounds of the present invention inhibit PDEl 0 enzyme activity, and hence raise the levels of cAMP or cGMP within cells that express PDElO. Accordingly, inhibition of PDEl 0 enzyme activity would be useful in the treatment of diseases caused by deficient amounts of cAMP or cGMP in cells. PDElO inhibitors would also be of benefit in cases wherein raising the amount of cAMP or cGMP above normal levels results in a therapeutic effect. Inhibitors of PDElO may be used to treat disorders of the peripheral and central nervous system, cardiovascular diseases, cancer, gastro-enterological diseases, endocrinological diseases and urological diseases.
[00182] Indications that may be treated with PDElO inhibitors, either alone or in combination with other drugs, include, but are not limited to, those diseases thought to be mediated in part by the basal ganglia, prefrontal cortex, and hippocampus. These indications include psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
[00183] Psychoses are disorders that affect an individual's perception of reality.
Psychoses are characterized by delusions and hallucinations. The compounds of the present invention are suitable for use in treating patients suffering from all forms of psychoses, including, but not limited to, schizophrenia, late-onset schizophrenia, schizoaffective disorders, prodromal schizophrenia, and bipolar disorders. Treatment can be for the positive symptoms of schizophrenia as well as for the cognitive deficits and negative symptoms. Other indications for PDElO inhibitors include psychoses resulting from drug abuse (including amphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus, sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewy bodies, or hypoglycemia. Other psychiatric disorders, like posttraumatic stress disorder (PTSD), and schizoid personality can also be treated with PDElO inhibitors. [00184] Obsessive-compulsive disorder (OCD) has been linked to deficits in the frontal-striatal neuronal pathways (Saxena et al., Br. J. Psychiatry Suppl, 35:26-37, 1998). Neurons in these pathways project to striatal neurons that express PDElO. PDEl 0 inhibitors cause cAMP to be elevated in these neurons; elevations in cAMP result in an increase in CREB phosphorylation and thereby improve the functional state of these neurons. The compounds of the present invention are therefore suitable for use in the indication of OCD. OCD may result, in some cases, from streptococcal infections that cause autoimmune reactions in the basal ganglia (Giedd et n\., Am J Psychiatry. 157:281-283, 2000). Because PDElO inhibitors may serve a neuroprotective role, administration of PDElO inhibitors may prevent the damage to the basal ganglia after repeated streptococcal infections and thereby prevent the development of OCD.
[00185] In the brain, the level of cAMP or cGMP within neurons is believed to be related to the quality of memory, especially long term memory. Without wishing to be bound to any particular mechanism, it is proposed that, since PDElO degrades cAMP or cGMP, the level of this enzyme affects memory in animals, for example, in humans. A compound that inhibits cAMP phosphodiesterase (PDE) can thereby increase intracellular levels of cAMP, which in turn activate a protein kinase that phosphorylates a transcription factor (cAMP response binding protein). The phosphoylated transcription factor then binds to a DNA promoter sequence to activate genes that are important in long term memory. The more active such genes are, the better is long-term memory. Thus, by inhibiting a phosphodiesterase, long term memory can be enhanced.
[00186] Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The compounds of the present invention are suitable for use in treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld- Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus. [00187] The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. The present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline. The present invention includes methods of treatment for memory impairment as a result of disease. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntingdon's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. The compounds of the present invention are suitable for use in the treatment of memory impairment due to, for example, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, depression, aging, head trauma, stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetes associated cognitive impairment, memory deficits from early exposure of anesthetic agents, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases.
[00188] The compounds of the present invention are also suitable for use in the treatment of a class of disorders known as polyglutamine-repeat diseases. These diseases share a common pathogenic mutation. The expansion of a CAG repeat, which encodes the amino acid glutamine, within the genome leads to production of a mutant protein having an expanded polyglutamine region. For example, Huntington's disease has been linked to a mutation of the protein huntingtin. In individuals who do not have Huntington's disease, huntingtin has a polyglutamine region containing about 8 to 31 glutamine residues. For individuals who have Huntington's disease, huntingtin has a polyglutamine region with over 37 glutamine residues. Aside from Huntington's disease (HD), other known polyglutamine- repeat diseases and the associated proteins include dentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1); spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar ataxia tyρe-2 (ataxin-2); spinocerebellar ataxia type-3 (also called Machado-Joseph disease or MJD) (ataxin-3); spinocerebellar ataxia type-6 (alpha Ia- voltage dependent calcium channel); spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar muscular atrophy (SBMA, also know as Kennedy disease). [00189] The basal ganglia are important for regulating the function of motor neurons; disorders of the basal ganglia result in movement disorders. Most prominent among the movement disorders related to basal ganglia function is Parkinson's disease (Obeso et al., Neurology. 62(1 Suppl l):S17-30, 2004). Other movement disorders related to dysfunction of the basal ganglia include tardive dyskinesia, progressive supranuclear palsy and cerebral palsy, corticobasal degeneration, multiple system atrophy, Wilson disease, dystonia, tics, and chorea. The compounds of the invention are also suitable for use to treat movement disorders related to dysfunction of basal ganglia neurons.
[00190] PDElO inhibitors are useful in raising cAMP or cGMP levels and prevent neurons from undergoing apoptosis. PDElO inhibitors may be anti-inflammatory by raising cAMP in glial cells. The combination of anti-apoptotic and anti-inflammatory properties, as well as positive effects on synaptic plasticity and neurogenesis, make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy (MSA).
[00191] Autoimmune diseases or infectious diseases that affect the basal ganglia may result in disorders of the basal ganglia including ADHD, OCD, tics, Tourette's disease, Sydenham chorea. In addition, any insult to the brain can potentially damage the basal ganglia including strokes, metabolic abnormalities, liver disease, multiple sclerosis, infections, tumors, drug overdoses or side effects, and head trauma. Accordingly, the compounds of the invention can be used to stop disease progression or restore damaged circuits in the brain by a combination of effects including increased synaptic plasticity, neurogenesis, anti-inflammatory, nerve cell regeneration and decreased apoptosis.
[00192] The growth of some cancer cells is inhibited by c AMP and cGMP. Upon transformation, cells may become cancerous by expressing PDElO and reducing the amount of c AMP or cGMP within cells. In these types of cancer cells, inhibition of PDElO activity inhibits cell growth by raising cAMP. In some cases, PDElO may be expressed in the transformed, cancerous cell but not in the parent cell line. In transformed renal carcinoma cells, PDElO is expressed and PDElO inhibitors reduce the growth rate of the cells in culture. Similarly, breast cancer cells are inhibited by administration of PDElO inhibitors. Many other types of cancer cells may also be sensitive to growth arrest by inhibition of PDElO. Therefore, compounds disclosed in this invention can be used to stop the growth of cancer cells that express PDElO.
[00193] The compounds of the invention are also suitable for use in the treatment of diabetes and related disorders such as obesity, by focusing on regulation of the cAMP signaling system. By inhibiting PDE-10, especially PDE-IOA, intracellular levels of c AMP are increased, thereby increasing the release of insulin-containing secretory granules and, therefore, increasing insulin secretion. See, for example, WO 2005/012485, which is hereby incorporated by reference in its entirety. The compounds of Formula (I) can also be used to treat diseases disclosed in US Patent application publication No. 2006/019975, the disclosure of which is incorporated herein by reference in its entirety.
Testing
[00194] The PDEl 0 inhibitory activities of the compounds of the present invention can be tested, for example, using the in vitro and in vivo assays described in the Biological Examples below.
Administration and Pharmaceutical Compositions
[00195] In general, the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of a compound of this invention, i.e., the active ingredient, depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
[00196] Therapeutically effective amounts of compounds of formula (I) may range from approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day, more preferably 3.5 mg to 70 mg per day.
[00197] In general, compounds of this invention can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
[00198] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 ran in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00199] The compositions are comprised of, in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
[00200] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
[00201] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. [00202] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
[00203] The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.
[00204] The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of psychoses, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss, e.g., nicotinic α-7 agonists, PDE4 inhibitors, other PDElO inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and galanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range, and can be administered either simultaneously or sequentially.
[00205] Drugs suitable in combination with the compounds of the present invention include, but are not limited to, other suitable schizophrenia drugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolar disorder drugs, including, but not limted to, Lithium, Zyprexa, and Depakote; Parkinson's disease drugs, including, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin; agents used in the treatment of Alzheimer's disease, including, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used in the treatment of dementia, including, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon; agents used in the treatment of epilepsy, including, but not limited to, Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton, and Felbatol; agents used in the treatment of multiple sclerosis, including, but not limited to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone; agents used in the treatment of Huntington's disease, including, but not limited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone; agents useful in the treatment of diabetes, including, but not limited to, PPAR ligands (e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues (e.g., sulfonylurea drugs, such as Glyburide, Glimepiride, Chlorpropamide, Tolbutamide, and Glipizide, and non-sulfonyl secretagogues), oc-glucosidase inhibitors (such as Acarbose, Miglitol, and Voglibose), insulin sensitizers (such as the PPAR-γ agonists, e.g., the glitazones; biguanides, PTP-IB inhibitors, DPP-IV inhibitors, and 1 lbeta-HSD inhibitors), hepatic glucose output lowering compounds (such as glucagon antagonists and metaformin, e.g., Glucophage and Glucophage XR), insulin and insulin derivatives (both long and short acting forms and formulations of insulin); and anti- obesity drugs, including, but not limited to, β-3 agonists, CB-I agonists, neuropeptide Y5 inhibitors, Ciliary Neurotrophic Factor and derivatives (e.g., Axokine), appetite suppressants (e.g., Sibutramine), and lipase inhibitors (e.g., Orlistat).
EXAMPLES
[00206] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
[00207] All NMR spectra were recorded at 300 MHz on a Bruker Instruments NMR unless otherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks are listed relative to TMS (δ 0.00 ppm). Microwave reactions were performed using a Personal Chemistry Optimizer™ microwave reactor in Personal Chemistry microwave reactor vials. Sulfonic acid ion exchange resins (SCX) were purchased from Varian Technologies. Analytical HPLC was performed on 4.6 mm x 100 mm Waters Sunfire RP Cl 8 5 μm column. 4-Bromo-6,7- dimethoxyquinoline, a starting material for making certain compounds of Formula (I), is commercially available. Synthetic Examples
Example 1 Synthesis of l-bromo-6J-dimethoxyisoαuinoline
Figure imgf000057_0001
[00208] Step 1. A mixture of 3,4-dimethoxybenzaldehyde (30 g, 180.72 mmol), malonic acid (28.4 g, 273.08 nimol), and piperidine (3 mL) in pyridine (90 mL) was stirred at 120 0C for 6 hr. The reaction mixture was monitored by TLC (EtOAc/PE (1 :1, v/v)). Upon completion, the reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 by the addition of concentrated HCl. The product was isolated by filtration, and the filter cake was washed with water. The solid was dried in an oven under reduced pressure to provide 30 g (80%) of (E)-3-(3,4-dimethoxyphenyl)acrylic acid as a light yellow solid.
[00209] Step 2. To a solution of (E)-3-(3,4-dimethoxyphenyl) acrylic acid (10 g, 48.08 mmol) in THF (500 mL) was added a solution of DPPA (13.3 g, 48.36 mmol) in THF (20 mL) dropwise with stirring at 0 to 5 0C. TEA (5 g, 49.50 mmol) was then added dropwise with stirring over a time period of 1.5 hr, and the resulting mixture was stirred for additional 12 hr at room temperature. The reaction mixture was concentrated, followed by the dropwise addition of CH3OH (300 mL) with stirring. The resulting solution was refluxed for additional 48 hr. The reaction was monitored by TLC (EtOAc:PE(l : 1 , v/v). The reaction mixture was quenched by the addition of H2O, and then extracted with EtOAc and the organic layers combined. The residue was purified by silica gel chromatography using EtOAc/PE (1:10, v/v) as an eluant to provide (E)-methyl 3, 4-dimethoxystyryl carbamate as a white solid (2.5 g).
[00210] Step 3. A solution of (E)-methyl-3,4-dimethoxystyrylcarbamate (15 g, 63.29 mmol) and Bu3N (7.5 g) in 1-phenoxybenzene (150 mL) was refluxed for 12 hr. The reaction was monitored by TLC (EtOAc/PE (1:1. v/v)). Upon completion, PE (2 L) was added, and the product was isolated by filtration to provide 6,7-dimethoxy-isoquinolin-l(2H)-one as a light yellow solid (2.0 g).
[00211] Step 4. A solution of 6,7-dimethoxyisoquinolin-l(2H)-one (2 g, 8.29 mmol) and phosphorus oxybromide (14 g, 48.78 mmol) in dry acetonitrile (200 mL) was reflexed for 4 hr. The reaction mixture was monitored by TLC(EtO Ac:PE (1 :1, v/v)). Upon completion, the reaction was quenched with ice. The reaction mixture was neutralized with solid potassium carbonate. The resulting aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using EtOAc/hexane (1:10, v/v) as an eluant to provide l-bromo-6,7-dimethoxyisoquinoline as a yellow solid (650 mg, 51%). 1H NMR (400MHz, DMSO) δ: 3.99 (6H5 s), 7.41(1H, s), 7.49 (H, s), 7.75 (IH, d), 8.13 (IH, d). LCMS [M+H]+ calcd for Ci1HnBrNO 269, found 269.
Example 2 Synthesis of 6,7-dimethoxy- 1 -rnethyl-isoquinolin-4-yl-trifluoromethanesulfonate
Figure imgf000058_0001
[00212] Step 1. Acetic anhydride (150 mL) was added to a mixture of 2-(3 ,4- dimethoxyphenyl)ethanamine (40 g, 220.99 mmol), DMAP (2 g, 16.39 mmol), and Et3N (40 g, 396.04 mmol) in a 500 mL 3-necked round bottom flask. The resulting solution was stirried for 5 hr at room temperature. The reaction was monitored by TLC (EtOAc:PE, (1 :1, v/v)). A filtration was performed to provide N- (3,4-dimethoxy-phenethyl)acetamide as a white solid (32 g).
[00213] Step 2. A mixture of N-(3s4-dimethoxyphenethyl)acetamide (25 g, 112.11 mmol) and POCl3 (37 mL) in toluene (187 mL) was stirred at 120 0C for 3.5 hr. The reaction was monitored by TLC (EtOAc: PE (1 :1, v/v)). Upon completion, the reaction mixture was cooled to room temperature and the pH was adjusted to 12 by the addition of NaOH (4N). The resulting mixture was washed with EtOAc and filtration was performed to yield 6,7- dimethoxy-l-methyl-3,4-dihydroisoquinoline as a yellow solid (20 g).
[00214] Step 3. Into a 1000 mL 3-necked round bottom flask' purged and maintained with an inert atmosphere of nitrogen while cooling in an ice bath at 0 0C was added 6,7- dimethoxy-l-methyl-3,4-dihydroisoquinoline (8 g, 39.02 mmol), 1,2,3,4- tetrahydronaphthalene (650 mL) and Pd/C (8 g). The reaction mixture was then refluxed for 3 hr. The reaction was monitored by TLC (EtOAc/MeOH (10:1, v/v)). Upon completion, the reaction mixture was cooled to room temperature, and filtered. The pH was adjusted to 2 by the addition of 10% aqueous HCl. The aqueous layer was separated and the pH was adjusted to 10 by the addition of 10% aqueous NaOH. The resulting solution was extracted with EtOAc, and the organic fraction was dried over anhydrous Na2SO4 and concentrated to provide 6,7-dimethoxy-l-methylisoquinoline as a brown solid (7 g).
[00215] Step 4. A solution of 6,7-dimethoxy-l-methylisoquinoline (3.3 g, 16.26 mmol) and m-CPBA (3.7 g, 21.45 mmol) in DCM (80 mL) was refluxed overnight. The mixture was cooled to room temperature, the pH was adjusted to 8 by the addition of NaOH (4N), and then extracted one time with EtOAc. The organic fraction was dried over anhydrous Na2SO4 and concentrated to provide 6,7-dimethoxy-l-methyl-isoquinoline-N-oxide as a yellow solid (3-3 g).
[00216] Step 5. A solution of 6,7-dimethoxy-l-methylisoquinoline-N-oxide (500 mg, .
2.46 mmol) and NaOAc (0.6 g) in Ac2O (5 mL) and AcOH (3 mL) was stirred at 85 0C for 2 hr and the reaction was monitored by TLC (DCM:MeOH (10: 1 , v/v)). Upon completion, the reaction mixture was concentrated, taken up in 50 mL OfH2O and 100 mL OfCH2Cl2. The organic fraction was separated, washed with Na2CO3, dried over anydrous Na2SO4 and concentrated. The mixture was diluted with 20 mL of 10% HCl, refluxed for 1 hr. Upon cooling to room temperature, the pH was adjusted to 7 by the addition of aqueous Na2CO3, and then extracted with CH2Cl2. The organic fraction was dried over anydrous Na2SO4, concentrated and purified by silica gel chromatography using a gradient elution going from 15: 1 (v/v) to 10:1 (v/v) of DCM:MeOH to provide 6,7-dimethoxy-l-methyϊisoquinolin-4-ol as a brown solid (20 mg).
[00217] Step 6. To a solution of 6,7-dimethoxy-l-methylisoquinolin-4-ol (400 mg,
1.83 mmol) in DCM (30 mL) in the presence OfEt3N (930 mg, 9.21 mmol) was added Tf2O (780 mg, 2.77 mmol) dropwisely with stirring at 0 0C, and the reaction mixture was stirred for 20 min at 0 0C. The reaction was monitored by TLC (CH3OH: CH2Cl2 (1:10, v/v)). Upon completion, the resulting mixture was washed with H2O, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 1 :6 (v/v) EtOAc/PE as an eluant to provide 6,7-dimethoxy-l-methylisoquinolin-4-yl trifluoromethanesulfonate as a white solid (265 mg). 1HNMR (400Hz,DMSO) δ 2.88(3H,S), 3.98(3H3S), 4.01 (3H,S), 7.19(1H,S), 7.52(1H,S), 8.37(1H,S). LCMS [M+H]+ calcd for C13Hi3F3NO5S 352, found 352.
Example 3 Synthesis of 6,7-dimethoxvisoquinolin-4-vl-trtfluoromethanesulfonate
Figure imgf000060_0001
[00218] Stepl. To a solution of ethyl 2-aminoacetate hydrochloride (20 g, 143.37 mmol) in MeOH (300 mL) was added Et3N (14.6 g, 144.27 mmol) dropwise at 0 °C. The reaction mixture was stirred for 10-20 min and then 3,4-dimethoxybenzaldehyde (24 g) was added in several batches. The resulting solution was stirred for 2 hr, and then NaBH4 (11 g, 297.30 mmol) was added in several batches. The resulting solution was stirred overnight at room temperature. The reaction was monitored by TLC (EtOAc/PE, (1 :2, v/v)). The reaction mixture was concentrated, quenched by adding H2O and extracted with several portions of EtOAc. The combined organic layers were dried over anhydrous Na2SO4, and concentrated to provide ethyl 2-(3,4-diπiethoxybenzyl-arnino)acetate as a yellow solid (37 g).
Alternatively, ethyl 2-(3,4-dimethoxybenzylamino)acetate was also prepared as following. To a stirred solution of 3,4-dimethoxy benzaldehyde (25g, 150.5 mmol) in dichloroethane (250ml) was added glycine ethyl ester (25.2g, 180.6 mmol) and magnesium sulfate (4Og). Triethyl amine (42.23ml, 301 mmol) was then added dropwise at 0 0C over 60 min. The resulting solution was first brought to room temperature and then stirred for overnight. Sodium triacetoxy borohydride (64g. 301 mmol) was added in portions at 0 0C and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction mixture was filtered out and washed with DCM (200ml). The filtrate was concentrated, and the residue was dissolved in H2O and the resulting mixture was washed with ethyl acetate to remove non-polar impurities. The mixture was adjusted to pH 8 with NaHCO3 and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give ethyl 2-(3,4- dimethoxybenzylamino)acetate as an oil (2 Ig, 56%). [00219] Step 2. To a solution of ethyl 2-(3,4-dimethoxybenzylamino) acetate (50 g,
167.98 mmol) and DMAP (1.2 g, 9.68 mmol) in DCM (300 mL) in the presence OfEt3N (52 g, 514.85 mmol) was added 4-methylbenzene-l-sulfonyl chloride (41 g, 215.79 mmol) dropwise with stirring at 0 0C. The resulting solution was stirred for 1 hr at room temperature and then quenched by adding 2N HCl. The reaction solution was washed with H2O and brine, dried over anydrous Na2SO-J, and concentrated. The crude product was purified by silica gel chromatography using 1 :5 (v/v) EtOAc :PE as an eluant to provide ethyl 2-(N-(3,4- dimethoxybenzyl)-4-methylphenylsulfonamido)acetate as a white solid (55 g).
[00220J Step 3. A solution of ethyl 2-(N-(3,4-dimethoxybenzyl)-4- methylphenylsulfonamido)acetate (55 g, 135.14 mmol) in 15% NaOH (300 mL) was refluxed for 30 min. The reaction mixture was cooled in a bath of HjO/ice, and the pH was adjusted to 5-6 with 2N HCl solution. The resulting mixture was extracted with EtOAc three times, and the organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to provide 2-(N-(3,4-dimethoxybenzyl)-4- methylphenylsulfonamido)acetic acid as a white solid (47 g) which was used in the next step without further purification.
[00221] Step 4. To a solution of 2~(N-(3,4-dimethoxybenzyl)-4-methylphenyl- sulfonamido)acetic acid (47 g, 124.01 mmol) in dichloromethane (300 mL) was added oxalyl chloride (78 g, 655.46 mmol) at 0 0C. The resulting solution was refluxed for 5 hr. The reaction mixture was concentrated to provide 2-(N-(3,4-dimethoxybenzyl)-4-methylphenyl- sulfonamido)acetyl chloride as a yellow solid (50 g).
[00222] Step 5. Into a 500 mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen and maintained at -78 0C in a bath of liquid N2 was added 2-(N-(3,4-dimethoxybenzyl)-4-methylphenylsulfonamido)acetyl chloride (50 g, 100.55 mmol), DCM (300 mL) and AlCl3 (53 g, 398.50 mmol). The resulting solution was stirred for 4 hr at -78 0C and then for 4 hr at -10 0C, followed by the dropwise addition of 10% aqueous HCl/ice at -10 0C with stirring over 30 min. The resulting solution was extracted with CH2Cl2, and the combined organic fractions were washed with H2O and brine, dried over anhydrous Na2SO-I, and concentrated to provide 35 g of crude 6,7-dimethoxy-2-tosyl- 2,3-dihydroisoquinolin-4(lH)-one as red oil. [00223] Step 6. A mixture of 6,7-dimethoxy-2-tosyl-2,3-dihydroisoquinolin-4(lH)-one
(20 g, 55.40 mmol) in saturated aqueous NaHCO3 (150 mL) and EtOH (30 mL) was refluxed overnight. The mixture was concentrated and extracted with EtOAc. The organic fraction was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 5:1 (v/v) CHaCl2ZMeOH as an eluant to provide 1 g of 6,7-dimethoxyisoquinolin-4-ol as a brown solid.
[00224] Step 7. Into a 250 mL 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen and maintained at 0 0C was added 6,7- dimethoxyisoquinolin-4-ol (1.35 g, 5.27 mmol), DCM (200 mL), Et3N (3.4 g, 33.66 mmol) and TfjO (2.4 g, 8.51 mmol). The resulting solution was stirred for 30 min at 0 0C and reaction was monitored by TLC (EtOAc/PE (1:1, v/v)). The resulting mixture was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 1:6 (v/v) EtOAc/PE as an eluant to provide 6,7- dimethoxyisoquinolin-4-yl trifluoromethanesulfonate as a yellow solid (650 mg). 1HNMR (400Hz5 DMSO) δ 3.97(3H,s), 3.99(3H,s), 7.20(lH5s), 7.73(lH,s), 8.52(lH,s), 9.19(lH,s), LCMS [M+H]+ calcd for Ci2H, 1F3NO5S 338, found 338.
Example 4 Synthesis of 6,7-dimethoxy-l -C6-morpholin-4-ylpyridin-3-yl)isoquinoline
Figure imgf000062_0001
[00225] A mixture of 1 -bromo-6,7-dimethoxyisoquinoline (50.2 mg, 0.187 mmol), 4-
[5-(4,4,5,5-tetramethyl-[l,332]dioxaborolan-2-yl)-pyridin-2-yl]morpholine (140 mg, 0.482 mmol), bis(triphenylphosphine)palladium(II) chloride (27.1 mg, 0.039 mmol), and 2.0 M sodium carbonate in water (40 μL) in l,2-dimethoxyethane:water:ethanol (7:3:2, v/v/v) (901 μL) was irradiated in a microwave reactor at 140 0C for 5.0 min. The reaction mixture was filtered through a plug of celite, and rinsed with methanol. The product was purified by rotary chromatography using a gradient from 0 to 10 v% MeOH in chloroform as an eluant to provide 45 mg of 6,7-dimethoxy-l -(6-morpholin-4-ylpyridin-3-yl)isoquinoline. 1H NMR (300 MHz CDCl3) δ 8.52 (d, IH), 8.39 (d, IH)5 7.88 (dd, IH)5 7.40 (d, IH)5 7.36 (s, IH), 7.05 (S5 IH), 6.75 (d, IH)5 3.98 (s5 3H), 3.86 (s, 3H), 3.82-3.79 (m, 4H), and 3.58-3.54 (m, 4H). LC/MS Method (2080_8miπ), retention time, 2.01 min, M+H = 352.1.
Example 5 Synthesis of 6.7-dimethoxy-4-r2-(4-methoxyphenvπmorpholin-4-vnquinoline
Figure imgf000063_0001
[00226] A mixture of 4-bromo-6,7-dimethoxyquinoline (60 mg, 0.22 mmol), 2-(4- methoxyphenyl)morpholine (51 mg, 0.26 mmol), 2-dicyclohexylphosphino-2',3',6'-tri- isopropyl-1,1 '-biphenyl (13 mg, 0.026 mmol), and sodium tert-butoxide (64.5 mg, 0.67 mmol), tris(dibenzylideneacetone)dipalladium (0) (13 mg, 0.014 mmol) in and tetrahydrofuran (3.8 mL) was irradiated in a microwave reactor to 135 0C for 20 min. The reaction mixture was then filtered through a plug of celite. After concentration, the crude product was purified by column chromatography using a gradient from 0 to 5 v% MeOH in 1:1 (v/v) EtOAc/hexane and DMEA 0.3 v%, followed by preparative HPLC over a Cl 8 reverse phase column using a gradient from 5 v% to 60 v% acetonitrile in water with 0.1 v% formic acid over 8 min with a flow rate of 40 mL/min to provide 6,7-dimethoxy-4-[2-(4- methoxyphenyl)morphoIin-4-yl]quinoIine as a yellow gum (28 mg, 34%). 1H NMR (300 MHz CDCl3) δ 8.60 (d, IH), 7.80 (s, IH), 7.36-7.25 (m, 3H), 6.94-6.89 (m, 3H), 4.82 (dd, IH), 4.30-4.26 (m, IH), 4.18-4.13 (m, IH), 4.09 (s, 3H), 4.05 (s, 3H), 3.82 (s, 3H)5 3.74-3.64 (m, 2H)3 3.33 (dt, IH)5 3.12 (dd, IH). LC/MS Method (2080_8min), retention time, 3.94 min, M+H = 381.2. Example 6 Synthesis of r-(6,7-dimethoxyisoquinolin- 1 -yli- 1.3'-biρiperidin-2-one
Figure imgf000064_0001
[00227] To a flame-dried microwave tube under argon was added 1 -bromo-6,7- dimethoxyisoquinoline (49.9 mg, 0.186 mol), 3-(N-delta-valerolactam)piperidine hydrochloride (50.0 mg, 0.228 mmol), tris(dibenzylideneacetone)dipalladium(0) (8.6 mg, 0.0094 mmol), 9,9-dimethyl-455-bis(diphenylphosphino)xanthene (11.5 mg, 19.9 mmol), sodium tert-butoxide (44.4 mg, 0.462 mol), and toluene (0.5 mL). The dark brown suspension was stirred at 50 0C overnight. The reaction mixture was filtered through celite, rinsed with ~30 mL of 10 v% MeOH in DCM, and concentrated (rotovap). The compound was purified on a C18 preparative HPLC column (30x100 mm) using acetonitrile: water (with 0.1 v% formic acid) in a gradient from 20 v% CH3CN to 80 v% CH3CN at a flow rate of 45 mL/min. The fractions were monitored at a wavelength of 352 nm and the product had a retention time of 2 to 3 min. The material was loaded onto an SCX column, rinsed with one column volume of MeOH, and eluted with 2.0 M ammonia in methanol (8 mL). Concentration of the solvent provided r-(6,7-dimethoxyisoquinolin-l-yl)-l,3'-bipiperidin-2- one as a white solid (7.3 mg). 1H NMR (300 MHz CDCl3) δ 8.05 (d, IH), 7.49 (s, IH), 7.17 (d, IH), 7.02 (s, IH), 5.07 (tt, IH), 4.12 (s, 3H), 4.01 (s, 3H), 3.64 (d, 2H) 3.33-3.23 (m, 2H), 2.91-2.75 (m, 2H), 2.50-2.30 (m, 2H), 2.05-1.88 (m, 3H), 1.83-1.67 (m, 5H). LCMS: Retention time = 2.83, M+H= 370.2.
Example 7 Synthesis of 1 '-C6.7-dimethoxvquinolin-4-vlVL3 '-bipiperidin-2-one
[00228] Into a flame-dried 5 mL microwave tube under argon was added 4-bromo-6,7- dimethoxyquinoline (73.3 mg, 0.273 mmol), 3-(N-delta-valerolactam)piperidine hydrochloride (81.8 mg, 0.374 mmol), tris(dibenzylideneacetone)dipalladium(0) (12.3 mg, 0.0134 mmol), 9,9-dimethyl-4,5-bis(diρhenylphosphino)xanthene (16.6 mg, 0.0287 mmol), sodium tert-butoxide (74.2 mg. 0.772 mmol), and toluene (0.7 mL). The yellow suspension was stirred at 60 0C for 65 hr, filtered through ceiite, rinsed with ~30 mL of 10 v% MeOH in DCM, and concentrated (rotovap). The crude product was purified on a Cl 8 preparative HPLC column (30x100 mm) using 15 v% CH3CN in water (with 0.1 v% formic acid) for 5 min, and then using a gradient from 15 v% CH3CN to 80 v% CH3CN over 2 min at a flow rate of 45 mL/min. Fractions were monitored at a wavelength of 357 run and the product was collected from 3.25 to 5.25 min. The material was loaded onto an SCX column (0.71 g), rinsed with one column volume of MeOH, and eluted with 2.0 M ammonia in methanol (8 mL). Removal of the solvent (rotovap) and dried under reduced pressure provided l'-(6,7- dimethoxyquinolin-4-yl)-l,3'-bipiperidin-2-one as a white solid (51.1 mg).
Example 8 Synthesis of l-(6-fluoropyridin-3-yl)-6,7-dirnethoxyisoquinoline
Figure imgf000065_0001
[00229] To a mixture of 1 -bromo-6,7-dimethoxyisoquinoline (0.4834 g, 1.803 mmol) and tetrakis(triphenylphosphine)palladium (0.1 152 g, 0.09015 mmol) in 1 ,2-dimethoxyethane (30 mL) was added 6-fluoropyridin-3-ylboronic acid (0.2849 g, 1.983 mmol) with stirring. A solution of cesium carbonate (1.6792 g, 4.868 mmol) in water (10 mL) was then added. The resulting mixture was stirred at 80 0C for 3 hr. The reaction was monitored by LCMS. Upon completion, the reaction was allowed to cool to room temperature. The solution was moved to a seperatory funnel, and water and ethyl acetate was added. The aqueous layer was extracted ethyl acetate three times. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10 v% to 60 v% ethyl acetate in hexane, to provide l-(6-fluoropyridin-3-yl)-657-dimethoxyisoquinoline (0.5 g).
Example 9 Synthesis of 5-f6,7-dimethoxyisoquinolin-l -ylVN-isopropylpyridin-2-amine
Figure imgf000066_0001
[00230] A mixture of 1 -(6-fluoropyridin-3-yl)-6,7-dimethoxyisoquinoline (0.0580 g,
0.204 mmol) and propan-2-amine in 2mL DMSO (0.174 ml, 2.04 mmol) was stirred at 90 0C overnight. The reaction was monitored by LCMS. Upon completion, the reaction mixture was allowed to cool to room temperature. The solution was moved to a seperatory funnel and DI water and EtOAc was added. The aqueous layer was extracted EtOAc three times. The combined organic layers were washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1 v% to 5 v% MeOH in CH2CI2, to provide 5-(6,7-dimethoxyisoquinolin-l-yl)-N- isoρropylpyridin-2-amine (0.0356 g, 0.110 mmol).
Example 10 Synthesis of 5-f6.7-dimethoxvisoαuinolin-l -vD-N-ethvl-N-propvlpvridin-Σ-amine
Figure imgf000066_0002
[00231] To a microwave reaction vessel was added l-(6-fluoropyridin-3-yl)-6,7- dimethoxyisoquinoline (0.0792 g, 0.28 mmol) in 2mL DMSO. N-Ethylpropan-1 -amine (0.34 ml, 2.8 mmol) was added and allowed to stir at 90 0C overnight. Reaction was monitored by LCMS. An additional 10 equivalents of N-ethylpropan-1 -amine was added and allowed to stir overnight. When the reaction was recorded to be 70% complete by LCMS5 the reaction was allowed to cool to room temperature. The solution was moved to a separatory funnel and DI water and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in CH2CI2, to provide 5-(6,7-dimethoxyisoquinolin-l-yl)-N-ethyl-N-propylpyridin-2- amine (0.0700 g, 0.20 mmol).
Example 11 Synthesis of 1 -f6-(Y2S,6R)-2,6-dimethylmorpholino)pyridin-3-yiy6.7-dimethoχyisoquinoline
Figure imgf000067_0001
To a microwave reaction vessel was added l-(6-fluoropyridin-3-yl)-6,7- dimethoxyisoquinoline (0.0733 g, 0.26 mmol) in 2mL DMSO. Cis-2,6-dimethyl-morpholine (0.320 ml, 2.6 mmol) was added and allowed to stir at 90 0C overnight. Reaction was monitored by LCMS. Upon completion, the reaction was allowed to cool to room temperature. The solution was moved to a seperatory funnel and DI water and EtOAc was added. The aqueous layer was extracted EtOAc three times. The combined organic layers were washed with water, brine, dried with MgSθ4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage prepacked silica gel column (40S), eluting with a gradient of 1 v% to 5 v% MeOH in CH2Cl2, to provide l-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-6,7-dimethoxyisoquinoline (0.0765 g, 0.20 mmol). Example 12 Synthesis of 6.7-dimethoxv-4-(<2-methvlben2ord1thiazol-5-vl')isoαuinoline
Figure imgf000068_0001
[00232] To a solution of 6,7-dimethoxyisoquinolin-4-yl trifluoromethanesulfonate
(165 mg, 489 μmol) in dimethoxyethane was added 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo[d]thiazole (188 mg, 685 μmol), followed by trans- dichlorobis(triphenyl-phosphine)palladium (ii) (17 mg, 24 μmol). An aqueous solution of cesium carbonate (430 mg, 1321 μmol) in H2O (5.2 mL) was then added and the mixture was heated to 80 0C for two hr. LCMS analysis showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with ethyl acetate and H2O, the layers were separated and the aqueous was extracted with ethyl acetate three times. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Biotage, 25 m column, 20-100% EA/DCM to yield the title compound.
Biological Examples
Example 13 mPDE10A7 Enzyme Activity and Inhibition
[00233] Enzyme Activity. To analyze the enzyme activity, 5 μL of serial diluted mPDE10A7 containing lysate were incubated with equal volumes of diluted (100-fold) fluorescein labeled cAMP or cGMP for 30 min in MDC HE 96-well assay plates (Molecular Devices Corp., Sunnyvale CA) at room temperature. Both the enzyme and the substrates were diluted in the following assay buffer: Tris/HCl (pH 8.0) 50 mM, MgCl2 5 mM, 2- mercaptoethanol 4 mM, and BSA 0.33 mg/mL. After incubation, the reaction was stopped by adding 20 μL of diluted (400-fold) binding reagents and was incubated for an hour at room temperature. The plates were counted in an Analyst GT (Molecular Devices) for fluorescence polarization. An IMAP assay kit (Molecular Devices) was used to assess enzyme properties of mPDE10A7. Data were analyzed with SOFTMAX PRO software (Molecular Devices).
[00234] Enzyme Inhibition. To check the inhibition profile, 10 μL of serial diluted compounds were incubated with 30μl of diluted PDE enzymes in a 96-well polystyrene assay plate for 30 min at room temperature. After incubation, 5 μL of the compound-enzyme mixture were ali quoted into a MDC HE black plate, mixed with 5μL of 100-fold diluted fluorescein labeled substrates (cAMP or cGMP), and incubated for 30 min at room temperature. The reaction was stopped by adding 20 μL of diluted binding reagents and counted in an Analyst GT for fluorescence polarization. The data were analyzed with SoftMax Pro.
Example 14
Apomorphine Induced Deficits in Prepulse Inhibition of the Startle Response in Rats, an in vivo Test for Antipsychotic Activity
[00235] The thought disorders that are characteristic of schizophrenia may result from an inability to filter, or gate, sensorimotor information. The ability to gate sensorimotor information can be tested in many animals as well as in humans. A test that is commonly used is the reversal of apomorphine-induced deficits in the prepulse inhibition of the startle response. The startle response is a reflex to a sudden intense stimulus such as a burst of noise. In this example, rats are exposed to a sudden burst of noise, at a level of 120 db for 40 msec, e.g., the reflex activity of the rats is measured. The reflex of the rats to the burst of noise may be attenuated by preceding the startle stimulus with a stimulus of lower intensity, at 3 to 12 db above background (65 db), which attenuates the startle reflex by 20 to 80%.
[00236] The prepulse inhibition of the startle reflex, described above, may be attenuated by drugs that affect receptor signaling pathways in the CNS. One commonly used drug is the dopamine receptor agonist apomorphine. Administration of apomorphine reduces the inhibition of the startle reflex produced by the prepulse. Antipsychotic drugs such as haloperidol prevents apomorphine from reducing the prepulse inhibition of the startle reflex. This assay can be used to test the antipsychotic efficacy of PDElO inhibitors, as they reduce the apomorphine-induced deficit in the prepulse inhibition of startle.
[00237] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.
[00238] • All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

What is Claimed: 1. A compound of Formula (I) :
Figure imgf000071_0001
or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, wherein:
X is nitrogen and Y and Z are each -CH= or one of Y and Z is nitrogen and the other is -CH= and X is -CR= (where R is hydrogen, alkyl, halo, or cyano);
R1 , R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino,dialkylamino, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -{alkylene)NRl3R14 and -O-(alkylene)NRlsR16 (where R13, R14, R15, and R16 are independently hydrogen or alkyl), wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -<alkylene)NRI3R14 or-O-(alkylene)NRI5R16 are optionally replaced by one to two oxygen or nitrogen atom(s), and provided that at least one of R1, R2, and R3 is not hydrogen; and
R3a is aryl, heteroaryl, or heterocyclyl ring substituted with:
R4, where R4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, or -X1R7 (where X1 is -O-, -CO-, -C(O)O-, -OC(O)-, -NR8CO-, -CONR9-, -NR]0-, -S-, -SO-, -SO2-, -NR11SO2-, or -SO2NR12- where R8, R9, R10, R11, and R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
R5 and R6, where R5 and R6 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfϊnyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, amiπosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl, and provided that at least one of R4, R5, and R6 is not hydrogen; wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; and additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro; provided that:
(a) when R is hydrogen, R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, and:
(i) R3a is pyrrolidin-1-yl, then R4 is not -X1R7 where X1 is -O- and R7 is substituted or unsubstituted aryl or heteroaryl;
(ii) R3a is piperidin-1-yl, where one of R4, R5 and R6 is hydrogen and another of R4, R5 and R6 is substituted or unsubstituted aryl or heteroaryl, then the remaining member of R4, R5 and R6 is not hydrogen; alkyl; carboxy; cyano; hydroxyl; alkoxy; - COR', -CONR'R" or -NR'R" (where R' and R" are independently hydrogen, alkyl, or unsubstituted aryl); or -NHCOR' (where R' is alkyl or unsubstituted aryl); or
(iii) R3a is piperidin-l-yl, where two of R4, R5 and R6 are hydrogen, then remaining of R4, R5 and R6 is not -COR' (where R' is alkyl or unsubstituted aryl), -COOR' (where R' is alkyl or unsubstituted aryl), -CONR'R", -NR'R" or -NHCOR' (where each R" is hydrogen, alkyl, or unsubstituted aryl, and each R' is unsubstituted aryl);
(b) when R is hydrogen, R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, and cycloalkyl, then:
(i) R3a is not substituted or unsubstituted l,2,3,4-tetrahydroisoquinolin-3-yl or 1 ,2,3,4-tetrahydroisoquinolin-2-yl; or
(ii) R3a is not monosubstituted or disubstituted pyrrolidinyl where the one or two substituents are alkyl;
(c) when R is hydrogen, alkyl, or alkoxy, R1, R2, and R3 are independently hydrogen, halo, haloalkyl, alkyl, alkoxy, carboxy, hydroxymethyl or hydroxy, and R3a is aryl, then one of R4, R5, and R6 is an aromatic or alicyclic ring or a group that contains an aromatic or alicyclic ring provided that the aromatic or alicyclic ring is not phenyl (optionally substituted with one, two or three substitutents independently selected from cyano, halo, -CONH2 and haloalkyl), benzyl, benzyloxy, lH-benzimidazol-2-ylthio, lH-benzimidazol-2- ylsulfinyl, pyridinyl (optionally substituted with halo or -CONH2), pyrimidinyl, or morpholin-4-yl-carbonyl ;
(d) when R is hydrogen, R1, R2, and R3 are independently hydrogen, halo, alkoxy, or hydroxy, and R3a is heteroaryl, then the heteroaryl ring is not phthalazin-1-yl optionally substituted with R4, R5, and R6 where R4 is alkyl and R5 and R6 are alkoxy; isoquinolinyl optionally substituted with one or two substituents selected from alkoxy and hydroxy; lH-indolyl optionally substituted with R4, R5, and R6 where R4 is hydrogen, one of R5 and R6 is hydrogen, alkyl, or alkoxy, and the other of R5 and R6 is alkyl, alkoxy, haloalkyl, dialkylaminoalkyl, or hydroxyalkyl; benzo[c]isoxazolyl optionally substituted with R4, R5, and R6 where one of R4, R5, and R6 is hydrogen and the other two of R4, R5, and R6 are independently selected from alkoxy, aryl, or benzyloxy; lH-indazolyl optionally substituted with one or two alkoxy or hydroxy; pyrrolyl substituted with R4, R5, and R6 where one of R4, R5, and R6 is hydrogen or alkyl and the other two of R4, R5, and R6 are phenyl optionally substituted with one or two alkoxy; thienyl optionally substituted with halo; or pyrazolyl optionally substituted with R4, R5, and R6 where R4 is hydrogen, one of R5 and R6 is alkoxycarbonyl and the other of R5 and R6 is alkoxyalkyl;
(e) when R is hydrogen or alkoxy, R1, R2, and R3 are independently hydrogen, halo, alkyl, haloalkyl, haloalkoxy, alkoxy, carboxy, hydroxymethyl or hydroxy, then R3a is not monosubstituted piperazinyl [wherein the substitutent on piperazinyl ring is alkyl, alkoxycarbonyl, phenyl, -COR' (where R' is alkyl; or piperidinyl or pyrrolidinyl each optionally substituted with one or two substituents each independently selected from alkyl or hydroxyl), hydroxyalkyl, -CONHR' (where R' is phenyl substituted with fluoro or phenoxy), lH-benzo[d]imidazol-2(3H)-one optionally substituted with alkyl, or 3,4-dihydroquinolinyl- 2(lH)-one]; substituted or unsubstituted benzimidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquiπolinyl, isobenzofuranyl-l(3H)-one, l,2,3-oxadiazolyl-5(2H)-one, 1,3,4-oxadiazolyl- 2(3H)-one, 2,3-dihydrobenzo[b][l,4]dioxinyl9 benzo[d][l,3]dioxolyl, 1,2,4,5,6,7- hexahydropyrazolo[l-5-a]pyridinyl, 1 ,2-dihydropyrazolo[l,5-a]pyridinyl, H-pyrazolo[l,5- a]pyridinyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, benzisoxazolyl, l,l-dioxo-3H- benzo [c] [ 1 ,2]oxathiolyl, benzofurany l-2(3H)~one, (Z)- 1 H-benzo [e] [ 1 ,4] diazepiny 1-2(3 H)-one, ls3a-dihydropyrazolo[l,5-α]pyridinyl, oxazolyl-2(3H)-one, naphthyl, or imidazo[5,l- a]isoquinolinyl; mono or disubstituted piperidinyl (where one substituent is hydrogen or hydroxyl, and the other substitutent is alkoxy, hydroxyl, carboxy, or lH-benzo[d]imidazol- 2(3H)-one optionally substituted with alkyl); or pyrrolidinyl optionally substuted with alkyl or alkoxy;
(f) when X is N, then at least two of R1, R2 and R3 are not simultaneously hydrogen; and
(g) the compound is not a salt of (a)-(f).
2. The compound of Claim 1, wherein X is nitrogen and Y and Z are -CH=.
3. The compound of Ciaim 1, wherein Y is nitrogen and X and Z are -CH=.
4. The compound of Claim 1 , wherein Z is nitrogen and X and Y are -CH= .
5. The compound of Claim 2, wherein R1 is hydrogen and R2 and R3 are independently alkoxy.
6. The compound of Claim 2, wherein R1 is hydrogen, one of R2 and R3 is alkoxy, and the other is alkyl.
7. The compound of Claim 2, wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is halo or haloalkoxy.
8. The compound of Claim 3, wherein R1 is hydrogen and R2 and R3 are independently alkoxy.
9. The compound of Claim 3, wherein R is hydrogen, one of R and R is alkoxy, and the other is alkyl.
10. The compound of Claim 3, wherein R1 is hydrogen, one of R2 and R3 is alkoxy, and the other is halo or haloalkoxy.
11. The compound of Claim 4, wherein R1 is hydrogen, and R2 and R3 are independently alkoxy.
12. The compound of Claim 4, wherein R1 is hydrogen, one of R2 and R3 is alkoxy, and the other is alkyl.
13. The compound of Claim 4, wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is halo or haloalkoxy.
14. The compound of any one of Claims 2 and 5-7, wherein R3a is a ring of formula:
Figure imgf000075_0001
where R4 is phenyl, heteroaryl, or six-membered saturated heterocyclyl each optionally substituted with Ra, Rb and Rc and where the rings are substituted, including the hydrogen atom on the -NH- group within the ring, with R5 and R6.
15. The compound of any one of Claims 3 and 8-10, wherein R3a is a ring of formula:
Figure imgf000075_0002
where R4 is phenyl, heteroaryl, or six-membered saturated heterocyclyl each optionally substituted with Ra, Rb and Rc and where the rings are substituted, including the hydrogen atom on the -NH- group within the ring, with R5 and R6.
16. The compound of any one of Claims 4 and 11-13 wherein R3a is a ring of formula:
Figure imgf000076_0001
where R4 is phenyl, heteroaryl, or six-membered saturated heterocyclyl each optionally substituted with Ra, Rb and Rc and where the rings are substituted, including the hydrogen atom on the -NH- group within the ring, with Rs and R6.
17. The compound of Claim 14 wherein R4 is phenyl substituted with Ra and Rb that are meta to each other.
18. The compound of Claim 15 wherein R4 is phenyl substituted with Ra and Rb that are meta to each other.
19. The compound of Claim 16 wherein R4 is phenyl substituted with Ra and Rb that are meta to each other..
20. The compound of Claim 1, wherein R3a is a ring of formula:
Figure imgf000076_0002
where R4 is phenyl substituted with Ra and Rb that are meta to each other.
21. The compound of any one of Claims 2 and 5-7 wherein R3a is a ring of formula:
Figure imgf000076_0003
22. The compound of any one of Claims 3 and 8-10 wherein R3a is a ring of formula:
Figure imgf000076_0004
23. The compound of any one of Claims 4 and 1 1-13 wherein R3a is a ring of formula:
Figure imgf000077_0001
24. The compound of Claim 1 wherein R3a is a ring of formula:
Figure imgf000077_0002
25. The compound of any one of Claims 1-13 and 21-24 wherein R3a is a ring of formula:
Figure imgf000077_0003
where R5 is heterocyclyl, monosubstituted or disubstituted amino wherein the aromatic or alicyclic rings in R5 are optionally substituted, and R4 is hydrogen, alkyl, or halo.
26. The compound of any one of Claims 1-13 wherein R3a is 5-, 6-, 7-, or -8-azaindolyl or benzthiazolyl, substituted with R4, R5, or R6.
27. A pharmaceutical composition comprising a compound of any one of Claims 1-26 and a pharmaceutically acceptable expicient.
28. Use of compound of any one of Claims 1 -26 for the manufacture of a medicament for treating a disorder treatable by inhibition of PDElO enzyme in a patient.
29. The use of Claim 28, wherein the disease is schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
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