WO2009070583A1 - Pyrido[3,2-e]pyrazines, process for preparing the same, and their use as inhibitors of phosphodiesterase 10 - Google Patents
Pyrido[3,2-e]pyrazines, process for preparing the same, and their use as inhibitors of phosphodiesterase 10 Download PDFInfo
- Publication number
- WO2009070583A1 WO2009070583A1 PCT/US2008/084688 US2008084688W WO2009070583A1 WO 2009070583 A1 WO2009070583 A1 WO 2009070583A1 US 2008084688 W US2008084688 W US 2008084688W WO 2009070583 A1 WO2009070583 A1 WO 2009070583A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrido
- methoxy
- alkyl
- pyrazine
- dimethylimidazo
- Prior art date
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 1
- OSXXGBUMRXAAFP-UHFFFAOYSA-N tetramethylazanium;cyanide Chemical compound N#[C-].C[N+](C)(C)C OSXXGBUMRXAAFP-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/04—Anorexiants; Antiobesity agents
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- 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
Definitions
- the invention relates to pyrido[3,2-e]pyrazines, which are inhibitors of phosphodiesterase 10 and useful for treating diseases related to the central nervous system as well as obesity and metabolic disorders.
- Psychotic disorders especially schizophrenia, are severe mental disorders which extremely impair daily life.
- the symptoms of psychosis may be divided into two fractions. In the acute phase, it is predominated by hallucinations and delusions being called the positive symptoms. When the agitated phase abates the so called negative symptoms become obvious. They include cognitive deficits, social phobia, reduced vigilance, indifference and deficits in verbal learning and memory, verbal fluency and motor function.
- Clozapine which has emerged as a benchmark therapeutic ameliorating positive, negative and cognitive symptoms of schizophrenia and devoid of EPS shows agranulocytosis as a major, potential lethal side-effect (Capuano et al., Curr Med Chem 9: 521-548, 2002). Besides, there is still a high amount of therapy resistant cases (Lindenmayer et al., J Clin Psychiatry 63: 931-935, 2002). In conclusion, there is still a need for developing new antipsychotics which ameliorate positive, negative and cognitive symptoms of psychosis and have a better side effect profile. The exact pathomechanism of psychosis is not yet known. A dysfunction of several neurotransmitter systems has been shown. The two major neurotransmitter systems that are involved are the dopaminergic and the glutamatergic system: Thus, acute psychotic symptoms may be stimulated by dopaminergic drugs (Capuano et al.,
- NMDA antagonists like phencyclidine and ketamine are able to stimulate schizophrenic symptoms in humans and rodents (Abi-Saab et ah, Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Lahti et ah, Neuropsychopharmacology 25: 455-467, 2001).
- Acute administration of phencyclidine and MK-801 induce hyperactivity, stereotypies and ataxia in rats mimicking psychotic symptoms.
- NMDA antagonists do not only mimic the positive symptoms but also the negative and cognitive symptoms of psychosis (Abi-Saab et ah, Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Jentsch and Roth, Neuropsychopharmacology 20: 201-225, 1999).
- NMDA antagonists additionally induce cognitive deficits and social interaction deficits.
- the PDE families differ in their substrate specificity for the cyclic nucleotides, their mechanism of regulation and their sensitivity to inhibitors. Moreover, they are differentially localized in the organism, among the cells of an organ and even within the cells. These differences lead to a differentiated involvement of the PDE families in the various physiological functions.
- PDElO PDElO
- PDElO is primarily expressed in the brain and here in the nucleus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et ah, William Harvey Research Conference, Porto, December 6 th - 8 th , 2001). All these brain areas are described to participate in the pathomechanism of schizophrenia (Lapiz et ah, Neurosci Behav Physiol 33: 13-29, 2003) so that the location of the enzyme indicates a predominate role in the pathomechanism of psychosis.
- PDEl OA In the striatum PDEl OA is predominately found in the medium spiny neurons and they are primarily associated to the postsynaptic membranes of these neurons (Xie et ah, Neuroscience 139: 597-607, 2006). By this location PDElOA may have an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the medium spiny neurons two neurotransmitter systems playing a predominate role in the pathomechanism of psychosis.
- PDElOA inhibitors The antipsychotic potential of PDElOA inhibitors is further supported by studies of Kostowski et al. (Pharmacol Biochem Behav 5 : 15-17, 1976) who showed that papaverine, a moderate selective PDElOA inhibitor, reduces apomorphine -induced stereotypies in rats, an animal model of psychosis, and increases haloperidol-induced catalepsy in rats while concurrently reducing dopamine concentration in rat brain, activities that are also seen with classical antipsychotics. This is further supported by a patent application establishing papaverine as a PDElOA inhibitor for the treatment of psychosis (US Patent Application Pub. No. 2003/0032579).
- PDElOA In addition to classical antipsychotics which mainly ameliorate the positive symptoms of psychosis, PDElOA also bears the potential to improve the negative and cognitive symptoms of psychosis.
- PDElOA inhibitors by up- regulating cAMP and cGMP levels act as Dl agonists and D2 antagonists because the activation of Gs-protein coupled dopamine Dl receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., Mutschler Arzneistoffnhofen. 8 th ed. Stuttgart: Stuttgart Verlagsgesellschaft mbH, 2001).
- Elevated intracellular cAMP levels mediated by Dl receptor signalling seems to modulate a series of neuronal processes responsible for working memory in the prefrontal cortex (Sawaguchi, Parkinsonism Relat Disord 7: 9-19, 2000), and it is reported that Dl receptor activation may improve working memory deficits in schizophrenic patients (Castner et al., Science 287: 2020-2022, 2000). Thus, it seems likely that a further enhancement of this pathway might also improve the cognitive symptoms of schizophrenia.
- EP 0 736 532 reports pyrido[3,2-e]pyrazinones and a process for their preparation. These compounds are described to have anti-asthmatic and anti-allergic properties. Examples of this invention are inhibitors of PDE4 and PDE5.
- WO 00/43392 reports the use of imidazo[l,5-a]pyrido[3,2-e]pyrazinones which are inhibitors of PDE3 and PDE5 for the therapy of erectile dysfunction, heart failure, pulmonic hypertonia and vascular diseases which are accompanied by insufficient blood supply.
- pyrido[3,2-e]pyrazinones reported in WO 01/68097 are inhibitors of PDE5 and can be used for the treatment of erectile dysfunction.
- WO 92/22552 refers to imidazo[l,5-a]quinoxalines which are generally substituted at position 3 with a carboxylic acid group and derivatives thereof. These compounds are described to be useful as anxiolytic and sedativelhypnotic agents.
- WO 99/45009 refers to a group of imidazopyrazines which are described to be inhibitors of protein tyrosine kinases used in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.
- the present invention provides compounds of Formula I:
- the present invention further provides pharmaceutical compositions containing one or more of the above-described pyrido[3,2-e]pyrazine compounds of the invention, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.
- the present invention further provides methods of treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of the invention described herein, or composition thereof, or pharmaceutically acceptable salt thereof.
- the present invention further provides methods of treating or preventing central nervous system disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention described herein, or composition thereof, or pharmaceutically acceptable salt thereof.
- the present invention further provides methods for treating or preventing obesity, type 2 diabetes, metabolic syndrome, or glucose intolerance using pyrido[3,2-e]pyrazines which are inhibitors of PDElO.
- the invention further relates to methods of reducing body fat or body weight.
- the present invention further provides compounds of the invention, N-oxides of the same, and pharmaceutically acceptable salts thereof, for use in therapy.
- the present invention further provides use of compounds of the invention, N-oxides of the same, and pharmaceutically acceptable salts thereof, for the preparation of a medicament for use in therapy.
- the present invention further provides processes for preparing the compounds of Formula (I), N-oxides of the same, or pharmaceutically acceptable salts thereof, the process comprising reacting a compound of Formula (E)
- the compound of Formula (D) can be prepared by the process comprising a) reacting a compound of Formula (G)
- Figure 1 depicts the characterization of the collected proteins from FPLC by Western blot.
- Figure 2 depicts PDE 10 present in the membrane fraction.
- Figure 3 depicts the alignment of the pig PDElO (SEQ ID NO: 5), guinea pig PDElO (SEQ ID NO: 9), and rat PDE 10 (SEQ ID NO: 10) gene sequences to provide the depicted consensus sequence (SEQ ID NO: 8).
- Figure 4 depicts the alignment of the pig PDElO (SEQ ID NO: 11), guinea pig PDElO (SEQ ID NO: 12), and rat PDE 10 (SEQ ID NO: 13) protein sequences within the catalytic domain to provide the depicted consensus sequence (SEQ ID NO: 14).
- the present invention provides pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors having Formula I: wherein:
- R 2 is Ci -S alkyl, C 3 . 8 cyclo(hetero)alkyl, aiyl-Ci -5 alkyl, or heteroaryl-Ci_ 5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
- R 3 is: cyano
- R 5 , R 6 , and R 7 are independently selected from H, a cyclic radical, Ci_ 8 alkyl, O- Ci -5 alkyl, C 3 .
- Ci -S alkyl, O-Ci_ 5 alkyl, C 3 _ 6 cycloalkyl, aryl-Ci -5 alkyl, and heteroaryl-Ci -5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_ 3 alkyl, and a cyclic radical; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
- R 4 is halo, R 8 , or OR 8 , wherein R 8 is: H, Ci-8 alkyl or C3.6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-C 1 . 3 alkyl, C 2 _ 8 alkynyl, and a cyclic radical; aryl-Ci.
- alkyl or heteroaryl-Ci_ 5 alkyl each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
- R 1 is Ci_ 8 alkyl, C 2 _ 8 alkenyl, or C 2 _ 8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical. In some embodiments, R 1 is Ci_ 8 alkyl optionally mono- or polysubstituted with halo.
- R 1 is propyl optionally mono- or polysubstituted with halo.
- R 1 is propyl optionally mono- or polysubstituted with fluoro.
- R 1 is C 2 _ 8 alkynyl optionally mono- or polysubstituted with a cyclic radical. In some embodiments, R 1 is C 2 alkynyl monosustituted with a cyclic radical.
- R 1 is C 2 alkynyl mono substituted with C 3 . 8 cycloalkyl.
- R 1 is C 2 alkynyl mono substituted with cyclopropyl or cyclohexyl.
- R 1 is C 2 alkynyl mono substituted with C 3 . 8 aryl, and said aryl is optionally mono- or polysubstituted with halo, Cu alkyl, O-Cu alkyl, cyano, or Cu haloalkyl.
- R 1 is C 2 alkynyl mono substituted with phenyl optionally mono- or polysubstituted with substitents independently selected from fluoro, methyl, and OCH 3 .
- R 1 is aryl mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, and a cyclic radical.
- R 1 is aryl mono-substituted with a cyclic radical.
- R 1 is aryl mono-substituted with phenyl.
- R 1 is aryl mono-substituted with morpholino.
- R 1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO 2 NR 6 R 7 .
- R 1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO 2 NH 2 .
- R 1 is heteroaryl mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
- R 1 is 5- or 6-membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, C1-5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, and a cyclic radical.
- R 1 is 5- or 6-membered heteroaryl optionally mono- or noly substituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
- R 1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
- R 1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
- R 1 is furan, thiophene, isoxazole, pyridine, or pyrimidine.
- R 1 is furan or thiophene. In some embodiments, R 1 is pyrrole or pyrazole, each optionally mono- or polysubstituted with halo, Cu alkyl, cyano, or Cu haloalkyl.
- R 1 is pyrazole optionally mono- or polysubstituted with Cu alkyl.
- R 1 is pyrazole mono-substituted with methyl.
- R 1 is pyrazole polysubstituted with methyl.
- R 1 is l,3,5-trimethyl-lH-pyrazole-4-yl.
- R 1 is 3,5-dimethyl-lH-pyrazole-4-yl.
- R 1 is 6-membered heteroaryl optionally mono- or polysubstituted with halo, Ci -5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, or a cyclic radical.
- R 1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
- R 1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from halo, C 1 . 5 alkyl, cyano, and Cu haloalkyl.
- R 1 is pyridine optionally mono- or polysubstituted with halo or C 1 . 5 alkyl.
- R 1 is pyridine optionally mono- or polysubstituted with fluoro, chloro, or methyl. In some embodiments, R 1 is pyridine mono-substituted with methyl.
- R 1 is 4-methylpyridin-3-yl or 2-methylpyridin-3-yl.
- R 1 is pyridine optionally mono-substituted with di-methylamino, OCH 3 , or morpholino.
- R is Ci_ 8 alkyl optionally mono- or polysubstituted with halo.
- R 2 is methyl optionally mono- or polysubstituted with halo. In some embodiments, R 2 is methyl. In some embodiments, R 2 is CF 3 .
- R 3 is Ci_ 8 alkyl, Ci_ 8 haloalkyl, C 3 . 8 cyclo(hetero)alkyl, aryl-Ci -5 alkyl, heteroaryl-Ci_ 5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical.
- R 3 is Ci_ 8 alkyl or Ci_ 8 haloalkyl. In some embodiments, R 3 is CH 3 , CH 2 F, or CF 3 . In some embodiments, R 3 is Ci -8 alkyl.
- R 3 is C 1 . 4 alkyl. In some embodiments, R 3 is CH 3 .
- R 3 is (CO)NR 6 R 7 , and said R 6 and R 7 are independently selected from H or Ci -8 alkyl. In some embodiments, R 3 is cyano.
- R 4 is OR 8 , and said R 8 is Ci -8 alkyl optionally mono- or polysubsituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
- R 4 is OR 8
- R 8 is methyl optionally mono- or polysubsituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical.
- R 4 is OR 8 , and said R 8 is Ci -8 alkyl optionally polysubsituted with halo. In some embodiments, R 8 is methyl or ethyl. In some embodiments, R 4 is OCH 3 .
- R 4 is OR 8
- said R 8 is Ci_ 8 alkyl optionally mono-substituted with a cyclic radical.
- R 4 is OR 8
- said R 8 is Ci_ 8 alkyl mono- or polysubsituted with cyclopropyl.
- R 4 is OR 8 , and said R 8 is methyl mono- or polysubsituted with cyclopropyl.
- R 4 is OR 8
- said R 8 is Ci_ 8 alkyl mono-substituted with cyclopropyl.
- R 4 is OR 8
- R 8 is ethyl optionally mono- or polysubsituted with halo.
- R 4 is OCH 2 CH 2 F, OCH 2 CHF 2 , or OCH 2 CF 3 .
- R 4 is OR 8 , wherein said R 8 is aryl-Ci -5 alkyl or heteroaryl-Ci_ 5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, Cu alkyl, and O-Cu alkyl.
- said R 8 is benzyl optionally mono- or polysubstituted with fluoro.
- said R 8 is pyridinyl.
- R 2 is Ci -8 alkyl
- R 3 is Ci -8 alkyl
- R 4 is OR 8 , wherein R 8 is Ci -8 alkyl.
- R 1 is heteroaryl optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci -5 alkyl, OCu alkyl, cyano, Cu haloalkyl, and OCu haloalkyl;
- R 2 is Ci -8 alkyl
- R 3 is Ci -8 alkyl
- R 4 is OR 8 , wherein R 8 is Ci -8 alkyl.
- R 1 is a 5- or 6- membered heteroaryl group containing at least one ring- forming N atom, optionally mono- or polysubstituted with substituent independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci -5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, and O-Cu haloalkyl;
- R 2 is Ci -8 alkyl
- R 3 is Ci -8 alkyl
- R 4 is OR 8 , wherein R 8 is Ci -8 alkyl.
- R 1 is a 5- or 6- membered heteroaryl group containing at least one ring- forming N atom, optionally mono- or polysubstituted with Ci -5 alkyl;
- R 2 is Ci -8 alkyl;
- R 3 is Ci -8 alkyl
- R 4 is OR 8 , wherein R 8 is Ci -8 alkyl.
- the compounds of the invention have Formula (I): wherein:
- R is Ci- 8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
- R 3 is: cyano
- Ci-8 alkyl or Ci-S haloalkyl each optionally mono- or polysubstituted with substitents independently selected from halo, OH, OCu alkyl, and a cyclic radical;
- R 6 and R 7 are independently selected from H, a cyclic radical, Ci -S alkyl, OCi -5 alkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
- R 4 is R 8 or OR 8 , wherein R 8 is Ci -S alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, C 2 _s alkynyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
- the invention includes a compound having Formula (I):
- Ci_ 8 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical; aryl, heteroaryl, C 3 _s cyclo(hetero)alkyl, aryl-Ci_ 5 alkyl, or heteroaryl-Ci_ 5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, -(C O)-NR 6 R 7 , and a cyclic radical; or two adjacent O-Cu alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group;
- R 2 is Ci -S alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
- R 3 is: cyano
- Ci -S alkyl or Ci -S haloalkyl each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical; or
- R 6 and R 7 are independently selected from H, a cyclic radical, Ci -S alkyl, O-Ci- 5 alkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group;
- R 4 is R 8 or OR 8 , wherein R 8 is Ci -S alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
- R 1 is aryl or heteroaryl, each optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, and O-Cu alkyl; each of R 2 and R 3 is independently Ci -S alkyl; and
- R 4 is Ci -8 alkyl or O-Ci -8 alkyl.
- the present invention also provides pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors having Formula I: wherein:
- R is Ci -S alkyl, C 3 . 8 cyclo(hetero)alkyl, aryl-Ci -5 alkyl, or heteroaryl-Ci_ 5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, or a cyclic radical;
- R 3 is: cyano
- R 5 , R 6 , and R 7 are independently selected from H, a cyclic radical, Ci -S alkyl, O- Ci -5 alkyl, C 3 .
- Ci -S alkyl, OCi -5 alkyl, C 3 _ 6 cycloalkyl, aryl-Ci -5 alkyl, and heteroaryl-Ci -5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, OCu alkyl, or a cyclic radical; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
- R 4 is halo, R 8 , or OR 8 , wherein R 8 is: H, Ci-8 alkyl or C 3 _6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-C 1 . 3 alkyl, and a cyclic radical; aryl-Ci.
- R 3 is: cyano
- R 5 , R 6 , and R 7 are independently selected from H, a cyclic radical, Ci -S alkyl, O-C 1 . 5 alkyl, C 3 _ 6 cycloalkyl, aryl-Ci -5 alkyl, and heteroaryl-Ci_ 5 alkyl, wherein Ci -S alkyl, O-C 1 . 5 alkyl, C 3 . 6 cycloalkyl, aryl-Ci. 5 alkyl, and heteroaryl-Ci. 5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C 1 . 3 alkyl, or a cyclic radical; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group.
- the present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising reacting a compound of Formula (E)
- X is B(OH) 2 or H. In some embodiments, X is B(OH) 2 . In other embodiments, X is H.
- the reacting is carried out in the presence of a catalyst.
- catalyst comprises Pd(PPh 3 ) 4 .
- catalyst comprises Pd(PPd 3 ) 2 C1 2 .
- the reacting is carried out at an elevated temperature. In some embodiments, the temperature is from about 85 0 C to about 100 0 C. In some embodiments, L 1 is bromo.
- the compound of Formula (E) is prepared by the process comprising reacting a compound of Formula (D):
- the halogenating reagent is a brominating reagent.
- brominating reagent is NBS.
- the compound of Formula (D) is prepared by the process comprising: a) reacting said compound of Formula (A)
- R 2 and R 3 are each Ci_ 8 alkyl and R 4 is O-Ci_ 8 alkyl. In some embodiments, R 2 is methyl, R 3 is methyl, and R 4 is methoxy.
- the reducing agent comprises a combination Of HCO 2 NH 2 , 10%Pd/C, and MeOH.
- cyclizing reagent comprises P 2 O 5 /POC1 3 .
- the compound of Formula (D) is prepared by the process comprising: a) reacting a compound of Formula (G)
- R 2 is Ci_ 8 haloalkyl
- R 3 is Ci_ 8 alkyl
- R 4 is O-Ci_ 8 alkyl.
- R 2 is a CF 3
- R 3 is methyl
- R 4 is methoxy
- the reducing agent is a Na 2 S 2 C ⁇ .
- the reacting of step (c) is carried out at an elevated temperature. In some embodiments, the reacting of step (c) is carried out at about 90-120 0 C. In other embodiments, the reacting of step (c) is carried out at about 110 0 C. In some embodiments, the reacting of step (c) is carried out in the presence of a catalyst.
- the catalyst is Pd(PPli 3 ) 4 .
- R 3 Y is AlMe 3 .
- the compound of Formula (D) is prepared by the process comprising reacting a compound of Formula (J)
- R 3 is methyl.
- R 3 Y is AlMe 3 .
- the compound of Formula (J) is prepared by the process comprising:
- R 2 is Ci_ 8 haloalkyl and R 4 is O-Ci_ 8 alkyl. In some embodiments, R 2 is CF 3 and R 4 is methoxy. In some embodiments, the reducing agent is a Na 2 S 2 U 4 .
- the halogenating reagent is POCI 3 .
- the present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising: a) reacting a compound of Formula (D):
- the compound of Formula (D) is prepared by the process comprising reacting said compound of Formula (C)
- the compound of Formula (C) is prepared by the process comprising: a) reacting a compound of Formula (A)
- the compound of Formula (D) is prepared by the process comprising: a) reacting a compound of Formula (G)
- the compound of Formula (D) is prepared by the process comprising reacting a compound of Formula (J)
- the compound of Formula (J) is prepared by the process comprising: a) reacting a compound of Formula (G)
- the present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising: a) reacting a compound of Formula (J)
- the compound of Formula (J) is prepared by the process comprising: c) reacting a compound of Formula (G)
- the present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors.
- Example processes are provided below in Schemes 1 and 2, wherein the variables are independently defined anywhere herein.
- the compounds of Formula (I) can be prepared via a coupling reaction affixing the R 1 substituent to the imidazole portion of the ring as a final step.
- Example processes of the invention include Suzuki and Sonogashira methods using aryl derivatives or alkynyl derivatives, respectively.
- the compounds of Formula (I) can be prepared by reacting a compound of Formula (E)
- X is B(OH) 2 or H. In some embodiments, X is B(OH) 2 . In some embodiments, X is H.
- the coupling reaction can be carried out at an elevated temperature, e.g., at about 40-100 0 C, about 50-100 0 C, about 60-100 0 C, about 70-100 0 C, about 80-100 0 C, about 85-100 0 C, or about 85-90 0 C, or about 90-100 0 C, or about 85 0 C, or about 90 0 C.
- the coupling reaction can also be carried out in the presence of water.
- the molar ratio of water to organic solvent is about 1 :2, about 1 :3, or about 1 :4.
- Suitable organic solvents include, DMF, dioxane, THF, or acetonitrile.
- the coupling reaction employs either an organic base or an inorganic base.
- Suitable organic bases include, but are not limited to, triethylamine, diisopropylethylamine, and pyridine.
- Suitable inorganic bases include, but are not limited to, NaOH and K 2 CO 3 .
- the leaving group L 1 can be chloro, bromo, or iodo. In other embodiments, the leaving group L 1 can be bromo.
- R 1 is optionally substituted aryl or heteroaryl. In some embodiments, R 1 is alkyl substituted with aryl or heteroaryl.
- the coupling reaction can be carried out in the presence of a catalyst.
- the catalyst is a palladium catalyst such as Pd(PPh 3 ) 2 C1 2 or Pd(PPh 3 ⁇ .
- the catalyst further comprises CuI.
- the coupling reaction is the Suzuki coupling reaction (See, e.g., Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749).
- the coupling reaction is the Sonogashira coupling reaction (See (a) Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2,4; (b) Sonogashira, Synthesis 1977, 777.). Halogenation Reaction
- a compound of Formula (E) can be prepared by reacting a compound of Formula (D):
- the halogenating reagent is a brominating or chlorinating reagent.
- Some example brominating reagents include, for example, Br 2 , N-bromosuccinimide (NBS), l,3-dibromo-5,5- dimethylhydantoin, pyridiniurn tribromide (pyrHBr3) and the like.
- An example chlorinating reagent is N- chlorosuccinimide.
- the halogenating reagent is N- bromosuccinimide.
- any suitable organic solvent can be optionally used to carry out the halogenating reaction.
- the organic solvent contains an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, mixtures thereof and the like.
- the organic solvent is acetonitrile.
- the organic solvent is methanol.
- the organic solvent includes dimethylformamide or tetrahydrofuran.
- Suitable temperatures for the halogenating reaction can vary.
- the reaction temperature can be at or below about room temperature such as, for example, from about 0 to about 25 0 C.
- the molar ratio of halogenating reagent to compound of Formula (D) can be routinely selected or optimized by the skilled artisan to miminize di-halogenated by products and maximize yield of the mono-halogenated product.
- the molar ratio is from about 1 :0.8 to about 1 : 1 :2, from about 1 :0.9 to about 1 :1.1, from about 1 :0.95 to about 1 : 1.05, or about 1 :1.
- a compound of Formula (D) can be prepared by reacting a compound of Formula (C)
- Suitable cyclizing reagents include, but are not limited to, POCI3, PCl 5 , P2O5, or SOCI2.
- the cyclizing reagent comprises P 2 (VPOCl 3 .
- the cyclizing reagent can be a combination of two reagents, e.g., P 2 (VPOCl 3 .
- the cyclization reaction is carried out in the presence of a base, e.g., an organic base such as triethylamine, diisopropylamine, or pyridine.
- the cyclization reaction is carried out at an elevated temperature, such as about 90-120 0 C, about 100-120 0 C, or about 110-120 0 C. In some embodiments, the cyclization reaction is carried out for a certain time, such as about 2-6 hours, or about 4-6 hours, or about 6 hours. In some embodiments, the cyclizing reaction is carried out under anhydrous conditions.
- the compound of Formula (C) can be prepared by reacting a compound of Formula (B)
- the reaction can be carried out at room temperature. In some embodiments, the reaction can be carried out at an elevated temperature, e.g., 40-80 0 C, 50-80 0 C, 60- 80 0 C, or 70-80 0 C.
- the reaction solvent comprises toluene (e.g., toluene or a mixture of toluene and heptane).
- R 2 and R 3 are each Ci_ 8 alkyl and R 4 is O-Ci_ 8 alkyl.
- R 2 is methyl, R 3 is ethyl, and R 4 is methoxy.
- R 2 is methyl, R 3 is methyl, and R 4 is methoxy.
- a compound of Formula (B) can be prepared by reacting a compound of Formula (A):
- the nitro group of a compound of Formula (A) can be reduced to the corresponding amino group by numerous reducing agents known in the art including, but not limited to, hydrogen (usually in the presence of a metal catalyst such as Pd), tin chloride, Na 2 S 2 U 4 , or a combination of 10% Pd- C/HCO 2 NH 4 /CH 3 OH.
- the reducing agent is tin chloride.
- the reducing agent comprises a combination of HCO 2 NH 4 , 10%Pd/C, and MeOH.
- the reaction is carried out at room temperature. In some embodiments, the reduction reaction is carried out at an elevated temperature, e.g., about 35-60 0 C, about 45-60 0 C, about 50-60 0 C, or about 55-60 0 C.
- a compound of Formula (A) can be prepared by reacting a compound of Formula: wherein L 2 is a leaving group; with a compound of Formula:
- the substitution reaction can be carried out in the presence of a base.
- the base can be sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, or potassium carbonate.
- the base such as sodium hydroxide or potassium hydroxide can be used in a powder form.
- Suitable solvents for the substitution reaction include, but are not limited to, polar or weakly polar solvents such as DMF, THF, DMSO, NMP, or dioxane.
- the leaving group L is halo, for example, bromo, chloro, or fluoro.
- L 2 is chloro.
- a compound of Formula (D) can be prepared by the process comprising reacting a compound of Formula (J)
- the alkylation reaction can be carried out at an elevated temperature.
- the temperature can be about 70-120 0 C, about 80-120 0 C, about 90-120 0 C, about 100-120 0 C, about 105-120 0 C, about 110-120 0 C, about 110 0 C, or about 120 0 C.
- Suitable solvents include, but are not limited to, DMF, ⁇ -methyl-2-pyrrolidinone, toluene, or dioxane.
- the alkylating agents R Y can include alkyl halides or otheralkylating agents such as organometallic compounds, e.g., Grinard reagents, organolithium reagents, organocopper reagents, or organoaluminum reagents.
- the alkylating agents R 3 Y is a Grinard reagent.
- the alkylating agent R 3 Y is an organoaluminum reagent.
- the alkylating agent R 3 Y is trimethylaluminum.
- the alkylation reaction can be carried out in the presence of a catalyst.
- the alkylation reacton can be catalyzed by a palladium catalyst, for example, Pd(PPh 3 ) 4 .
- R 2 is Ci_ 8 haloalkyl
- R 3 is Ci_ 8 alkyl
- R 4 is O-Ci_ 8 alkyl
- R 2 is a CF 3
- R 3 is methyl
- R 4 is methoxy
- R is ethyl
- a compound of Formula (J) can be prepared by reacting a compound of Formula (H)
- the halogenation reaction requires an organic solvent. In some embodiments, the halogenation reaction is a neat reaction (i.e., substantially no solvent is required). In some embodiments, the halogenating reagent can be POCl 3 , PCl 3 , SOCI2, or PPI13/CCI4. In some embodiments, the halogenating reagent is POCI 3 .
- the halogenation reaction temperature can be about 60-130 0 C, about 70-130 0 C, about 80-130 0 C, about 90-130 0 C, about 100-130 0 C, about 110-130 0 C, or about 120-130 0 C.
- a compound of Formula (H) can be prepared by reacting a compound of Formula (G):
- the reduction reaction can be carried out by numerous reducing agents known in the art.
- Example reducing agents include, but not limited to, catalystic hydrogenation, tin chloride, Na 2 S 2 O 4 , or a combination of 10% Pd-CZHCO 2 NHVCHsOH.
- the reducing agent comprises tin chloride.
- the reducing agent comprises Na 2 S 2 O 4 .
- Any suitable solvent can be optionally used to carry out the reduction reaction.
- the solvent can include organic solvents or inorganic solvents.
- the solvent is a mixture of two or more solvents.
- the solvent is anhydrous.
- the solvent comprises water.
- the solvent is a mixture of water and an organic solvent.
- the organic solvent can be fully miscible with water.
- the solvent can be an alcohol (e.g., methanol or ethanol), THF, or acetic acid.
- he solvent is a mixture of water and acetic acid.
- the molar ratio of water and acetic acid can be about 1 :1.5, about 1 :1.6, about 1 :1.7, about 1 :1.8 , about 1 :1.9, or about 1 :2.0.
- the reduction reaction can be carried out at an elevated temperature, e.g., about 70-110 0 C, about 80-110 0 C, about 90-110 0 C, or about 100-110 0 C.
- R 2 is Ci_ 8 haloalkyl and R 4 is O-Ci_s alkyl. In other embodiments, R 2 is CF 3 and R 4 is methoxy.
- R is ethyl
- a compound of Formula (G) can be prepared by reacting a compound of Formula (F):
- a compound of Formula (F) can be prepared by reacting a compound of Formula:
- the imidazole formation reaction can be carried out at an elevated temperature, e.g., about 60-140 0 C, about 80-140 0 C, about 100-140 0 C, about 110-140 0 C, or about 120-140 0 C.
- the imidazole formation reaction can be carried out in a polar protic solvent.
- Example polar protic solvents include, but are not limited to, water, methanol, and acetic acid.
- substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
- the term "Ci_ 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
- the compounds of the invention are stable. As used herein "stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
- alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
- Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
- An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
- alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
- Example alkenyl groups include ethenyl, propenyl, and the like.
- alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
- Example alkynyl groups include ethynyl, propynyl, and the like.
- haloalkyl refers to an alkyl group having one or more halogen substituents.
- Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
- cyclic radical refers to a saturated, unsaturated, or aromactic carbocycle or heterocycle, optionally mono- or polysubstituted with halo, amino, Ci_ 3 alkylamino, di-Ci_ 3 alkylamino, nitro, Q_ 3 alkyl, OH, or O-Ci_ 3 alkyl.
- the cyclic radical can be a 3 to 24 membered mono- or polycyclic ring. In some embodiments, the cyclic radical is a 3-, 4-, 5-, 6-, or 7- membered ring.
- the cyclic radical can contain 3 to 20, or in some embodiments, 4 to 10 ring forming carbon atoms.
- the cyclic radical includes cyclo(hetero)alkyl, aryl and heteroaryl groups as defined below.
- Cyclo(hetero)alkyl refers to both cycloalkyl and cycloheteroalkyl groups. Cycloheteroalkyl and heteroaryl groups may, for example, contain 1 to 6, or in some embodiments, 1 to 3 ring forming heteroatoms, selected from O, N, S, and/or P.
- the cyclic radical can be bound via a carbon atom or optionally via a N, O, S, SO, or SO 2 group.
- An example of an aryl cyclic radical is phenyl.
- cycloalkyl cyclic radicals examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- heteroaryl cyclic radicals include thienyl, furanyl, pyrroly, imidazolyl, triazolyl, oxazolyl, isoxazoly, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like.
- cycloheteroalkyl cyclic radicals include pyrrolidinyl, tetrahydrofuranyl, morpholino, thiomorpholino, piperazinyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and imidazolidinyl.
- heteroaryl groups are provided below.
- aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms.
- arylalkyl refers to an alkyl group substituted by an aryl group.
- Example arylalkyl groups include benzyl and phenylethyl.
- cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
- Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
- cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds.
- cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
- a cycloalkyl group having one or more fused aromatic rings can be attached through either the aromatic or non-aromatic portion.
- One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
- Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
- heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
- Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring- forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
- heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
- the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
- heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group.
- An example of a heteroarylalkyl group is pyridylmethyl.
- cycloheteroalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom.
- Cycloheteroalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
- Example cycloheteroalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
- cycloheteroalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
- a cycloheteroalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
- moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups.
- the cycloheteroalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the cycloheteroalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the cycloheteroalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the cycloheteroalkyl group contains 0 to 3 double bonds. In some embodiments, the cycloheteroalkyl group contains 0 to 2 triple bonds.
- halo or “halogen” includes fluoro, chloro, bromo, and iodo.
- haloalkyl refers to an alkyl group substituted by one or more halogen atoms. Examples of haloalkyl groups include CF 3 and CF 2 CF 3 .
- alkoxy refers to an -O-alkyl group.
- Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
- substituted refers to the replacement of a hydrogen moiety with a non-hydrogen moiety in a molecule or group.
- polysubstituted means substituted with more than one substituent up to the valence of the substituted group.
- a polysubstituted group can be substituted with 2, 3, 4, or 5 substituents.
- substituents can be independently selected from that group.
- leaving group refers to a moiety that can be displaced by another moiety, such as by nucleophilic attack, during a chemical reaction. Leaving groups are well known in the art and include, for example, halogen, hydroxy, alkoxy, -O(CO)R a , -OSO 2 -R b , and -Si(R c ) 3 wherein R a can be Q.s alkyl, C 3 .
- R b can be Ci -S alkyl, aryl (optionally substituted by one or more halo, cyano, nitro, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, or Ci_ 4 haloalkoxy), or heteroaryl (optionally substituted by one or, more halo, cyano, nitro, Ci_ 4 alkyl, C 14 haloalkyl, Ci_ 4 alkoxy, or Ci_ 4 haloalkoxy), and wherein R c can be Ci -S alkyl.
- Example leaving groups include chloro, bromo, iodo, mesylate, tosylate, trimethylsilyl, and the like.
- reacting is meant to refer to the bringing together of the indicated reagents in such a way as to allow their molecular interaction and chemical transformation according to the thermodynamica and kinetics of the chemical system. Reacting can be facilitated, particularly for solid reagents, by using an apporopriate solvent or mixture of solvents in which at least one of the reagents is at least partially soluble. Reacting is typically carried out for a suitable time and under conditions suitable to bring about the desired chemical transformation.
- the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
- the invention relates to the D form, the L form, and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms.
- Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid.
- Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
- Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
- Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H-pyrazole.
- Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
- Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
- the compounds of the invention, and salts thereof are substantially isolated.
- substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
- Partial separation can include, for example, a composition enriched in the compound of the invention.
- Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
- the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
- pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 ( 1977), each of which is incorporated herein by reference in its entirety.
- the physiologically acceptable salts may be obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases.
- suitable inorganic acids are hydrochloric acid, sulphuric acid, phosphoric acid, or hydrobromic acid
- suitable organic acids are carboxylic acid, sulpho acid, or sulphonic acid, such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, maleic acid, salicylic acid, 3 -aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, gluconic acid, amino acids, methanesulphonic acid,
- suitable inorganic bases are sodium hydroxide, potassium hydroxide and ammonia
- suitable organic bases are amines, e.g., tertiary amines, such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, ⁇ -picoline, ⁇ -picoline, ⁇ - picoline, quinaldine, or pyrimidine.
- physiologically acceptable salts of the compounds according to formula (I) can be obtained by converting derivatives which possess tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se using quaternizing agents.
- suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide, and n-propyl chloride, and also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- compositions and Administration are inhibitors of phosphodiesterase 10. It is therefore a part of the subject-matter of this invention that the compounds according to formula (I), and their salts and also pharmaceutical preparations which comprise these compounds or their salts, can be used for treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity and/or disorders in which inhibiting phosphodiesterase 10 is of value.
- compounds of formula (I) including their salts, solvates and prodrugs and also pharmaceutical compositions comprising an amount of a compound of formula (I) or one of its salts, solvates or prodrugs effective in inhibiting PDE 10 can be used for the treatment of central nervous system disorders of mammals including a human.
- An effective dose of the compounds according to the invention, or their salts, is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition.
- the dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors.
- the daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
- Suitable administration forms are oral, parenteral, intravenous, transdermal, topical, inhalative, intranasal and sublingual preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal, e.g. dry powder or sublingual preparations of the compounds according to the invention.
- the customary galenic preparation forms such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.
- Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings andlor sweetening agents, if desired.
- carrier substances such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular
- Liquid medicinal forms can be sterilized andlor, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.
- auxiliary substances such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.
- additives examples include tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its nontoxic salts).
- High molecular weight polymers such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity.
- solid carrier substances examples include starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
- Oily suspensions for parenteral or topical applications can be vegetable synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol.
- vegetable synthetic or semisynthetic oils such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tride
- fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia.
- Silicone oils of differing viscosity are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil. Suitable solvents, gelatinizing agents and solubilizers are water or watermiscible solvents.
- suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2- octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
- alcohols such as ethanol or isopropyl alcohol
- benzyl alcohol 2- octyldodecanol
- polyethylene glycols phthalates, adipates
- propylene glycol glycerol
- di- or tripropylene glycol waxes
- methyl cellosolve cellosolve
- esters morpholines
- dioxane dimethyl sulphoxide
- dimethylformamide
- Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents. Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
- ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or car
- glycerol paraffin of differing viscosity
- triethanolamine collagen
- allantoin and novantisolic acid Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl- ⁇ - iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g.
- cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation.
- Stabilizers such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
- Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials.
- Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions.
- These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
- Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.
- Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
- the preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.
- the compounds of the invention may be administered as a combination therapy with further active agents, e.g. therapeutically active compounds useful in the treatment of central nervous system disorders.
- these further compounds may be PDE 10 inhibitors or compounds which have an activity which is not based on PDE 10 inhibition such as dopamine D2 receptor modulating agents or NMDA modulating agents.
- the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be coadministered or administered separately.
- Compounds of the invention or pharmaceutically acceptable salts of the compounds are phosphodiesterase 10 inhibitors which are useful in treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity and/or disorders such as central nervous system disorders.
- the present invention relates to the treatment of neurological disorders and psychiatric disorders including, but not limited to, schizophrenia and other psychotic disorders; mood [affective] disorders; neurotic, stress-related and somatoform disorders including anxiety disorders; eating disorders; sexual dysfunction; excessive sexual drive; disorders of adult personality and behavior; disorders usually first diagnosed in infancy, childhood or adolescence; mental retardation; disorders of psychological development; disorders comprising the symptom of cognitive deficiency in a mammal, including a human; and factitious disorders.
- schizophrenia and other psychotic disorders including, but not limited to, schizophrenia and other psychotic disorders; mood [affective] disorders; neurotic, stress-related and somatoform disorders including anxiety disorders; eating disorders; sexual dysfunction; excessive sexual drive; disorders of adult personality and behavior; disorders usually first diagnosed in infancy, childhood or adolescence; mental retardation; disorders of psychological development; disorders comprising the symptom of cognitive deficiency in a mammal, including a human; and factitious disorders.
- Exemplary schizophrenia and other psychotic disorders that can be treated according to the present invention include, but are not limited to, continuous or episodic schizophrenia of different types (for instance, paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; induced acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different types (for instance, manic depressive or mixed type); puerperal psychosis, and other nonorganic psychosis.
- continuous or episodic schizophrenia of different types for instance, paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorders
- schizotypal disorders such as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and sch
- Exemplary mood [affective] disorders that can be treated according to the present invention include, but not limited to, manic episodes associated with bipolar disorder and single manic episodes; hypomania; mania with psychotic symptoms; bipolar affective disorders (including for instance bipolar affective disorders with current hypomanic and manic episodes with or without psychotic symptoms, bipolar I disorder or bipolar II disorder); depressive disorders, such as single episode or recurrent major depressive disorder of the mild moderate or severe type; depressive disorder with postpartum onset; depressive disorders with psychotic symptoms; persistent mood [affective] disorders; cyclothymia; dysthymia; and premenstrual dysphoric disorder.
- Exemplary neurotic, stress-related and somatoform disorders that can be treated according to the present invention include, but not limited to, phobic anxiety disorders; agoraphobia and social phobia related to psychosis; anxiety disorders; panic disorders; general anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders; post traumatic stress disorder; dissociative disorders; neurotic disorders; and depersonalisation-derealisation syndrome.
- disorders of adult personality and behavior include, but not limited to, specific personality disorders of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; mixed personality disorders; habit and impulse disorders (such as trichotillomania, pyromania, maladaptive aggression); and disorders of sexual preference.
- Exemplary disorders usually first diagnosed in infancy, childhood or adolescence that can be treated according to the present invention include, but not limited to, hyperkinetic disorders; attentional deficit/hyperactivity disorder (AD/HD); conduct disorders; mixed disorders of conduct and emotional disorders; nonorganic enuresis; nonorganic encopresis; stereotyped movement disorder; and specified behavioural emotional disorders; attention deficit disorder without hyperactivity; excessive masturbation; nail-biting; nose-picking and thumb-sucking; disorders of psychological development; schizoid disorder of childhood; pervasive development disorders; and psychotic episodes associated with Asperger's syndrome.
- ADHD attentional deficit/hyperactivity disorder
- conduct disorders mixed disorders of conduct and emotional disorders
- nonorganic enuresis nonorganic encopresis
- stereotyped movement disorder and specified behavioural emotional disorders
- attention deficit disorder without hyperactivity excessive masturbation
- nail-biting nail-biting
- nose-picking and thumb-sucking disorders of psychological development
- pervasive development disorders and psychotic
- Exemplary neurological disorders include neurodegenerative disorders including, without being limited to, Parkinson's disease, Huntington's disease, dementia (for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, or fronto temperal dementia), neurodegeneration associated with cerebral trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct, hypoglycemia-induced neurodegeneration, neurodegeneration associated with epileptic seizure, neurodegeneration associated with neurotoxic poisoning or multi-system atrophy.
- Parkinson's disease Huntington's disease
- dementia for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, or fronto temperal dementia
- neurodegeneration associated with cerebral trauma neurodegeneration associated with stroke
- neurodegeneration associated with cerebral infarct a neurodegeneration associated with cerebral infarct
- hypoglycemia-induced neurodegeneration neurodegeneration associated with epileptic seizure
- neurodegeneration associated with neurotoxic poisoning or multi-system atrophy neurodegenerative disorders including, without being limited to, Parkinson
- Exemplary disorders of psychological development include, but not limited to, developmental disorders of speech and language; developmental disorders of scholastic skills; specific disorder of arithmetical skills; reading disorders and spelling disorders and other learning disorders, which disorders are predominantly diagnosed in infancy, childhood or adolescence.
- cognitive deficiency refers to a subnormal functioning or a suboptimal functioning in one or more cognitive aspects such as memory, intellect, learning and logic ability, or attention in a particular individual comparative to other individuals within the same general age population.
- Exemplary disorders comprising as a symptom cognitive deficiency that can be treated according to the present invention include, but not limited to, cognitive deficits related to psychosis including schizophrenia; depression; age-associated memory impairment; autism; autistic spectrum disorders; fragile X syndrome; Parkinson's disease; Alzheimer's disease; multi infarct dementia; spinal cord injury; CNS hypoxia; Lewis body dementia; stroke; frontotemporal dementia; progressive supranuclear palsy Huntington's disease and in HIV disease; cerebral trauma; cardiovascular disease; drug abuse; diabetes associated cognitive impairment; and mild cognitive disorder.
- the present invention relates to the treatment of movement disorders with malfunction of basal ganglia.
- Exemplary movement disorders with malfunction of basal ganglia that can be treated according to the present invention include, but not limited to, different subtypes of dystonia, such as focal dystonias, multiple-focal or segmental dystonias, torsion dystonia (induced by psychopharmacological drugs), hemispheric, generalised and tardive dyskinesias, akathisias, dyskinesias such as Huntington's disease, Parkinson's disease, Lewis body disease, restless leg syndrome, PLMS.
- dystonia such as focal dystonias, multiple-focal or segmental dystonias, torsion dystonia (induced by psychopharmacological drugs), hemispheric, generalised and tardive dyskinesias, akathisias, dyskinesias such as Huntington's disease, Parkinson's disease, Lewis body disease, restless leg syndrome, PLMS.
- the present invention relates to the treatment of organic disorders.
- organic disorders include, but not limited to, symptomatic mental disorders, organic delusional (schizophrenia-like) disorders; presenil or senile psychosis associated with dementia; psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; and personality and behavioural disorders due to brain disease, damage and dysfunction.
- the present invention relates to the treatment of mental and behavioural disorders due to psychoactive compounds, more particular to the treatment of psychotic disorders and residual and late-onset psychotic disorders induced by alcohol, opioids, cannabinoids, cocaine, hallucinogens, other stimulants, including caffeine, volatile solvents and other psychoactive compounds.
- the present invention relates to a general improvement of learning and memory capacities in a mammal, including a human.
- Compounds currently used to treat schizophrenia have been associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension, and obesity), glucose abnormalities (such as hyperglycemia, elevated blood glucose and impaired glucose tolerance), and the exhibition of extrapyramidal symptoms.
- the weight gain observed with conventional atypical antipsychotics, such as risperidone and olanzapine has been associated with an increased risk of cardiovascular disease and diabetes mellitus.
- compounds of the present invention are useful in treating schizophrenia to effect a clinically relevant improvement such as reduction of a PANSS total score in a patient, while maintaining body weight, maintaining or improving glucose levels and/or tolerance, maintaining and/or improving triglycerides levels and/or total cholesterol levels and/or maintaining an EPS profile similar to baseline measurements before administration.
- the PDElO inhibitors of the invention are further useful in the prevention and treatment of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders. As such, the compounds can also be used to reduce body fat or body weight of an overweight or obese individual.
- the PDElO inhibitor is selective for PDElO, meaning that it is a better inhibitor of PDElO than for any other PDE.
- the selective PDElO inhibitor can reduce PDElO activity at least 10-fold or at least 100-fold compared to other PDE 's.
- overweight and “obese” are meant to refer to adult persons 18 years or older having a greater than ideal body weight (or body fat) measured by the body mass index (BMI).
- BMI is calculated by weight in kilograms divided by height in meters squared (kg/m ) or, alternatively, by weight in pounds, multiplied by 703, divided by height in inches squared (lbs x 703/in 2 ).
- Overweight individuals typically have a BMI of between 25 and 29, whereas obsess individuals typically have a BMI of 30 or more (see, e.g., National Heart, Lung, and Blood institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC:U.S. Department of Health and Human Services, NIH publication no. 98-4083,1998).
- Other means for indicating excess body weight, excess body fat, and obesity include direct measure of body fat and/or waist-to-hip ratio measurements.
- metabolic syndrome is used according to its usual meaning in the art.
- the American Heart Association characterizes metabolic syndrome as having at least 3 of the 5 below symptoms: l)Elevated waist circumference (>102 cm (40 inches) in men;
- Elevated triglycerides >150 mg/dL (>1.7 mmol/L) or drug treatment for elevated triglycerides
- 3) Reduced HDL-C ⁇ 40 mg/dL (1.03 mmol/L) in men ⁇ 50 mg/dL (1.3 mmol/L) in women or drug treatment for reduced HDL-C
- Elevated blood pressure >130/85 mmHg or drug treatment for hypertension
- Elevated fasting glucose >100 mg/dL or drug treatment for elevated glucose. See, Grundy, S.M. et al., Circulation, 2005, 112(17, e285
- Metabolic syndrome includes individuals suffering from diabetes, glucose intolerance, low fasting glucose, or insulin resistance plus two or more of 1) High blood pressure (>160/90 mmHg), 2) Hyperlipdemia (triglycerides >150 mg/dL or HDL cholesterol ⁇ 35 mg/dL in men and ⁇ 39 mg/dL in women), 3) Central obesity (waist-to-hip ratio of >0.90 for men and >0.85 for women or BMI > 30 kg/m2), and 4) Microalbuminuria (urinary albumin excretion rate >20 ⁇ g/min or an albumin-to-creatine ratio >20 ⁇ g/kg).
- the present methods relating to reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders can be carried out by the administration of one or more compounds of the present invention.
- one or more additional therapeutic agents can be administered such as anti-obesity agents.
- Example anti- obesity agents include apolipoprotein-B secretion/mi crosomal triglyceride transfer protein(apo- B/MTP) inhibitors, 11 -beta -hydro xysteroid dehydrogenase- 1 (1 lbeta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), cannabinoid receptor-I antagonists (such as rimona an , sympathomimetic agents, P3 adrenergic receptor agonists, 5 dopamine agonists; (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT 2 c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin
- anorectic agents such as a bombesin agonist
- neuropeptide-Y receptor antagonists e.g., NPY Y5 receptor antagonists, such as the compounds described in U.S. Patent Nos. 6,566,367; 61649,624; 61638,942; 61605,720; 61495,569; 61462,053; 61388,077; 6,335,345; and 6,326,375; US Pat. Appl. Publ. Nos. 2002/0151456 and 20031036652; and PCT Publication Nos.
- WO 031010175 WO 03/082190 and receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors, human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like.
- Other anti-obesity agents are readily apparent to one of ordinary skill in the art.
- PDElO inhibitors for the reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms are reported in WO 2005/120514.
- the present invention also includes method of treating pain conditions and disorders.
- pain conditions and disorders include, but are not limited to, inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatory pain, neuropathic pain, sub-categories of neuropathic pain including peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain.
- compounds of the present invention are administered in combination with one or more other agents effective for treating pain.
- agents include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opiods and antidepressants.
- one or more agents are selected from the group consisting of buprenorphine, naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol (LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide, carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram, acamprosate, topiramate, ondansetron, sertraline, bupropion, amantadine, amiloride, isradipine, tiagabine, baclofen, propranolol, tricyclic antidepressants, desipramine, carbamazepine, valproate
- the present invention also includes methods of treating schizophrenia and other psychotic disorders, as described above, with a combination of compounds of the present invention with one or more antipsychotic agents.
- suitable antipsychotic agents for use in combination with the compounds of the present invention include, but are not limited to, the phenothiazine (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipheyylbutylpiperidine (pimozide) and indolone (molindolone) classes of antipsychotic agents.
- Other antipsychotic agents with potential therapeutic value in combination with the compounds in the present invention include loxapine, s
- the present invention further includes methods of treating depression or treatment-resistant depression with a combination of compounds of the present invention with one or more antidepressants.
- suitable anti-depressants for use in combination with the compounds of the present invention include, but are not limited to, norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor antagonists, alpah-adrenoreceptor
- Scheme 3 shows a synthetic method that was used in the preparation of compounds of examples 1-4.
- Step l 4-Methyl-2-(3,3,3-trifluoro-propyl)-lH-imidazole Concentrated NH 4 OH (2.1 mL) and water (4.2 mL) were combined and stirred. To this was added 4,4,4-trifluro-butyraldehyde (3.5 g, 28 mmol) dissolved in methanol (7 mL). The reaction was let stir 10 min at room temperature and a 40% solution of methylglyoxal (6 mL, 31 mmol) dissolved water (6 mL) was added in one portion. The reaction was heated to 35 0 C for lhr then stirred at room temperature overnight and extracted with CHCl 3 3x.
- Step 2 6-Chloro-2-[4-methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-pyridine 4-Methyl-2-(3,3,3-trifluoro-propyl)-lH-imidazole (Example 1, step 1) (1.5 g, 8.4 mmol) was dissolved in DMF (25 mL) and cooled to 0 0 C. To this was added powdered KOH (0.49 g, 9.2 mmol). The reaction was stirred for 5 min and 2,6-dichloro-3-nitropyridine (1.6 g, 8.4 mmol) was added in one portion.
- Step 3 2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-6-(2,2,2-trifluoro-ethoxy)-pyridine
- Example 1 6-Chloro-2-[4-methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-pyridine (Example 1, Step 2) (1.4 g, 4.2 mmol) was dissolved in DMF (14 mL) and cooled to 0 0 C. To this was added powdered KOH (0.23 g, 4.2 mmol). The reaction was stirred for 5 min and 2,2,2-trifluroethanol (0.3 mL, 4.2 mmol) was added in one portion. The reaction was let stir at 0 0 C for 3hrs then diluted with water and extracted with ethyl acetate.
- Step 4 2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine
- the reaction mixture was stirred for 2 hrs and glacial acetic acid (0.12 mL, 1.9 mmol) added. The stirring was continued for further 6 hrs. The reaction mixture was allowed to cool to 70 0 C then diluted with water and stirred for 1 hr at 50 0 C. The warm mixture was filtered and the solids washed with water then dried. A tan solid was recovered (0.15 g) 70% yield.
- Examples 12-33 were prepared according to the following synthesis (Method B). Method B
- Example 32 2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine, was prepared from 9-bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B according to Method B.
- Scheme 5 2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
- Scheme 6 shows a synthetic method that was used in the preparation of examples 34-37.
- Step 6 l-Bromo-8-methoxy-4-methyl-3-trifluoromethyl-2,5,9,9b-tetraaz(i-cyclopenta[a]naphthalene
- Scheme 7 shows a synthetic method that was used in the preparation of Examples 38-39.
- Step 2 l-Bromo-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaz(i-cyclopenta[a]naphthalen-4-ylamine l-Bromo-4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (Scheme 7, Step 1) (0.50 g, 1.3 mmol) was suspended in dioxane (3 mL). Ammonia 7M/methanol (3 mL) was then added and the reaction sealed and heated to 50 0 C overnight. The reaction was let cool the filtered and the solids collected. A white solid (0.1 g, 20%) was recovered as desired product. EIMS 362.0 [M+H]+.
- Scheme 8 shows a synthetic method that was used in the preparation of Example 40.
- Example 96 9-[(2-Chlorophenyl)ethynyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
- reaction of bromide 5B 80 mg, 0.26 mmol
- DMF 3 mL
- Et 3 N 0.11 mL, 0.78 mmol
- 2-chlorophenylacetylene 107 mg, 0.78 mmol
- Pd(PPh 3 ) 2 C1 2 3.6 mg, 0.0052 mmol
- CuI 2 mg, 0.0104 mmol
- Examples 108-128 were prepared according to the processes described in this application or U.S. Application Serial Nos. 11/753,207 and 11/753,260.
- Examples 129-132 were prepared according to the method described in Example 47. Table 2: Examples 129-132
- Example 152 6,7-Dimethyl-9-o-tolylimidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one The procedure to prepare compound 8B in Scheme 12 was followed to prepare Example 152, which was isolated as a yellow powder (82% yield). [M+H] + 305.1 (ESI).
- Scheme 14 shows a synthetic method that was used in the preparation of Intermediate 1 used in the preparation of Example 163.
- Example 164 9-Bromo-2-methoxy-7-(trifluoromethyl)imidazo[l,5-fl]pyrido[3,2-e]pyrazine-6-carbonitrile.
- Examples 111, 112, and 165-172 were prepared according to Example 40.
- Examples 173-191 were prepared according to Example 47.
- Phosphodiesterase isoenzyme 10 (PDElO) activity was determined in preparations of human recombinant PDElOA and PDElO from pig striatum, respectively.
- the DNA of PDEl OAl (AB 020593, 2340 bp) was synthesized and cloned into the vector pCR4.TOPO (Entelechon GmbH, Regensburg, Germany).
- the gene was than inserted into a baculovirus vector, ligated with the baculovirus DNA.
- the enzyme-protein was expressed in SF21- cells. The enzyme was isolated from these cells by harvesting the cells by a centrifugation at 200 g to collect the cells.
- Striatum from male hybrid pigs were collected and frozen at -70 0 C.
- 0.5 g striatum was homogenised in 10 ml 50 mM Tris/Mg-buffer at 4°C and centrifuged for one hour at 100000 g. The supernatant was removed and the pellet was resuspended in the same buffer, but containing l%Triton and incubated for 45 min at 4°C.
- the membrane fraction was applied onto a 5 ml Hi TrapTM QHP column at the Akta-FPLC.
- PDElO activity was determined in a one step procedure in microtiterplates.
- the reaction was initiated by addition of the substrate solution and was carried out at 37 0 C for 30 minutes. Enzymatic activity was stopped by addition of 25 ⁇ l YSi-SPA-beads (Amersham-Pharmacia).
- Papaverine was used as the most common PDElO inhibitor and inhibits the PDElO with IC50 values of 89 nM and 103 nM for PDElO from human recombinant PDE 1 OA and PDE 10 from striatum of pig respectively.
- the phosphodiesterase isoenzyme 10 (PDElO) activity was determined in preparations of rat, pig and guinea pig striatum respectively. Striatum from male Wistar rats (180-200 g), male hybrid pigs (150 kg) and male guinea pigs (CRL (HA), 500 g) respectively were collected and frozen at - 70 0 C.
- striatum was homogenized in 10 ml 50 mM Tris/Mg-buffer at 4°C and centrifuged for one hour at 100000 g. The supernatant is called the cytosolic fraction and was removed and stored on ice. The pellet was resuspended in the same buffer, but containing 1 %Triton and incubated for 45 min at 4°C. Both fractions were independently applied onto a 5ml Hi TrapTM QHP column at the Akta-FPLC.
- the eluted fractions from the FPLC were additionally characterized by Western blot (Fig. 1).
- RNA from the frozen striatum of the different animals was isolated according to the instructions of the RNeasy kit (Qiagen; Hilden; Germany) and transcribed into cDNA using Oligo-Primer provided with the 1st strand cDNA synthese kit for RT-PCR (Roche; Mannheim; Germany). These cDNA was used as template for the PCR-reaction to amplify the catalytic domain of the PDElO.
- Taq-Polymerase Promega; Mannheim; Germany
- the cloning vector was transformed into E.coli's (XL-2), replicated within the cells, prepared and the included gene sequence determined for the pig and the guinea pig.
- PDElO activity was determined in a one step procedure in microtiterplates.
- the reaction was initiated by addition of the substrate solution and was carried out at 37°C for 30 minutes. Enzymatic activity was stopped by addition of 25 ⁇ l YSi-SPAbeads (Amersham-Pharmacia).
- cGMP is the second substrate for PDElO, the Km values are 1800 nM, 2200 nM and 1700 nM for PDElO from these species. For the test with cGMP 500 nM of this substrate was used.
- the optimal amount of enzyme in the assay has been determined and optimized for each enzyme preparation and substrate separately before using the enzyme in compound testing.
- IC 50 values For determination of IC 50 values the Hill-plot, 2-parameter-model, was used. Specific inhibitors of other PDE-Subtypes do not inhibit the PDElO preparation significantly. Papaverine was used as the most common PDElO inhibitor and inhibits the PDElO with IC 50 values of 142 nM, 110 nM and 77 nM for PDElO from striatum of rat, pig and guinea pig respectively.
- the compounds of formula (I) are potent inhibitors of PDElO.
- a substance is considered to effectively inhibit PDElO if it has an IC 50 of less than 10 ⁇ M, e.g., less than 1 ⁇ M.
- IC 50 values for select compounds are provided in Tables 7, 8, and 9, where "+” indicates that the IC 50 value is less than or equal to 10 nM; "++” indicates that the IC 50 value is between 10 -100 nM; and "+++” indicates that the IC 50 value is equal to or greater than 100 nM.
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Abstract
The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical compositions which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating central nervous system disorders, obesity, and metabolic disorders.
Description
PYRIDO[3,2-E]PYRAZINES, PROCESS FOR PREPARING THE SAME, AND THEIR USE AS
INHIBITORS OF PHOSPHODIESTERASE 10
FIELD OF THE INVENTION
The invention relates to pyrido[3,2-e]pyrazines, which are inhibitors of phosphodiesterase 10 and useful for treating diseases related to the central nervous system as well as obesity and metabolic disorders.
BACKGROUND
Psychotic disorders, especially schizophrenia, are severe mental disorders which extremely impair daily life. The symptoms of psychosis may be divided into two fractions. In the acute phase, it is predominated by hallucinations and delusions being called the positive symptoms. When the agitated phase abates the so called negative symptoms become obvious. They include cognitive deficits, social phobia, reduced vigilance, indifference and deficits in verbal learning and memory, verbal fluency and motor function.
Although several antipsychotics are available since, the present therapy of psychosis is not satisfactory. The classic antipsychotics, such as haloperidol, with a high affinity to dopamine D2 receptor show extreme side effects, such as extrapyramidal symptoms (=EPS) and do not improve the negative symptoms of schizophrenia so that they do not enable the patient to return to everyday life.
Clozapine which has emerged as a benchmark therapeutic ameliorating positive, negative and cognitive symptoms of schizophrenia and devoid of EPS shows agranulocytosis as a major, potential lethal side-effect (Capuano et al., Curr Med Chem 9: 521-548, 2002). Besides, there is still a high amount of therapy resistant cases (Lindenmayer et al., J Clin Psychiatry 63: 931-935, 2002). In conclusion, there is still a need for developing new antipsychotics which ameliorate positive, negative and cognitive symptoms of psychosis and have a better side effect profile. The exact pathomechanism of psychosis is not yet known. A dysfunction of several neurotransmitter systems has been shown. The two major neurotransmitter systems that are involved are the dopaminergic and the glutamatergic system: Thus, acute psychotic symptoms may be stimulated by dopaminergic drugs (Capuano et al.,
Curr Med Chem 9: 521-548, 2002) and classical antipsychotics, like haloperidol, have a high affinity to the dopamine D2 receptor (Nyberg et al., Psychopharmacology 162: 37-41, 2002). Animal models based on a hyperactivity of the dopaminergic neurotransmitter system (amphetamine hyperactivity, apomorphine climbing) are used to mimic the positive symptoms of schizophrenia. Additionally there is growing evidence that the glutamatergic neurotransmitter system plays an important role in the development of schizophrenia (Millan, Prog Neurobiol 70: 83-244, 2005). Thus, NMDA antagonists like phencyclidine and ketamine are able to stimulate schizophrenic
symptoms in humans and rodents (Abi-Saab et ah, Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Lahti et ah, Neuropsychopharmacology 25: 455-467, 2001). Acute administration of phencyclidine and MK-801 induce hyperactivity, stereotypies and ataxia in rats mimicking psychotic symptoms. Moreover, in contrast to the dopaminergic models the animal models of psychosis based on NMDA antagonists do not only mimic the positive symptoms but also the negative and cognitive symptoms of psychosis (Abi-Saab et ah, Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Jentsch and Roth, Neuropsychopharmacology 20: 201-225, 1999). Thus, NMDA antagonists, additionally induce cognitive deficits and social interaction deficits.
Eleven families of phosphodiesterases have been identified in mammals so far (Essayan, J Allergy Clin Immunol 108: 671-680, 2001). The role of PDEs in the cell signal cascade is to inactivate the cyclic nucleotides cAMP and/or cGMP (Soderling and Beavo, Proc Natl Acad USA 96(12):7071- 7076, 2000). Since cAMP and cGMP are important second messenger in the signal cascade of G- protein-coupled receptors PDEs are involved in a broad range of physiological mechanisms playing a role in the homeostasis of the organism. The PDE families differ in their substrate specificity for the cyclic nucleotides, their mechanism of regulation and their sensitivity to inhibitors. Moreover, they are differentially localized in the organism, among the cells of an organ and even within the cells. These differences lead to a differentiated involvement of the PDE families in the various physiological functions.
PDElO (PDElOA) is primarily expressed in the brain and here in the nucleus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et ah, William Harvey Research Conference, Porto, December 6th - 8th, 2001). All these brain areas are described to participate in the pathomechanism of schizophrenia (Lapiz et ah, Neurosci Behav Physiol 33: 13-29, 2003) so that the location of the enzyme indicates a predominate role in the pathomechanism of psychosis. In the striatum PDEl OA is predominately found in the medium spiny neurons and they are primarily associated to the postsynaptic membranes of these neurons (Xie et ah, Neuroscience 139: 597-607, 2006). By this location PDElOA may have an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the medium spiny neurons two neurotransmitter systems playing a predominate role in the pathomechanism of psychosis. Phosphodiesterase (PDE) 1OA, in particular, hydrolyses both cAMP and cGMP having a higher affinity for cAMP (Km = 0.05 μM) than for cGMP (Km =3 μM) (Soderling et ah, Curr. Opin. Cell Biol 12: 174-179, 1999).
Psychotic patients have been shown to have a dysfunction of cGMP and cAMP levels and its downstream substrates (Kaiya, Prostaglandins Leukot Essent Fatty Acids 46: 33-38, 1992; MuIy, Psychopharmacol Bull 36: 92-105, 2002; Garver et ah, Life Sci 31 : 1987-1992, 1982). Additionally, haloperidol treatment has been associated with increased cAMP and cGMP levels in rats and patients, respectively (Leveque et ah, J Neurosci 20: 4011-4020, 2000; Gattaz et ah, Biol Psychiatry 19: 1229-
1235, 1984). As PDElOA hydrolyses both cAMP and cGMP (Kotera et al., Biochem Biophys Res Commun 261 : 551-557, 1999), an inhibition of PDElOA would also induce an increase of cAMP and cGMP and thereby have a similar effect on cyclic nucleotide levels as haloperidol.
The antipsychotic potential of PDElOA inhibitors is further supported by studies of Kostowski et al. (Pharmacol Biochem Behav 5 : 15-17, 1976) who showed that papaverine, a moderate selective PDElOA inhibitor, reduces apomorphine -induced stereotypies in rats, an animal model of psychosis, and increases haloperidol-induced catalepsy in rats while concurrently reducing dopamine concentration in rat brain, activities that are also seen with classical antipsychotics. This is further supported by a patent application establishing papaverine as a PDElOA inhibitor for the treatment of psychosis (US Patent Application Pub. No. 2003/0032579).
In addition to classical antipsychotics which mainly ameliorate the positive symptoms of psychosis, PDElOA also bears the potential to improve the negative and cognitive symptoms of psychosis.
Focusing on the dopaminergic input on the medium spiny neurons, PDElOA inhibitors by up- regulating cAMP and cGMP levels act as Dl agonists and D2 antagonists because the activation of Gs-protein coupled dopamine Dl receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., Mutschler Arzneimittelwirkungen. 8th ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 2001). Elevated intracellular cAMP levels mediated by Dl receptor signalling seems to modulate a series of neuronal processes responsible for working memory in the prefrontal cortex (Sawaguchi, Parkinsonism Relat Disord 7: 9-19, 2000), and it is reported that Dl receptor activation may improve working memory deficits in schizophrenic patients (Castner et al., Science 287: 2020-2022, 2000). Thus, it seems likely that a further enhancement of this pathway might also improve the cognitive symptoms of schizophrenia.
Further indication of an effect of PDElOA inhibition on negative symptoms of psychosis was given by Rodefer et al. (Eur.J Neurosci 21 : 1070-1076, 2005) who could show that papaverine reverses attentional set-shifting deficits induced by subchronic administration of phencyclidine, an NMDA antagonist, in rats. Attentional deficits including an impairment of shifting attention to novel stimuli belongs to the negative symptoms of schizophrenia. In the study the attentional deficits were induced by administering phencyclidine for 7 days followed by a washout period. The PDElOA inhibitor papaverine was able to reverse the enduring deficits induced by the subchronic treatment.
The synthesis of imidazo[l,5-a]pyrido[3,2-e]pyrazinones and some medical uses are well described in patents and the literature. The documents EP 0 400 583 and US 5,055,465 from Berlex Laboratories, Inc. report a group of imidazoquinoxalinones, their aza analogs and a process for their preparation. These compounds
have been found to have inodilatory, vasodilatory and yenodilatory effects. The therapeutic activity is based on the inhibition of phosphodiesterase 3 (PDE3).
EP 0 736 532 reports pyrido[3,2-e]pyrazinones and a process for their preparation. These compounds are described to have anti-asthmatic and anti-allergic properties. Examples of this invention are inhibitors of PDE4 and PDE5.
WO 00/43392 reports the use of imidazo[l,5-a]pyrido[3,2-e]pyrazinones which are inhibitors of PDE3 and PDE5 for the therapy of erectile dysfunction, heart failure, pulmonic hypertonia and vascular diseases which are accompanied by insufficient blood supply.
Another group of pyrido[3,2-e]pyrazinones, reported in WO 01/68097 are inhibitors of PDE5 and can be used for the treatment of erectile dysfunction.
Further methods for the preparation of imidazo[l,5-a]pyrido[3,2-e]pyrazinones are described also by D. Norris et al. (Tetrahedron Letters 42 (2001 ), 4297-4299).
WO 92/22552 refers to imidazo[l,5-a]quinoxalines which are generally substituted at position 3 with a carboxylic acid group and derivatives thereof. These compounds are described to be useful as anxiolytic and sedativelhypnotic agents.
In contrast, only a limited number of imidazo[l,5-a]pyrido[3,2-e]pyrazines and their medical use are already published.
WO 99/45009 refers to a group of imidazopyrazines which are described to be inhibitors of protein tyrosine kinases used in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders. (P. Chen et al., Bioorg. Med. Chem. Lett. 12 (2002), 1361-1364 and P. Chen et al., Bioorg. Med. Chem. Lett. 12 (2002), 3153-3156).
Further PDElO inhibitors are reported in U.S. Application Serial Nos. 11/753,207 and 11/753,260.
As is evidenced above, there is an ongoing need for improved pharmaceutical agents for the treatment of central nervous system disorders. Accordingly, the compounds and compositions provided herein are directed toward this end.
SUMMARY
The present invention provides compounds of Formula I:
I
N-oxides of the same, and pharmaceutically acceptable salts thereof, wherein the variables are defined herein below.
The present invention further provides pharmaceutical compositions containing one or more of the above-described pyrido[3,2-e]pyrazine compounds of the invention, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.
The present invention further provides methods of treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of the invention described herein, or composition thereof, or pharmaceutically acceptable salt thereof.
The present invention further provides methods of treating or preventing central nervous system disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention described herein, or composition thereof, or pharmaceutically acceptable salt thereof.
The present invention further provides methods for treating or preventing obesity, type 2 diabetes, metabolic syndrome, or glucose intolerance using pyrido[3,2-e]pyrazines which are inhibitors of PDElO. The invention further relates to methods of reducing body fat or body weight.
The present invention further provides compounds of the invention, N-oxides of the same, and pharmaceutically acceptable salts thereof, for use in therapy.
The present invention further provides use of compounds of the invention, N-oxides of the same, and pharmaceutically acceptable salts thereof, for the preparation of a medicament for use in therapy.
The present invention further provides processes for preparing the compounds of Formula (I), N-oxides of the same, or pharmaceutically acceptable salts thereof, the process comprising reacting a compound of Formula (E)
(E) with R1 -X; wherein the compound of Formula (E) is prepared by the process comprising reacting a compound of Formula (D)
(D)
with a halogenating reagent; wherein the compound of Formula (D) is prepared by the process comprising a) reacting a compound of Formula (A)
(A); with a reducing agent to prepare a compound of Formula (B)
(B); b) reacting the compound of Formula (B) with a compound of Formula:
to prepare a compound of Formula (C)
(C); and c) reacting the compound of Formula (C) with a cyclizing reagent. Alternatively, the compound of Formula (D) can be prepared by the process comprising a) reacting a compound of Formula (G)
(H); b) reacting the compound of Formula (H) with a halogenating reagent to prepare a compound of Formula (J)
(J); c) reacting a compound of Formula (J) with an alkylating reagent R3Y; wherein the variables above are as defined anywhere herein.
The details of one or more embodiments of the invention are set forth in the accompanying the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the characterization of the collected proteins from FPLC by Western blot.
Figure 2 depicts PDE 10 present in the membrane fraction.
Figure 3 depicts the alignment of the pig PDElO (SEQ ID NO: 5), guinea pig PDElO (SEQ ID NO: 9), and rat PDE 10 (SEQ ID NO: 10) gene sequences to provide the depicted consensus sequence (SEQ ID NO: 8).
Figure 4 depicts the alignment of the pig PDElO (SEQ ID NO: 11), guinea pig PDElO (SEQ ID NO: 12), and rat PDE 10 (SEQ ID NO: 13) protein sequences within the catalytic domain to provide the depicted consensus sequence (SEQ ID NO: 14).
DETAILED DESCRIPTION
The present invention provides pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors having Formula I:
wherein:
R1 Is:
Ci-S alkyl, C2_8 alkenyl, C2_8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, cyano, and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Ci_3 alkylamino, nitro, Ci-S alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, a cyclic radical, and C3.8 cyclo(hetero)alkyl; or two adjacent O- Cu alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group;
R2 is Ci-S alkyl, C3.8 cyclo(hetero)alkyl, aiyl-Ci-5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical;
NR6R7, (CO)OR6, (CO)NR6R7, NR5(CO)OR6, NR5(CO)R6, NR5(C=O)-NR6R7, or NR5(SO2R6), wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci_8 alkyl, O- Ci-5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl, wherein Ci-S alkyl, O-Ci_5 alkyl, C3_6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R4 is halo, R8, or OR8, wherein R8 is: H,
Ci-8 alkyl or C3.6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-C1.3 alkyl, C2_8 alkynyl, and a cyclic radical; aryl-Ci.5 alkyl or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is Ci_8 alkyl, C2_8 alkenyl, or C2_8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical. In some embodiments, R1 is Ci_8 alkyl optionally mono- or polysubstituted with halo.
In some embodiments, R1 is propyl optionally mono- or polysubstituted with halo.
In some embodiments, R1 is propyl optionally mono- or polysubstituted with fluoro.
In some embodiments, R1 is C2_8 alkynyl optionally mono- or polysubstituted with a cyclic radical. In some embodiments, R1 is C2 alkynyl monosustituted with a cyclic radical.
In some embodiments, R1 is C2 alkynyl mono substituted with C3.8 cycloalkyl.
In some embodiments, R1 is C2 alkynyl mono substituted with cyclopropyl or cyclohexyl.
In some embodiments, R1 is C2 alkynyl mono substituted with C3.8 aryl, and said aryl is optionally mono- or polysubstituted with halo, Cu alkyl, O-Cu alkyl, cyano, or Cu haloalkyl. In some embodiments, R1 is C2 alkynyl mono substituted with phenyl optionally mono- or polysubstituted with substitents independently selected from fluoro, methyl, and OCH3.
In some embodiments, R1 is aryl or heteroaryl each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, -(C=O)-NR6R7, and a cyclic radical. In some embodiments, R1 is aryl optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, - (C=O)-NR6R7, and a cyclic radical.
In some embodiments, R1 is aryl mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, and a cyclic radical.
In some embodiments, R1 is aryl mono-substituted with a cyclic radical.
In some embodiments, R1 is aryl mono-substituted with phenyl.
In some embodiments, R1 is aryl mono-substituted with morpholino.
In some embodiments, R1 is aryl mono-substituted with -(C=O)-NR6R7, and said R6 and R7 are independently selected from H, Ci-8 alkyl, and O-C1.5 alkyl.
In some embodiments, R1 is aryl mono-substituted with -(C=O)-NR6R7, and R6 and R7 are independently selected from H, methyl, and OCH3.
In some embodiments, R1 is aryl mono-substituted with -(C=O)-NR6R7, and said R6 and R7 together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group.
In some embodiments, R1 is aryl mono-substituted with -(C=O)-NR6R7, and said R6 and R7 together with the nitrogen atom to which they are attached, form a 5-6 membered cycloheteroalkyl group.
In some embodiments, R1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO2NR6R7.
In some embodiments, R1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO2NH2.
In some embodiments, R1 is heteroaryl mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
In some embodiments, R1 is 5- or 6-membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, C1-5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, and a cyclic radical.
In some embodiments, R1 is 5- or 6-membered heteroaryl optionally mono- or noly substituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
In some embodiments, R1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
In some embodiments R1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
In some embodiments, R1 is furan, thiophene, isoxazole, pyridine, or pyrimidine.
In some embodiments, R1 is furan or thiophene. In some embodiments, R1 is pyrrole or pyrazole, each optionally mono- or polysubstituted with halo, Cu alkyl, cyano, or Cu haloalkyl.
In some embodiments, R1 is pyrazole optionally mono- or polysubstituted with Cu alkyl.
In some embodiments, R1 is pyrazole mono-substituted with methyl.
In some embodiments, R1 is pyrazole polysubstituted with methyl.
In some embodiments, R1 is l,3,5-trimethyl-lH-pyrazole-4-yl.
In some embodiments, R1 is 3,5-dimethyl-lH-pyrazole-4-yl.
In some embodiments, R1 is 6-membered heteroaryl optionally mono- or polysubstituted with halo, Ci-5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, or a cyclic radical.
In some embodiments, R1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
In some embodiments, R1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from halo, C1.5 alkyl, cyano, and Cu haloalkyl.
In some embodiments, R1 is pyridine optionally mono- or polysubstituted with halo or C1.5 alkyl.
In some embodiments, R1 is pyridine optionally mono- or polysubstituted with fluoro, chloro, or methyl. In some embodiments, R1 is pyridine mono-substituted with methyl.
In some embodiments, R1 is 4-methylpyridin-3-yl or 2-methylpyridin-3-yl.
In some embodiments, R1 is pyridine optionally mono-substituted with di-methylamino, OCH3, or morpholino.
In some embodiments, R is Ci_8 alkyl optionally mono- or polysubstituted with halo.
In some embodiments, R2 is methyl optionally mono- or polysubstituted with halo. In some embodiments, R2 is methyl. In some embodiments, R2 is CF3.
In some embodiments, R3 is Ci_8 alkyl, Ci_8 haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical.
In some embodiments, R3 is Ci_8 alkyl or Ci_8 haloalkyl. In some embodiments, R3 is CH3, CH2F, or CF3. In some embodiments, R3 is Ci-8 alkyl.
In some embodiments, R3 is C1.4 alkyl. In some embodiments, R3 is CH3.
In some embodiments, R3 is (CO)NR6R7, and said R6 and R7 are independently selected from H or Ci-8 alkyl. In some embodiments, R3 is cyano.
In some embodiments, R4 is OR8, and said R8 is Ci-8 alkyl optionally mono- or polysubsituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
In some embodiments, R4 is OR8, and R8 is methyl optionally mono- or polysubsituted with substituents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical.
In some embodiments, R4 is OR8, and said R8 is Ci-8 alkyl optionally polysubsituted with halo. In some embodiments, R8 is methyl or ethyl.
In some embodiments, R4 is OCH3.
In some embodiments, R4 is OR8, and said R8 is Ci_8 alkyl optionally mono-substituted with a cyclic radical.
In some embodiments, R4 is OR8, and said R8 is Ci_8 alkyl mono- or polysubsituted with cyclopropyl.
In some embodiments, R4 is OR8, and said R8 is methyl mono- or polysubsituted with cyclopropyl.
In some embodiments, R4 is OR8, and said R8 is Ci_8 alkyl mono-substituted with cyclopropyl.
In some embodiments, R4 is OR8, and R8 is ethyl optionally mono- or polysubsituted with halo.
In some embodiments, R4 is OCH2CH2F, OCH2CHF2, or OCH2CF3.
In some embodiments, R4 is OR8, wherein said R8 is aryl-Ci-5 alkyl or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, Cu alkyl, and O-Cu alkyl. In some embodiments, said R8 is benzyl optionally mono- or polysubstituted with fluoro. In other embodiments, said R8 is pyridinyl.
In some embodiments:
R1 is aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Cu alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, C1.5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, and a cyclic radical; or two O-d_3 alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group; R2 is Ci-8 alkyl; R3 is Ci-8 alkyl; and R4 is OR8, wherein R8 is Ci-8 alkyl.
In some embodiments:
R1 is aryl or heteroaryl, each optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci-5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, and a cyclic radical; or two O-Cu alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group; R2 is Ci-8 alkyl; R3 is Ci-8 alkyl; and R4 is OR8, wherein R8 is Ci-8 alkyl.
In some embodiments:
R1 is aryl optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci-5 alkyl, O-Ci_3 alkyl, cyano, Cu haloalkyl, O-Ci.3 haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, and a cyclic radical; or two O-Ci_3 alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group;
R2 is Ci-8 alkyl;
R3 is Ci-8 alkyl; and
R4 is OR8, wherein R8 is Ci-8 alkyl.
In some embodiments:
R1 is heteroaryl optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci-5 alkyl, OCu alkyl, cyano, Cu haloalkyl, and OCu haloalkyl;
R2 is Ci-8 alkyl; R3 is Ci-8 alkyl; and
R4 is OR8, wherein R8 is Ci-8 alkyl.
In some embodiments:
R1 is a 5- or 6- membered heteroaryl group containing at least one ring- forming N atom, optionally mono- or polysubstituted with substituent independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci-5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, and O-Cu haloalkyl;
R2 is Ci-8 alkyl; R3 is Ci-8 alkyl; and R4 is OR8, wherein R8 is Ci-8 alkyl.
In some embodiments:
R1 is a 5- or 6- membered heteroaryl group containing at least one ring- forming N atom, optionally mono- or polysubstituted with Ci-5 alkyl; R2 is Ci-8 alkyl;
R3 is Ci-8 alkyl; and
R4 is OR8, wherein R8 is Ci-8 alkyl.
R1 Is:
Ci-S alkyl, C2_8 alkenyl, C2_8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, cyano, and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Ci-S alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, and cyclic radical; or two O-Ci_3 alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group;
R is Ci-8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
R3 is: cyano;
Ci-8 alkyl or Ci-S haloalkyl each optionally mono- or polysubstituted with substitents independently selected from halo, OH, OCu alkyl, and a cyclic radical;
(CO)NR6R7, wherein R6 and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, OCi-5 alkyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R4 is R8 or OR8, wherein R8 is Ci-S alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, C2_s alkynyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments, the invention includes a compound having Formula (I):
R1 Is:
Ci_8 alkyl, C2-8 alkenyl, C2-8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical; aryl, heteroaryl, C3_s cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substituents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, -(C=O)-NR6R7, and a cyclic radical; or two adjacent O-Cu alkyl groups, together with the atoms to which they are attached, form a fused 5-7 membered cycloheteroalkyl group;
R2 is Ci-S alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
R3 is: cyano;
Ci-S alkyl or Ci-S haloalkyl each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical; or
(CO)NR6R7, wherein R6 and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, O-Ci-5 alkyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group;
R4 is R8 or OR8, wherein R8 is Ci-S alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments,
R1 is aryl or heteroaryl, each optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, and O-Cu alkyl; each of R2 and R3 is independently Ci-S alkyl; and
R4 is Ci-8 alkyl or O-Ci-8 alkyl.
The present invention also provides pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors having Formula I:
wherein:
R1 Is:
Ci-S alkyl, C2-s alkenyl, or C2-s alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci-5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, -(C=O)-NR6R7, and a cyclic radical; or two adjacent O-Cu alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group ;
R is Ci-S alkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, or a cyclic radical;
R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci-5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, or a cyclic radical;
NR6R7, (CO)OR6, (CO)NR6R7, NR5(CO)OR6, NR5(CO)R6, NR5(C=O)-NR6R7, or NR5(SO2R6), wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, O- Ci-5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl, wherein said Ci-S alkyl, OCi-5 alkyl, C3_6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, OCu alkyl, or a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R4 is halo, R8, or OR8, wherein R8 is: H,
Ci-8 alkyl or C3_6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-C1.3 alkyl, and a cyclic radical; aryl-Ci.5 alkyl or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Ci_3 alkylamino, nitro, Cu alkyl, O-Ci_3 alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments, R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C1.3 alkyl, or a cyclic radical;
(CO)OR6 or (CO)NR6R7, wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, O-C1.5 alkyl, C3_6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci_5 alkyl, wherein Ci-S alkyl, O-C1.5 alkyl, C3.6 cycloalkyl, aryl-Ci.5 alkyl, and heteroaryl-Ci.5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C1.3 alkyl, or a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group.
The present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising reacting a compound of Formula (E)
(E) wherein L1 is halogen; with R1 -X, wherein X is a leaving group; to prepare said compound of Formula (I).
In some embodiments, X is B(OH)2 or H. In some embodiments, X is B(OH)2. In other embodiments, X is H.
In some embodiments, the reacting is carried out in the presence of a catalyst. In some embodiments, catalyst comprises Pd(PPh3 )4. In other embodiments, catalyst comprises Pd(PPd3 )2C12.
In some embodiments, the reacting is carried out at an elevated temperature. In some embodiments, the temperature is from about 850C to about 100 0C. In some embodiments, L1 is bromo.
In some embodiments, the compound of Formula (E) is prepared by the process comprising reacting a compound of Formula (D):
(D) with a halogenating reagent to prepare said compound of Formula (E). In some embodiments, the halogenating reagent is a brominating reagent. In some embodiments, brominating reagent is NBS.
In some embodiments, the compound of Formula (D) is prepared by the process comprising: a) reacting said compound of Formula (A)
(A); with a reducing agent to prepare a compound of Formula (B)
to prepare a compound of Formula (C)
(C); and c) reacting said compound of Formula (C) with a cyclizing reagent to prepare said compound of Formula (D).
In some embodiments, R2 and R3 are each Ci_8 alkyl and R4 is O-Ci_8 alkyl. In some embodiments, R2 is methyl, R3 is methyl, and R4 is methoxy.
In some embodiments, the reducing agent comprises a combination Of HCO2NH2, 10%Pd/C, and MeOH.
In some embodiments, cyclizing reagent comprises P2O5/POC13.
In some embodiments, the compound of Formula (D) is prepared by the process comprising: a) reacting a compound of Formula (G)
(G), wherein R is C1.4 alkyl; with a reducing agent to prepare a compound of Formula (H)
(H); b) reacting a compound of Formula (H) with a halogenating reagent to produce a compound of Formula (J)
(J); wherein L is halogen; and c) reacting a compound of Formula (J) with an alkylating reagent R3Y , wherein Y is a leaving group; to prepare said compound of Formula (D). In some embodiments, R2 is Ci_8 haloalkyl, R3 is Ci_8 alkyl, and R4 is O-Ci_8 alkyl.
In some embodiments, R2 is a CF3, R3 is methyl, and R4 is methoxy.
In some embodiments, the reducing agent is a Na2S2C^.
In some embodiments, the reacting of step (c) is carried out at an elevated temperature. In some embodiments, the reacting of step (c) is carried out at about 90-120 0C. In other embodiments, the reacting of step (c) is carried out at about 110 0C. In some embodiments, the reacting of step (c) is carried out in the presence of a catalyst.
In some embodiments, the catalyst is Pd(PPli3)4. In some embodiments, R3Y is AlMe3.
In some embodiments, the compound of Formula (D) is prepared by the process comprising reacting a compound of Formula (J)
(J) with an alkylating reagent R3Y, wherein R3 is Ci_8 alkyl and Y is a leaving group; to prepare said compound of Formula (D). In some embodiments, R3 is methyl.
In some embodiments, R3Y is AlMe3.
In some embodiments, the compound of Formula (J) is prepared by the process comprising:
a) reacting a compound of Formula (G)
(G), wherein R is C1.4 alkyl; with a reducing agent to prepare a compound of Formula (H)
(H); and
b) reacting a compound of Formula (H) with a halogenating reagent; to prepare said compound of Formula (J).
In some embodiments, R2 is Ci_8 haloalkyl and R4 is O-Ci_8 alkyl. In some embodiments, R2 is CF3 and R4 is methoxy. In some embodiments, the reducing agent is a Na2S2U4.
In some embodiments, the halogenating reagent is POCI3.
The present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising: a) reacting a compound of Formula (D):
(D) with a halogenating reagent to prepare a compound of Formula (E):
(E) wherein L1 is a halogen; and b) reacting a compound of Formula (E) with R!-X, wherein X is a leaving group; to prepare said compound of formula (I).
In some embodiments, the compound of Formula (D) is prepared by the process comprising reacting said compound of Formula (C)
(C) with a cyclizing reagent; to prepare said compound of Formula (D).
In some embodiments, the compound of Formula (C) is prepared by the process comprising: a) reacting a compound of Formula (A)
(A) with a reducing agent to prepare a compound of Formula (B)
to prepare said compound of Formula (C).
In some embodiments, the compound of Formula (D) is prepared by the process comprising: a) reacting a compound of Formula (G)
(G) wherein R is C1.4 alkyl; with a reducing agent to prepare a compound of Formula (H)
(H); and b) reacting a compound of Formula (H) with a halogenating reagent to produce said compound of Formula (J)
(J) wherein L3 is halogen; and c) reacting a compound of Formula (J) with an alkylating reagent R3Y, wherein Y is a leaving group; to prepare said compound of Formula (D).
In some embodiments, the compound of Formula (D) is prepared by the process comprising reacting a compound of Formula (J)
(J) with an alkylating reagent R3Y, wherein R3 is Ci .8 alkyl and Y is a leaving group.
In some embodiments, the compound of Formula (J) is prepared by the process comprising: a) reacting a compound of Formula (G)
(G) wherein R is C1.4 alkyl; with a reducing agent to prepare a compound of Formula (H)
(H); and b) reacting a compound of Formula (H) with a halogenating reagent; to prepare said compound of Formula (J).
The present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors, the process comprising: a) reacting a compound of Formula (J)
(J) wherein L3 is halogen; with an alkylating reagent R3Y to prepare a compound of Formula (D)
(D); b) reacting a compound of Formula (D) with a halogenating reagent to prepare a compound of
Formula (E):
(E) wherein L1 is a halogen; and b) reacting a compound of Formula (E) with R!-X, wherein X is a leaving group; to prepare said compound of Formula (I).
In some embodiments, the compound of Formula (J) is prepared by the process comprising: c) reacting a compound of Formula (G)
(H); and d) reacting a compound of Formula (H) with a halogenating reagent; to prepare said compound of Formula (J).
The present invention further provides processes for preparing pyrido[3,2-e]pyrazine compounds that are PDE 10 inhibitors. Example processes are provided below in Schemes 1 and 2, wherein the variables are independently defined anywhere herein.
Scheme 1
(C) (D)
(E) (I)
In one aspect of the invention are provided processes, such as are exemplied by Scheme 1, that involves compounds of Formulas (I), (F), (G), (H), (J), (D), and (E), or salt forms of the compounds.
Coupling Reaction
The compounds of Formula (I) can be prepared via a coupling reaction affixing the R1 substituent to the imidazole portion of the ring as a final step. Example processes of the invention include Suzuki and Sonogashira methods using aryl derivatives or alkynyl derivatives, respectively.
Accordingly, the compounds of Formula (I) can be prepared by reacting a compound of Formula (E)
(E) wherein L1 is a leaving group; with R!-X , wherein X is a leaving group; to prepare a compound of Formula (I).
In some embodiments, X is B(OH)2 or H. In some embodiments, X is B(OH)2. In some embodiments, X is H.
In some embodiments, the coupling reaction can be carried out at an elevated temperature, e.g., at about 40-100 0C, about 50-1000C, about 60-100 0C, about 70-100 0C, about 80-100 0C, about 85-100 0C, or about 85-90 0C, or about 90-100 0C, or about 85 0C, or about 90 0C. The coupling reaction can also be carried out in the presence of water. In some embodiments, the molar ratio of water to organic solvent is about 1 :2, about 1 :3, or about 1 :4. Suitable organic solvents include, DMF, dioxane, THF, or acetonitrile. In some embodiments, the coupling reaction employs either an organic base or an inorganic base. Suitable organic bases include, but are not limited to, triethylamine, diisopropylethylamine, and pyridine. Suitable inorganic bases include, but are not limited to, NaOH and K2CO3. In some embodiments, the leaving group L1 can be chloro, bromo, or iodo. In other embodiments, the leaving group L1 can be bromo. In some embodiments, R1 is optionally substituted aryl or heteroaryl. In some embodiments, R1 is alkyl substituted with aryl or heteroaryl. In some embodiments, the coupling reaction can be carried out in the presence of a catalyst. In some embodiments, the catalyst is a palladium catalyst such as Pd(PPh3 )2C12 or Pd(PPh3 \. In some embodiments, the catalyst further comprises CuI. In some embodiments, the coupling reaction is the Suzuki coupling reaction (See, e.g., Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749). In some embodiments, the coupling reaction is the Sonogashira coupling reaction (See (a) Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2,4; (b) Sonogashira, Synthesis 1977, 777.).
Halogenation Reaction
According to a further aspect of the invention, a compound of Formula (E) can be prepared by reacting a compound of Formula (D):
Any of numerous halogenating reagents known in the art can be used. In some embodiments, the halogenating reagent is a brominating or chlorinating reagent. Some example brominating reagents include, for example, Br2, N-bromosuccinimide (NBS), l,3-dibromo-5,5- dimethylhydantoin, pyridiniurn tribromide (pyrHBr3) and the like. An example chlorinating reagent is N- chlorosuccinimide. In some embodiments, the halogenating reagent is N- bromosuccinimide.
Any suitable organic solvent can be optionally used to carry out the halogenating reaction. In some embodiments, the organic solvent contains an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, mixtures thereof and the like. In some embodiments, the organic solvent is acetonitrile. In some embodiments, the organic solvent is methanol. In further embodiments, the organic solvent includes dimethylformamide or tetrahydrofuran. Suitable temperatures for the halogenating reaction can vary. For example, the reaction temperature can be at or below about room temperature such as, for example, from about 0 to about 25 0C. The molar ratio of halogenating reagent to compound of Formula (D) can be routinely selected or optimized by the skilled artisan to miminize di-halogenated by products and maximize yield of the mono-halogenated product. In some embodiments, the molar ratio is from about 1 :0.8 to about 1 : 1 :2, from about 1 :0.9 to about 1 :1.1, from about 1 :0.95 to about 1 : 1.05, or about 1 :1.
Cyclization Reaction
According to a further aspect, a compound of Formula (D) can be prepared by reacting a compound of Formula (C)
(C) with a cyclizing reagent to prepare said compound of Formula (D).
Suitable cyclizing reagents include, but are not limited to, POCI3, PCl5, P2O5, or SOCI2. In some embodiments, the cyclizing reagent comprises P2(VPOCl3. In some embodiments, the cyclizing reagent can be a combination of two reagents, e.g., P2(VPOCl3. In some embodiments, the cyclization reaction is carried out in the presence of a base, e.g., an organic base such as triethylamine, diisopropylamine, or pyridine. In some embodiments, the cyclization reaction is carried out at an elevated temperature, such as about 90-120 0C, about 100-120 0C, or about 110-120 0C. In some embodiments, the cyclization reaction is carried out for a certain time, such as about 2-6 hours, or about 4-6 hours, or about 6 hours. In some embodiments, the cyclizing reaction is carried out under anhydrous conditions.
Amidation Reaction
According to a further aspect of the invention, the compound of Formula (C) can be prepared by reacting a compound of Formula (B)
In some embodiments, the reaction can be carried out at room temperature. In some embodiments, the reaction can be carried out at an elevated temperature, e.g., 40-80 0C, 50-80 0C, 60- 80 0C, or 70-80 0C. In some embodiments, the reaction solvent comprises toluene (e.g., toluene or a mixture of toluene and heptane).
In some embodiments, R2 and R3 are each Ci_8 alkyl and R4 is O-Ci_8 alkyl. In some embodiments, R2 is methyl, R3 is ethyl, and R4 is methoxy. In other embodiments, R2 is methyl, R3 is methyl, and R4 is methoxy.
Reduction Reaction
According to a further aspect, a compound of Formula (B) can be prepared by reacting a compound of Formula (A):
(A) with a reducing agent.
The nitro group of a compound of Formula (A) can be reduced to the corresponding amino group by numerous reducing agents known in the art including, but not limited to, hydrogen (usually in the presence of a metal catalyst such as Pd), tin chloride, Na2S2U4, or a combination of 10% Pd- C/HCO2NH4/CH3OH. In some embodiments, the reducing agent is tin chloride. In some embodiments, the reducing agent comprises a combination of HCO2NH4, 10%Pd/C, and MeOH. In some embodimens, the reaction is carried out at room temperature. In some embodiments, the reduction reaction is carried out at an elevated temperature, e.g., about 35-60 0C, about 45-60 0C, about 50-60 0C, or about 55-60 0C.
Substitution Reaction
According to a further aspect, a compound of Formula (A) can be prepared by reacting a compound of Formula:
wherein L2 is a leaving group; with a compound of Formula:
HN' %
to prepare a compound of Formula (A).
The substitution reaction can be carried out in the presence of a base. In some embodiments, the base can be sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, or potassium carbonate. In some embodiments, the base such as sodium hydroxide or potassium hydroxide can be used in a powder form. Suitable solvents for the substitution reaction include, but are not limited to, polar or weakly polar solvents such as DMF, THF, DMSO, NMP, or dioxane.
In some embodiments, the leaving group L is halo, for example, bromo, chloro, or fluoro. In some embodiments, L2 is chloro.
In another aspect of the invention are provided processes, such as are exemplied by Scheme 2, that involves compounds of Formulas (I), (F), (G), (H), (J), (D), and (E), or salt forms of the compounds.
Scheme 2
(E)
(I)
Coupling Reaction and Halogenation Reaction
The coupling reaction and the Halogenation reaction (Halogenation-1) in Scheme 2 can be carried out as in Scheme 1.
Alkylation Reaction
According to a further aspect of the invention, a compound of Formula (D) can be prepared by the process comprising reacting a compound of Formula (J)
(J) wherein L3 is halogen; with an alkylating reagent R3Y, wherein Y is a leaving group; to prepare the compound of Formula (D).
The alkylation reaction can be carried out at an elevated temperature. In some embodiments, the temperature can be about 70-1200C, about 80-1200C, about 90-1200C, about 100-120 0C, about 105-120 0C, about 110-120 0C, about 110 0C, or about 120 0C. Suitable solvents include, but are not limited to, DMF, Λ^-methyl-2-pyrrolidinone, toluene, or dioxane. The alkylating agents R Y can include alkyl halides or otheralkylating agents such as organometallic compounds, e.g., Grinard reagents, organolithium reagents, organocopper reagents, or organoaluminum reagents. In some embodiments, the alkylating agents R3Y is a Grinard reagent. In some embodiments, the alkylating agent R3Y is an organoaluminum reagent. In some embodiments, the alkylating agent R3Y is trimethylaluminum. In some embodiments, the alkylation reaction can be carried out in the presence of a catalyst. In some embodiments, the alkylation reacton can be catalyzed by a palladium catalyst, for example, Pd(PPh3 )4.
In some embodiments, R2 is Ci_8 haloalkyl, R3 is Ci_8 alkyl, and R4 is O-Ci_8 alkyl.
In some embodiments, R2 is a CF3, R3 is methyl, and R4 is methoxy.
In some embodiments, R is ethyl.
Halogenation Reaction-2
According to a further aspect of the invention, a compound of Formula (J) can be prepared by reacting a compound of Formula (H)
(H) with a halogenating reagent to produce the compound of Formula (J).
In some embodiments, the halogenation reaction requires an organic solvent. In some embodiments, the halogenation reaction is a neat reaction (i.e., substantially no solvent is required). In some embodiments, the halogenating reagent can be POCl3, PCl3, SOCI2, or PPI13/CCI4. In some
embodiments, the halogenating reagent is POCI3. The halogenation reaction temperature can be about 60-1300C, about 70-1300C, about 80-130 0C, about 90-130 0C, about 100-130 0C, about 110-130 0C, or about 120-130 0C.
Reduction/Cyclization Reaction
According to a further aspect of the invention, a compound of Formula (H) can be prepared by reacting a compound of Formula (G):
The reduction reaction can be carried out by numerous reducing agents known in the art. Example reducing agents include, but not limited to, catalystic hydrogenation, tin chloride, Na2S2O4, or a combination of 10% Pd-CZHCO2NHVCHsOH. In some embodiments, the reducing agent comprises tin chloride. In some embodiments, the reducing agent comprises Na2S2O4. Any suitable solvent can be optionally used to carry out the reduction reaction. The solvent can include organic solvents or inorganic solvents. In some embodiments, the solvent is a mixture of two or more solvents. In some embodiments, the solvent is anhydrous. In some embodiments, the solvent comprises water. In some embodiments, the solvent is a mixture of water and an organic solvent. The organic solvent can be fully miscible with water. For example, the solvent can be an alcohol (e.g., methanol or ethanol), THF, or acetic acid. In some embodiments, he solvent is a mixture of water and acetic acid. The molar ratio of water and acetic acid can be about 1 :1.5, about 1 :1.6, about 1 :1.7, about 1 :1.8 , about 1 :1.9, or about 1 :2.0. The reduction reaction can be carried out at an elevated temperature, e.g., about 70-110 0C, about 80-110 0C, about 90-110 0C, or about 100-110 0C.
In some embodiments, R2 is Ci_8 haloalkyl and R4 is O-Ci_s alkyl. In other embodiments, R2 is CF3 and R4 is methoxy.
In some embodiments, R is ethyl.
Substitution Reaction
According to a further aspect of the invention, a compound of Formula (G) can be prepared by reacting a compound of Formula (F):
(F) with a compound of Formula:
The substitution reaction can be carried out in the same way as provided in Scheme 1.
Imidazole Formation
According to a further aspect of the invention, a compound of Formula (F) can be prepared by reacting a compound of Formula:
The imidazole formation reaction can be carried out at an elevated temperature, e.g., about 60-140 0C, about 80-140 0C, about 100-140 0C, about 110-140 0C, or about 120-140 0C. In some embodiments, the imidazole formation reaction can be carried out in a polar protic solvent. Example polar protic solvents include, but are not limited to, water, methanol, and acetic acid.
Definitions
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci_6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
It is further intended that the compounds of the invention are stable. As used herein "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, and the like. As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like.
As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.
As used herein, "cyclic radical" refers to a saturated, unsaturated, or aromactic carbocycle or heterocycle, optionally mono- or polysubstituted with halo, amino, Ci_3 alkylamino, di-Ci_3 alkylamino, nitro, Q_3 alkyl, OH, or O-Ci_3 alkyl. The cyclic radical can be a 3 to 24 membered mono- or polycyclic ring. In some embodiments, the cyclic radical is a 3-, 4-, 5-, 6-, or 7- membered ring. The cyclic radical can contain 3 to 20, or in some embodiments, 4 to 10 ring forming carbon atoms. The cyclic radical includes cyclo(hetero)alkyl, aryl and heteroaryl groups as defined below. "Cyclo(hetero)alkyl" refers to both cycloalkyl and cycloheteroalkyl groups. Cycloheteroalkyl and heteroaryl groups may, for example, contain 1 to 6, or in some embodiments, 1 to 3 ring forming heteroatoms, selected from O, N, S, and/or P. The cyclic radical can be bound via a carbon atom or optionally via a N, O, S, SO, or SO2 group. An example of an aryl cyclic radical is phenyl. Examples of cycloalkyl cyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of heteroaryl cyclic radicals include thienyl, furanyl, pyrroly, imidazolyl, triazolyl, oxazolyl, isoxazoly, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like. Examples of cycloheteroalkyl cyclic radicals include pyrrolidinyl, tetrahydrofuranyl, morpholino, thiomorpholino, piperazinyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and imidazolidinyl. Examples of heteroaryl groups are provided below.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms.
As used herein, "arylalkyl" refers to an alkyl group substituted by an aryl group. Example arylalkyl groups include benzyl and phenylethyl.
As used herein, "cycloalkyl" refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles. In some embodiments, cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. A cycloalkyl group having one or more fused aromatic rings can be attached through either the aromatic or non-aromatic portion. One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
As used herein, a "heteroaryl" group refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring- forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyridylmethyl.
As used herein, "cycloheteroalkyl" refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom. Cycloheteroalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
Example cycloheteroalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl,
pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of cycloheteroalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. A cycloheteroalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion. Also included in the definition of cycloheteroalkyl are moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups. In some embodiments, the cycloheteroalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the cycloheteroalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the cycloheteroalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the cycloheteroalkyl group contains 0 to 3 double bonds. In some embodiments, the cycloheteroalkyl group contains 0 to 2 triple bonds.
As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms. Examples of haloalkyl groups include CF3 and CF2CF3.
As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
As used herein, the term "substituted" refers to the replacement of a hydrogen moiety with a non-hydrogen moiety in a molecule or group. The term "polysubstituted" means substituted with more than one substituent up to the valence of the substituted group. For example, a polysubstituted group can be substituted with 2, 3, 4, or 5 substituents. Generally when a list of possible substituents is provided, the substituents can be independently selected from that group.
As used herein, the term "leaving group" refers to a moiety that can be displaced by another moiety, such as by nucleophilic attack, during a chemical reaction. Leaving groups are well known in the art and include, for example, halogen, hydroxy, alkoxy, -O(CO)Ra, -OSO2-Rb, and -Si(Rc)3 wherein Ra can be Q.s alkyl, C3.7 cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl, wherein Rb can be Ci-S alkyl, aryl (optionally substituted by one or more halo, cyano, nitro, Ci_4 alkyl, Ci_4 haloalkyl, Ci_4 alkoxy, or Ci_4 haloalkoxy), or heteroaryl (optionally substituted by one or, more halo, cyano, nitro, Ci_4 alkyl, C14 haloalkyl, Ci_4 alkoxy, or Ci_4 haloalkoxy), and wherein Rc can be Ci-S alkyl. Example leaving groups include chloro, bromo, iodo, mesylate, tosylate, trimethylsilyl, and the like.
The term "reacting" is meant to refer to the bringing together of the indicated reagents in such a way as to allow their molecular interaction and chemical transformation according to the thermodynamica and kinetics of the chemical system. Reacting can be facilitated, particularly for solid reagents, by using an apporopriate solvent or mixture of solvents in which at least one of the reagents is at least partially soluble. Reacting is typically carried out for a suitable time and under conditions suitable to bring about the desired chemical transformation.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In the case of the compounds which contain an asymmetric carbon atom, the invention relates to the D form, the L form, and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The term, "compound," as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
All compounds, and pharmaceuticaly acceptable salts thereof, are also meant to include solvated or hydrated forms.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 ( 1977), each of which is incorporated herein by reference in its entirety. The physiologically acceptable salts may be obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Examples of suitable inorganic acids are hydrochloric acid, sulphuric acid, phosphoric acid, or hydrobromic acid, while examples of suitable organic acids are carboxylic acid, sulpho acid, or sulphonic acid, such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, maleic acid, salicylic acid, 3 -aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, gluconic acid, amino acids, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ethane- 1,2- disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide and ammonia, while examples of suitable organic bases are amines, e.g., tertiary amines, such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, α-picoline, β-picoline, γ- picoline, quinaldine, or pyrimidine.
In addition, physiologically acceptable salts of the compounds according to formula (I) can be obtained by converting derivatives which possess tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se using quaternizing agents. Examples of suitable
quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide, and n-propyl chloride, and also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Compositions and Administration The compounds of the present invention are inhibitors of phosphodiesterase 10. It is therefore a part of the subject-matter of this invention that the compounds according to formula (I), and their salts and also pharmaceutical preparations which comprise these compounds or their salts, can be used for treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity and/or disorders in which inhibiting phosphodiesterase 10 is of value. It is an embodiment of this invention, that compounds of formula (I) including their salts, solvates and prodrugs and also pharmaceutical compositions comprising an amount of a compound of formula (I) or one of its salts, solvates or prodrugs effective in inhibiting PDE 10 can be used for the treatment of central nervous system disorders of mammals including a human.
An effective dose of the compounds according to the invention, or their salts, is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
Suitable administration forms are oral, parenteral, intravenous, transdermal, topical, inhalative, intranasal and sublingual preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal, e.g. dry powder or sublingual preparations of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.
Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol);
preparations which are suitable for oral administration can comprise additional flavourings andlor sweetening agents, if desired.
Liquid medicinal forms can be sterilized andlor, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.
Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its nontoxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol. Oily suspensions for parenteral or topical applications can be vegetable synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil. Suitable solvents, gelatinizing agents and solubilizers are water or watermiscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2- octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-β- iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent. Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions. As indicated above, the compounds of the invention may be administered as a combination therapy with further active agents, e.g. therapeutically active compounds useful in the treatment of central nervous system disorders.
These further compounds may be PDE 10 inhibitors or compounds which have an activity which is not based on PDE 10 inhibition such as dopamine D2 receptor modulating agents or NMDA modulating agents. For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active
ingredients in separate dose forms. The active ingredients used in combination therapy may be coadministered or administered separately.
Pharmaceutical Methods Compounds of the invention or pharmaceutically acceptable salts of the compounds are phosphodiesterase 10 inhibitors which are useful in treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity and/or disorders such as central nervous system disorders.
In one aspect, the present invention relates to the treatment of neurological disorders and psychiatric disorders including, but not limited to, schizophrenia and other psychotic disorders; mood [affective] disorders; neurotic, stress-related and somatoform disorders including anxiety disorders; eating disorders; sexual dysfunction; excessive sexual drive; disorders of adult personality and behavior; disorders usually first diagnosed in infancy, childhood or adolescence; mental retardation; disorders of psychological development; disorders comprising the symptom of cognitive deficiency in a mammal, including a human; and factitious disorders.
Exemplary schizophrenia and other psychotic disorders that can be treated according to the present invention include, but are not limited to, continuous or episodic schizophrenia of different types (for instance, paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; induced acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different types (for instance, manic depressive or mixed type); puerperal psychosis, and other nonorganic psychosis.
Exemplary mood [affective] disorders that can be treated according to the present invention include, but not limited to, manic episodes associated with bipolar disorder and single manic episodes; hypomania; mania with psychotic symptoms; bipolar affective disorders (including for instance bipolar affective disorders with current hypomanic and manic episodes with or without psychotic symptoms, bipolar I disorder or bipolar II disorder); depressive disorders, such as single episode or recurrent major depressive disorder of the mild moderate or severe type; depressive disorder with postpartum onset; depressive disorders with psychotic symptoms; persistent mood [affective] disorders; cyclothymia; dysthymia; and premenstrual dysphoric disorder.
Exemplary neurotic, stress-related and somatoform disorders that can be treated according to the present invention include, but not limited to, phobic anxiety disorders; agoraphobia and social phobia related to psychosis; anxiety disorders; panic disorders; general anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders; post traumatic stress disorder; dissociative disorders; neurotic disorders; and depersonalisation-derealisation syndrome.
Exemplary the disorders of adult personality and behavior that can be treated according to the present invention include, but not limited to, specific personality disorders of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; mixed personality disorders; habit and impulse disorders (such as trichotillomania, pyromania, maladaptive aggression); and disorders of sexual preference.
Exemplary disorders usually first diagnosed in infancy, childhood or adolescence that can be treated according to the present invention include, but not limited to, hyperkinetic disorders; attentional deficit/hyperactivity disorder (AD/HD); conduct disorders; mixed disorders of conduct and emotional disorders; nonorganic enuresis; nonorganic encopresis; stereotyped movement disorder; and specified behavioural emotional disorders; attention deficit disorder without hyperactivity; excessive masturbation; nail-biting; nose-picking and thumb-sucking; disorders of psychological development; schizoid disorder of childhood; pervasive development disorders; and psychotic episodes associated with Asperger's syndrome.
Exemplary neurological disorders include neurodegenerative disorders including, without being limited to, Parkinson's disease, Huntington's disease, dementia (for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, or fronto temperal dementia), neurodegeneration associated with cerebral trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct, hypoglycemia-induced neurodegeneration, neurodegeneration associated with epileptic seizure, neurodegeneration associated with neurotoxic poisoning or multi-system atrophy.
Exemplary disorders of psychological development that can be treated according to the present invention include, but not limited to, developmental disorders of speech and language; developmental disorders of scholastic skills; specific disorder of arithmetical skills; reading disorders and spelling disorders and other learning disorders, which disorders are predominantly diagnosed in infancy, childhood or adolescence.
The phrase "cognitive deficiency" as used here refers to a subnormal functioning or a suboptimal functioning in one or more cognitive aspects such as memory, intellect, learning and logic ability, or attention in a particular individual comparative to other individuals within the same general age population. Exemplary disorders comprising as a symptom cognitive deficiency that can be treated according to the present invention include, but not limited to, cognitive deficits related to psychosis including schizophrenia; depression; age-associated memory impairment; autism; autistic spectrum disorders; fragile X syndrome; Parkinson's disease; Alzheimer's disease; multi infarct dementia; spinal cord injury; CNS hypoxia; Lewis body dementia; stroke; frontotemporal dementia; progressive supranuclear palsy Huntington's disease and in HIV disease; cerebral trauma; cardiovascular disease; drug abuse; diabetes associated cognitive impairment; and mild cognitive disorder.
In other aspects, the present invention relates to the treatment of movement disorders with malfunction of basal ganglia. Exemplary movement disorders with malfunction of basal ganglia that can be treated according to the present invention include, but not limited to, different subtypes of dystonia, such as focal dystonias, multiple-focal or segmental dystonias, torsion dystonia (induced by psychopharmacological drugs), hemispheric, generalised and tardive dyskinesias, akathisias, dyskinesias such as Huntington's disease, Parkinson's disease, Lewis body disease, restless leg syndrome, PLMS.
In other aspects, the present invention relates to the treatment of organic disorders. Examples of organic disorders include, but not limited to, symptomatic mental disorders, organic delusional (schizophrenia-like) disorders; presenil or senile psychosis associated with dementia; psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; and personality and behavioural disorders due to brain disease, damage and dysfunction.
In another aspect, the present invention relates to the treatment of mental and behavioural disorders due to psychoactive compounds, more particular to the treatment of psychotic disorders and residual and late-onset psychotic disorders induced by alcohol, opioids, cannabinoids, cocaine, hallucinogens, other stimulants, including caffeine, volatile solvents and other psychoactive compounds.
In a further aspect, the present invention relates to a general improvement of learning and memory capacities in a mammal, including a human. Compounds currently used to treat schizophrenia have been associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension, and obesity), glucose abnormalities (such as hyperglycemia, elevated blood glucose and impaired glucose tolerance), and the exhibition of extrapyramidal symptoms. The weight gain observed with conventional atypical antipsychotics, such as risperidone and olanzapine, has been associated with an increased risk of cardiovascular disease and diabetes mellitus.
In contrast, compounds of the present invention are useful in treating schizophrenia to effect a clinically relevant improvement such as reduction of a PANSS total score in a patient, while maintaining body weight, maintaining or improving glucose levels and/or tolerance, maintaining and/or improving triglycerides levels and/or total cholesterol levels and/or maintaining an EPS profile similar to baseline measurements before administration.
The PDElO inhibitors of the invention are further useful in the prevention and treatment of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders. As such, the compounds can also be used to reduce body fat or body weight of an overweight or obese individual. In some embodiments, the PDElO inhibitor is selective for PDElO, meaning that it is a better inhibitor of PDElO than for any other PDE.
In some embodiments, the selective PDElO inhibitor can reduce PDElO activity at least 10-fold or at least 100-fold compared to other PDE 's.
As used herein, the terms "overweight" and "obese" are meant to refer to adult persons 18 years or older having a greater than ideal body weight (or body fat) measured by the body mass index (BMI). BMI is calculated by weight in kilograms divided by height in meters squared (kg/m ) or, alternatively, by weight in pounds, multiplied by 703, divided by height in inches squared (lbs x 703/in2). Overweight individuals typically have a BMI of between 25 and 29, whereas obsess individuals typically have a BMI of 30 or more (see, e.g., National Heart, Lung, and Blood institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC:U.S. Department of Health and Human Services, NIH publication no. 98-4083,1998). Other means for indicating excess body weight, excess body fat, and obesity include direct measure of body fat and/or waist-to-hip ratio measurements.
The term "metabolic syndrome" is used according to its usual meaning in the art. The American Heart Association characterizes metabolic syndrome as having at least 3 of the 5 below symptoms: l)Elevated waist circumference (>102 cm (40 inches) in men;
>88 cm (35 inches) in women), 2) Elevated triglycerides (>150 mg/dL (>1.7 mmol/L) or drug treatment for elevated triglycerides), 3) Reduced HDL-C (<40 mg/dL (1.03 mmol/L) in men <50 mg/dL (1.3 mmol/L) in women or drug treatment for reduced HDL-C, 4) Elevated blood pressure (>130/85 mmHg or drug treatment for hypertension), and 5) Elevated fasting glucose (>100 mg/dL or drug treatment for elevated glucose). See, Grundy, S.M. et al., Circulation, 2005, 112(17, e285
(online at circ.ahajournals.org/cgi/reprint/l 12/17/e285). Metabolic syndrome according to the World Health Organization (See, Alberti et al., Diabet. Med. 15, 539-553, 1998) includes individuals suffering from diabetes, glucose intolerance, low fasting glucose, or insulin resistance plus two or more of 1) High blood pressure (>160/90 mmHg), 2) Hyperlipdemia (triglycerides >150 mg/dL or HDL cholesterol <35 mg/dL in men and <39 mg/dL in women), 3) Central obesity (waist-to-hip ratio of >0.90 for men and >0.85 for women or BMI > 30 kg/m2), and 4) Microalbuminuria (urinary albumin excretion rate >20 μg/min or an albumin-to-creatine ratio >20 μg/kg).
The present methods relating to reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders can be carried out by the administration of one or more compounds of the present invention. In some embodiments, one or more additional therapeutic agents can be administered such as anti-obesity agents. Example anti- obesity agents include apolipoprotein-B secretion/mi crosomal triglyceride transfer protein(apo- B/MTP) inhibitors, 11 -beta -hydro xysteroid dehydrogenase- 1 (1 lbeta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), cannabinoid receptor-I antagonists (such as rimona an , sympathomimetic agents, P3 adrenergic receptor agonists, 5 dopamine agonists; (such as
bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists, such as the compounds described in U.S. Patent Nos. 6,566,367; 61649,624; 61638,942; 61605,720; 61495,569; 61462,053; 61388,077; 6,335,345; and 6,326,375; US Pat. Appl. Publ. Nos. 2002/0151456 and 20031036652; and PCT Publication Nos. WO 031010175, WO 03/082190 and receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors, human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like. Other anti-obesity agents are readily apparent to one of ordinary skill in the art.
Representative methods for using PDElO inhibitors for the reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms are reported in WO 2005/120514.
The present invention also includes method of treating pain conditions and disorders. Examples of such pain conditions and disorders include, but are not limited to, inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatory pain, neuropathic pain, sub-categories of neuropathic pain including peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain. In a further embodiment compounds of the present invention are administered in combination with one or more other agents effective for treating pain. Such agents include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opiods and antidepressants. In various embodiments, one or more agents are selected from the group consisting of buprenorphine, naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol (LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide, carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram, acamprosate, topiramate, ondansetron, sertraline, bupropion, amantadine, amiloride, isradipine, tiagabine, baclofen, propranolol, tricyclic antidepressants, desipramine, carbamazepine, valproate, lamotrigine, doxepin, fluoxetine, imipramine, moclobemide, nortriptyline, paroxetine, sertraline, tryptophan, venlafaxine, trazodone, quetiapine, Zolpidem, zopiclone, zaleplon, gabapentin, memantine, pregabalin, cannabinoids, tramadol, duloxetine, milnacipran, naltrexone, paracetamol, metoclopramide, loperamide, clonidine, lofexidine, and diazepam.
The present invention also includes methods of treating schizophrenia and other psychotic disorders, as described above, with a combination of compounds of the present invention with one or more antipsychotic agents. Examples of suitable antipsychotic agents for use in combination with the compounds of the present invention include, but are not limited to, the phenothiazine (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipheyylbutylpiperidine (pimozide) and indolone (molindolone) classes of antipsychotic agents. Other antipsychotic agents with potential therapeutic value in combination with the compounds in the present invention include loxapine, sulpiride and risperidone.
The present invention further includes methods of treating depression or treatment-resistant depression with a combination of compounds of the present invention with one or more antidepressants. Examples of suitable anti-depressants for use in combination with the compounds of the present invention include, but are not limited to, norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor antagonists, alpah-adrenoreceptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine).
In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.
EXAMPLES
Scheme 3 shows a synthetic method that was used in the preparation of compounds of examples 1-4.
Scheme 3
R — CFQCHO, CHQCHO X = CI, Me
Example 1
6-Chloro-7-methyl-2-(2,2,2-trifluoroethoxy)-9-(3,3,3- trifluoropropyl)imidazo[l,5-a]pyrido[3,2- e]pyrazine
Step l 4-Methyl-2-(3,3,3-trifluoro-propyl)-lH-imidazole Concentrated NH4OH (2.1 mL) and water (4.2 mL) were combined and stirred. To this was added 4,4,4-trifluro-butyraldehyde (3.5 g, 28 mmol) dissolved in methanol (7 mL). The reaction was let stir 10 min at room temperature and a 40% solution of methylglyoxal (6 mL, 31 mmol) dissolved water (6 mL) was added in one portion. The reaction was heated to 35 0C for lhr then stirred at room temperature overnight and extracted with CHCl3 3x. The extracts were separated and combined then brined and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in ethyl acetate. A pale yellow oil was recovered (2.1 g) 42% yield. MS (ES) m/z 179.1 [M+l]+
Step 2 6-Chloro-2-[4-methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-pyridine
4-Methyl-2-(3,3,3-trifluoro-propyl)-lH-imidazole (Example 1, step 1) (1.5 g, 8.4 mmol) was dissolved in DMF (25 mL) and cooled to 0 0C. To this was added powdered KOH (0.49 g, 9.2 mmol). The reaction was stirred for 5 min and 2,6-dichloro-3-nitropyridine (1.6 g, 8.4 mmol) was added in one portion. The reaction was let stir at 0 0C for 3hrs then diluted with water and extracted with ether. The extracts were separated and combined, washed with water, then brined and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 1 :1. A brown solid was recovered (0.8 g) 28% yield. MS (ES) m/z 335.1 [M+l]+
Step 3 2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-6-(2,2,2-trifluoro-ethoxy)-pyridine
6-Chloro-2-[4-methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-pyridine (Example 1, Step 2) (1.4 g, 4.2 mmol) was dissolved in DMF (14 mL) and cooled to 0 0C. To this was added powdered KOH (0.23 g, 4.2 mmol). The reaction was stirred for 5 min and 2,2,2-trifluroethanol (0.3 mL, 4.2 mmol) was added in one portion. The reaction was let stir at 0 0C for 3hrs then diluted with water and extracted with ethyl acetate. The extracts were separated and combined, washed with water, then brined and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A brown solid was recovered (0.38 g) 23% yield. MS (ES) m/z 399.1 [M+l]+
Step 4 2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine
2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-3-nitro-6-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1, Step 3) (0.34 g, 0.85 mmol) and 10% Pd/C (0.048 g, 5%mol) were combined in 20 mL flask (connected with a condenser) and loaded 4 mL THF, followed by slow addition of 4 mL MeOH with stirring. Ammonium formate (0.296 g, 4.6 mmol) was added in one portion into the stirring mixture and the final mixture was stirred at room temperature for 10 min (gas released) then warmed to 50 0C for 1 hr. The reaction was cooled to room temperature and filtered through celite. The solvent was evaporated by rotovap and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 1 : 1. A white solid was recovered (0.21 g) 68% yield. MS (ES) m/z 369.1 [M+ 1]+
Step 5
3-Methyl-8-(2,2,2-trifluoro-ethoxy)-l-(3,3,3-trifluoro-propyl)-5H-2,5,9,9b-tetraaza- cyclop en ta[a]n aphthalen-4-one
A mixture of 2-[4-Methyl-2-(3,3,3-trifluoro-propyl)-imidazol-l-yl]-6-(2,2,2-trifluoro-ethoxy)-pyridin- 3-ylamine (Example 1, Step 4) (0.2 g, 0.54 mmol) and urea (0.46 g, 7.5 mmol) were heated to 160 0C. The reaction mixture was stirred for 2 hrs and glacial acetic acid (0.12 mL, 1.9 mmol) added. The stirring was continued for further 6 hrs. The reaction mixture was allowed to cool to 70 0C then diluted with water and stirred for 1 hr at 50 0C. The warm mixture was filtered and the solids washed with water then dried. A tan solid was recovered (0.15 g) 70% yield.
Step 6
6-chloro-7-methyl-2-(2,2,2-trifluoroethoxy)-9-(3,3,3- trifluoropropyl)imidazo[l,5-a]pyrido[3,2- ejpyrazine 3-Methyl-8-(2,2,2-trifluoro-ethoxy)-l-(3,3,3-trifluoro-propyl)-5H-2,5,9,9b-tetraaza- cyclopenta[a]naphthalen-4-one (0.1 g, 0.25 mmol) (Example 1, Step 5) was dissolved in phosphorous oxychloride (1.5 mL) and heated to 120 0C for 4hrs. The reaction was poured onto ice and neutralized with sodium bicarbonate. The aqueous solution was then extracted with ethyl acetate. The organic layers were separated and combined then washed with water, brined and dried over MgSO/μ After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 10 : 2. A yellow solid was recovered (0.029 g) 28% yield. MS (ES) m/z 413.1 [M+ 1]+
Example 2 6-Chloro-2-ethoxy-7-methyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine
6-Chloro-2-ethoxy-7-methyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine was prepared in a manner similar to Example 1 starting with butyraldehyde (2 g, 28 mmol). A yellow solid was recovered (0.016 g) 19% yield overall. MS (ES) m/z 305.1 [M+l]+
6-Chloro-2-ethoxy-7-methyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine (0.1 g, 0.33 mmol) was dissolved in dry THF (3 mL). To this was added methyl magnesium bromide (3M/ether) (0.44 mL, 1.3 mmol). The reaction was let to stir at room temperature over night then poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layers were separated and combined then washed with water, brined and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A yellow solid was recovered (0.06 g) 64% yield. MS (ES) m/z 285.1 [M+ 1]+
Example 4 9-(2-Chlorophenyl)-2-ethoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
2-(2-Chloro-phenyl)-4-methyl-lH-imidazole
To concentrated NH4OH (4 mL) was added 2-chlorobenzaldeyde (1.0 g, 7.1 mmol) dissolved in ethanol (4 mL). The reaction was heated to 50 0C and a 40% solution of methylglyoxal (1.6 mL, 8.9 mmol) was added in one portion. The reaction temperature was maintained with stirring for 3 hrs then diluted with water and extracted with ethyl acetate. The extracts were separated and combined then brined and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The crude triturated with ethanol and filtered. A tan solid was recovered (0.41 g) 30% yield. MS (ES) m/z 193.1 [M+l]+
Step 2
9-(2-Chlorophenyl)-2-ethoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
9-(2-Chlorophenyl)-2-ethoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine was prepared in a manner similar to Example 3 starting with 2-(2-chloro-phenyl)-4-methyl-lH-imidazole (Example
4, step 1) (0.41 g, 2.1 mmol). A yellow solid was recovered (0.05 g) 2% yield overall. MS (ES) m/z 353.1 [M+l]+
Examples 5-11 were prepared according to the following synthetic scheme (Scheme 4).
Method A
Scheme 4
6-Methoxy-2-(4-methyl-lH-imidazol-l-yl)-3-nitropyridine (IB) To a Λ^Λ^-dimethylformamide (500 mL) solution of 4-methylimidazole (8.5 g, 103 mmol) was added freshly powdered KOH (6.72 g, 120 mmol) in two portions under N2 at 0 0C, followed by addition of 2-chloro-6-methoxy-3-nitropyridine (18.9 g, 100 mmol). The resulting solution was warmed to room temperature and stirred for 2 hours. Majority of solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate three times. The organic layer was combined and washed two more times with water to remove additional dimethyl formamide and dried over magnesium sulfate. Solvent was evaporated under vacuum and the residue was purified by column (15-25% gradient eluent of ethyl acetate in dichloromethane) to provide compound IB as a yellow oil (21.9 g, 93% yield) which becomes yellow solid after standing on bench.
1H NMR (400MHz, DMSO) δ ppm 8.48 (d, IH), 8.00 (s, IH), 7.18 (s, IH), 7.01 (d, IH), 3.97 (s, 3H), 2.12 (s, 3H); EIMS 235.0 [M+H]+.
6-Methoxy-2-(4-methyl-lH-imidazol-l-yl)pyridin-3-amine (2B)
To a mixture of intermediate (IB) (21.4 g, 91.5 mmol) and 10% Pd/C (5.12 g, 4.58 mmol) in a 1 L RB flask (connected with a condenser) was loaded 240 mL THF, followed by slow addition of 240 mL MeOH under N2 with stirring. HCOONH4 (34.75 g, 503.25 mmol) was added in two portions into the stirring mixture and the final mixture was stirred at room temperature for 10 min (gas
released) and then warmed to 50 0C for 1 hr. The reaction was cooled to room temperature and filtered through celite. Solvent was evaporated under vacuum to dryness to provide a clean product as an offwhite powder (18.6 g, 99% yield). NMR indicated a 4:1 ratio mixture of two regioisomers with the major one as the desired regioisomer (confirmed by NOE studies). 1H NMR (400MHz, DMSO) δ ppm 7.91 (s, IH), 7.30 (d, IH), 7.25 (s, IH), 6.63 (d, IH), 4.70
(s, br, 2H), 3.70 (s, 3H), 2.13 (s, 3H); EIMS 205.0 [M+H]+.
N-(6-Methoxy-2-(4-methyl-lH-imidazol-l-yl)pyridin-3-yl)acetamide (3B)
To a solution of intermediate (2B) (8.16 g, 40 mmol, 4 : 1 mix) in 200 mL toluene was added acetic anhydride (18.8 mL, 200 mmol) in dropwise. The resulting mixture was stirred at room temperature for 3.5 hours. Stop the agitation for 30 min and the precipitate was filtered to provide a product as an offwhite solid 5.45 g (70% yield based on the major isomer) as a single regioisomer.
1H NMR (400MHz, DMSO) δ ppm 9.58 (s, IH), 8.00 (s, IH), 7.72 (d, IH), 7.30 (s, IH), 6.80 (d, IH), 3.84 (s, 3H), 2.12 (s, 3H), 1.95 (s, 3H); EIMS 247.1 [M+H]+.
2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine (4B)
To a solution of intermediate (3B) (2.04 g, 8.2 mmol) in 16 mL OfPOCl3 was added P2O5 quickly (minimize the moisture induction). The resulting mixture was refluxed at 110-120 0C for 4 hours. POCl3 was evaporated and the residue was quenched with ice-water very carefully. The mixture was neutralized with saturated Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Condensation followed by column chromatography using 2- 5% MeOH in dichloromethane as eluent to provide a product as a yellow powder 1.12 g (55% yield). 1H NMR (400MHz, DMSO) δ ppm 8.82 (s, IH), 8.07 (d, IH), 6.95 (d, IH), 3.99 (s, 3H), 2.69 (s, 3H), 2.64 (s, 3H); EIMS 229.0 [M+H]+.
9-Bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine (5B)
To a mixture of intermediate (4B) (172 mg, 0.75 mmol) and NBS (200 mg, 1.13 mmol) was added anhydrous CH3CN (6 mL) under N2. The resulting solution was stirred in dark for 24 hours. The reaction was concentrated to dryness and the residue was dissolved in 30 mL ethyl acetate. The solution was washed twice with brine (2 x 30 mL), saturated Na2SO3 solution (20 mL) and brine (20 mL). All aqueous phase were combined and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and dried over magnesium sulfate. Evaporation under vacuum to dryness to provide a clean product as a light yellow powder (206 mg, 88% yield).
1H NMR (400 MHz, DMSO) δ ppm 8.08 (d, IH), 7.01 (d, IH), 4.04 (s, 3H), 2.67 (s, 3H), 2.62 (s, 3H); EIMS 306.9 [M+H]+.
Example 5 9-(3-Fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
9-Bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) was suspended in a solution containing ethanol (2 niL) and toluene (2mL). To this was added 3-flurophenylboronic acid (0.12 g, 0.72 mmol) followed by potassium carbonate (0.15 g, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 5% mole). After bubbling argon thru the reaction for 1 min, the reaction was sealed and heated to 110 0C overnight. The reaction was then removed of solvent under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetatel :1. A tan solid was recovered (0.06 g) 47% yield. MS (ES) m/z 323.2 [M+l]+
Example 6 9-(3,5-Dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
9-(3,5-Dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B synthesized in a manner similar to compound 5, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine (0.12 g, 0.39 mmol) and 3,5-dichlorophenylboronic acid (0.13 g, 0.72 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetatel :1. A tan solid was recovered (0.08 g) 55% yield. MS (ES) m/z 373.1 [M+l]+
9-(3,4-Dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine synthesized in a manner similar to Example 5, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 3,4-dichlorophenylboronic acid (0.13 g, 0.72 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetatel :l . A tan solid was recovered (0.09 g) 62% yield. MS (ES) m/z 373.1 [M+l]+
Example 8 9-(2,4-Difluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
9-(2,4-Difluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-α]pyrido[3,2-e]pyrazine synthesized in a manner similar to Example 5, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 1,4-diflurorophenylboronic acid (0.11 g, 0.72 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetatel : 1. A yellow solid was recovered (0.04 g) 30% yield. MS (ES) m/z 341.1 [M+ 1]+
Example 9 9-(6-Fluoropyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(6-Fluoropyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine synthesized in a manner similar to Example 5, starting with 9-bromo-2-methoxy-6,7-
dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-5-pyridineboronic acid (0.1 g, 0.72 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.07 g) 55% yield. MS (ES) m/z 324.1 [M+l]+
Example 10 2-Methoxy-6,7-dimethyl-9-pyridin-3-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine
2-Methoxy-6,7-dimethyl-9-pyridin-3-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine synthesized in a manner similar to Example 5, starting with 9-bromo-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 3-pyridineboronic acid (0.86 g, 0.72 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.05 g) 42% yield. MS (ES) m/z 306.2 [M+l]+
Example 11
2-Methoxy-6,7-dimethyl-9-pyridin-4-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine
2-Methoxy-6,7-dimethyl-9-pyridin-4-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine synthesized in a manner similar to Example 5, starting with 9-bromo-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 4-pyridineboronic acid (0.86 g, 0.72 mmol). The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.02 g) 17% yield. MS (ES) m/z 306.2 [M+l]+
Examples 12-33 were prepared according to the following synthesis (Method B).
Method B
5B 6B
Example 12 9-(2-Chloro-4-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-Bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) was suspended in a solution containing dioxane (4 niL) and water (ImL). To this was added 2- chlorophenylboronic acid (0.1 g, 1.2 mmol) followed by potassium carbonate (0.15 g, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 5% mole). After bubbling argon thru the reaction for 1 min, the reaction was sealed and heated to 100 0C overnight. The reaction was then removed of solvent under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate2:l. A white solid was recovered (0.06 g) 44% yield. MS (ES) m/z 353.0 [M+l]+
Example 13 9-(4-Chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(4-Chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-methyl-4- chlorophenylboronic acid (0.1 g, 0.58 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.07 g) 51% yield. MS (ES) m/z 353.0 [M+ 1]+
Example 14 9-(2-Fluoro-4-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Fluoro-4-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine wa synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-4- methylphenylboronic acid (0.1 g, 0.58 mmol) The crude was purified by flash chromatography on silica gel in hexane/hyl acetate 2:1. A white solid was recovered (0.09 g) 68% yield. MS (ES) m/z 337.1 [M+l]+
Example 15 9-(2-Fluoro-3-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Fluoro-3-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-3- methoxyphenylboronic acid (0.1 g, 0.58 mmol) The crude was purified by flash chromatography on silica gel in hexane/ ethyl acetate 2:1. A pale yellow solid was recovered (0.02 g) 14% yield. MS (ES) m/z 353.1 [M+l]+
Example 16 9-(2-Chloro-4-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Chloro-4-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-4- flurophenylboronic acid (0.2 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A pale yellow solid was recovered (0.03 g) 22% yield. MS (ES) m/z 357.0 [M+l]+
Example 17 9-(4-Chloro-2-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(4-Chloro-2-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-4- chlorophenylboronic acid (0.2 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2 : 1. A pale yellow solid was recovered (0.08 g) 56% yield. MS (ES) m/z 353.1 [M+l]+
Example 18 9-(2-Chloro-4-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Chloro-4-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-4- methoxyphenylboronic acid (0.22 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.06 g) 41% yield. MS (ES) m/z 369.0 [M+l]+
Example 19 9-(2-Chloro-5-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Chloro-5-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l ,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5- methoxyphenylboronic acid (0.22 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.07 g) 50% yield. MS (ES) m/z 369.0 [M+l]+
Example 20
9-[2-Chloro-4-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine
9-[2-Chloro-4-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-4- trifluromethylphenylboronic acid (0.27 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2: 1. A white solid was recovered (0.1 g) 63% yield. MS (ES) m/z 407.0 [M+l]+
9-(2-Fluoro-5-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fTuro-5- methylphenylboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.11 g) 83% yield. MS (ES) m/z 337.1 [M+l]+
Example 22 9-(2-Chloro-5-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
9-(2-Chloro-5-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5- flurophenylboronic acid (0.2 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.06 g) 43% yield. MS (ES) m/z 357.0 [M+ 1]+
Example 23 9-[2-Chloro-5-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine
9-[2-Chloro-5-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5-
trifluromethylphenylboronic acid (0.27 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.02 g) 13% yield. MS (ES) m/z 407.0 [M+l]+
Example 24
9-[2-Chloro-5-(trifluoromethoxy)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine
9-[2-Chloro-5-(trifluoromethoxy)phenyl]-2-methoxy-6,7-dimethylimidazo[l ,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5- trifluromethoxyphenylboronic acid (0.29 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.1 g) 61 % yield. MS (ES) m/z 423.1 [M+ 1]+
Example 25
4-Chloro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl)benzonitrile
4-Chloro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl)benzonitrile was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5- cyanophenylboronic acid (0.22 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2 : 1. A white solid was recovered (0.09 g) 63% yield. MS (ES) m/z 364.1 [M+ 1]+
9-(2-Chloro-5-ethoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-chloro-5- ethoxyphenylboronic acid (0.24 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.09 g) 60% yield. MS (ES) m/z 383.1 [M+l]+
Example 27
2-Methoxy-6,7-dimethyl-9-pyrimidin-5-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine
XOΛNANY-
2-Methoxy-6,7-dimethyl-9-pyrimidin-5 w-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 5-pyrimidineboronic acid (0.14 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.02 g) 17% yield. MS (ES) m/z 307.1 [M+l]+
Example 28
2-Methoxy-9-(6-methoxypyridin-3-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
2-Methoxy-9-(6-methoxypyridin-3-yl)-6,7-dimethylimidazo[l ,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7-
dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-methoxy-5- pyridineboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.05 g) 38% yield. MS (ES) m/z 336.1 [M+l]+
Example 29 2-Methoxy-9-(2-methoxypyridin-3-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
2-Methoxy-9-(2-methoxypyridin-3-yl)-6,7-dimethylimidazo[l ,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-methoxy-3- pyridineboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.05 g) 38% yield. MS (ES) m/z 336.1 [M+l]+
Example 30
2-Methoxy-9-(4-methoxypyridin-3-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
2-Methoxy-9-(4-methoxypyridin-3-yl)-6,7-dimethylimidazo[l ,5-a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 4-methoxy-3- pyridineboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.05 g) 38% yield. MS (ES) m/z 336.1 [M+l]+
Example 31
9-(6-Fluoro-2-methylpyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-4-methyl-5- pyridineboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.06 g) 45% yield. MS (ES) m/z 338.1 [M+l]+
Example 32 2-Methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine
A mixture of bromide 5B (2.0 g, 6.53 mmol), 4-methylpyridine-3-boronic acid (1.79 g, 13.06 mmol), K2CO3 (2.70 g, 19.60 mmol) and Pd(PPh3)4 (150 mg, 0.1306 mmol) in a 250 Ml flask was vacuumed and flushed with nitrogen, followed by addition ofp-dioxane (120 mL) and water (40 mL). The final mixture was stirred at 90 0C for 4 hours, then cooled to room temperature. The reaction was quenched with NH4CI solution, extracted with ethyl acetate. Combined organic layer was washed with brine, dried over magnesium sulfate. Column chromatography using 50% ethyl acetate in dichloromethane as eluent provided 2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5- a]pyrido[3,2- e]pyrazine as an offwhite powder (1.68 g, 81% yield). 1H NMR (400 MHz, DMSO) δ ppm 8.55 (s, IH), 8.50 (m, IH), 8.10 (d, IH), 7.40 (m, IH),
6.85 (d, IH), 3.10 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H), 2.05 (s, 3H); EIMS 320.1 [M+H]+.
Example 32 Method C The intermediate 5B 9-Bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine was alternately prepared according to Scheme 5.
Example 32, 2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine, was prepared from 9-bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B according to Method B.
Scheme 5
2-Methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (7B)
A mixture of substrate 2B (3.06 g, 15 mmol) and urea (12.8 g, 210 mmol) was heated to 160 0C for 4 hours, then 4 mL of glacial acetic acid was added and stirring was continued at 120 0C for additional 2 hours. The mixture was cooled to 70 0C and 80 mL water was added, stirred for 0.5 hour at room temperature and the mixture was filtered to provide 1.2 g (33% yield) of the desired product 7B. [M+H]+ 231.1 (ES).
6-Chloro-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine (8B)
A suspension of substrate 7B (920 mg, 4 mmol) in 20 mL POCI3 was stirred at 110 0C for 5 hours. Major solvent was removed under vacuo and the residue was added slowly to iced methanol. Extraction with dichloromethane and condensation by rotavap provided 200 mg (20% yield) of product 8B as an offwhite solid. [M+H]+ 249.0 (ES).
2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine (4B)
To a suspension of substrate 8B (280 mg, 1.12 mmol) in 8 mL THF was added dropwise MeMgBr (3.0 M in Et2O, 1.5 mL, 4.5 mmol) at 0 0C. The resulting mixture was stirred at the same temperature for 20 minutes, then warmed to room temperature for 6 hours. The mixture was poured into iced-NH4Cl solution slowly, stirred for 0.5 hour. Standard workup procedure followed by column purification provided 180 mg (70% yield) of product 4B as an offwhite solid. EIMS 229.0 [M+H]+.
Example 33 9-(6-Fluoro-5-methylpyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-α]pyrido[3,2-e]pyrazine
9-(6-Fluoro-5-methylpyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-α]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with 9-bromo-2-methoxy-6,7- dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine 5B (0.12 g, 0.39 mmol) and 2-fluro-3-methyll-5- pyridineboronic acid (0.18 g, 1.2 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.05 g) 37% yield. MS (ES) m/z 338.1 [M+l]+
Scheme 6 shows a synthetic method that was used in the preparation of examples 34-37.
Scheme 6
2-Methoxy-9-(4-methoxypyridin-3-yl)-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine
5-Trifluoromethyl-3H-imidazjole-4-carboxylic acid ethyl ester
Ethyl 2-chloro-4,4,4-trifluroacetate (25 g, 0.114 mol) was combined with amidine (50 g, 1.1 mol) and water (5 mL). The reaction became warm and was heated to 130 0C for 1.5 hrs. The reaction was then cooled to room temperature and 100 mL of ice water added. The resulting solids were collected and washed with water then dried. 5.5 g, 23% of a brown solid was recovered as desired product. EIMS 209.05 [M+H]+.
Step 2 3-(6-Methoxy-3-nitro-pyridin-2-yl)-5-trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester
5-Trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester (Scheme 6, step 1) (5 g, 24 mmol) and 2-chloro-3-nitro-6-methoxypyridine (4.5 g, 24 mmol) were dissolved in DMF (60 mL). To this was added freshly powdered KOH (1.3 g, 24 mmol). The reaction was heated to 70 0C for 16 hrs then cooled to room temperature and diluted with water. The solution was then extracted with ethyl acetate 2x. The organic layers were combined and washed with water then brined and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The crude was purified using flash chromatography on silica gel in hexane/ ethyl acetate 2 : 1. A yellow oil (3.4 g, 39%) was recovered as desired product. EIMS 361.0 [M+H]+.
Step 3
S-Methoxy-S-trifluoromethylSH-lyS^^b-tetraaza-cyclopentalaJnaphthalen^-one
3-(6-Methoxy-3-nitro-pyridin-2-yl)-5-trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester (Scheme 6, step 2) (2.9 g, 8.0 mmol) was dissolved in glacial acetic acid (45 mL). To this was added water (23mL) followed by sodium hydrogensulfite (10 g, 80 mmol). The reaction was heated to 105 0C for 16 hrs. 2 g of the hydrogensulfite is then added every 2 hrs until starting material consumed, as indicated by TLC. The reaction was diluted with water and the solids filtered and collected. The solids were washed with water followed by a small amount of chloroform then dried. A grey/white solid (1.8 g, 79%) was recovered as desired product. EIMS 285.1 [M+H]+.
Step 4
4- Ch loro-8-meth oxy-3-trifluorom ethyl-2, 5, 9, 9b-tetraaza-cyclopen ta[a]n aph th alen e
8-Methoxy-3-trifluoromethyl-5H-2,5,9,9b-tetraaza-cyclopenta[a]naphthalen-4-one (Scheme 6, step 3) (1.0 g, 3.5 mmol) was suspended in POCl3 (11 niL) and heated to 120 0C for 3 hrs. POCl3 was removed under reduced pressure and the residue taken in water and neutralized with solid sodium bicarbonate. The resulting solids were filtered and collected then dried. A pale yellow solid (0.98 g, 99%) was recovered as desired product. EIMS 303.0 [M+H]+.
Step S
8-Methoxy-4-methyl-3-trifluoromethyl-2,5,9,9b-tetraazM-cyclopenta[a]naphthalene
4-Chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (Scheme 6, step 4) (0.2 g, 0.66 mmol) was dissolved in dry dioxane (4 mL). To this was added Pd(PPh3 )4 (0.012 g, 5%mol) followed by trimethylaluminum (2 M/toluene) (1.6 mL, 3.3 mmol). The reaction was heated to 110 0C for 2 hrs, then cooled in an ice bath. Dilute HCl (2 mL) was slowly added followed by dilute sodium hydroxide (4 mL). The reaction was extracted with ethyl acetate and the organic layers separated and combined. The combined extracts were washed with water then brined and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The crude was purified using flash chromatography on silica gel in hexane/ ethyl acetate 10 : L A white solid (0.12 g, 60%) was recovered as desired product. EIMS 283.0 [M+H]+.
Step 6 l-Bromo-8-methoxy-4-methyl-3-trifluoromethyl-2,5,9,9b-tetraaz(i-cyclopenta[a]naphthalene
8-Methoxy-4-methyl-3-trifluoromethyl-2,5,9,9b-tetraazacyclopenta[a]naphthalene (Scheme 6, step 5, step 5) (0.12 g, 0.42 mmol) was suspended in acetonitrile (4 mL). N-bromosuccinimide
(0.11 g, 0.6 mmol) was then added and the reaction protected from light and stirred for 16 hrs at room temperature. The reaction was then poured into aqueous sodium sulfite and extracted with ethyl acetate 2x. The organic layers were separated and combined then washed with water, brined and dried over MgSO4. The solution was filtered and removed of solvent under reduced pressure. The crude was purified using flash chromatography on silica gel in hexane/ ethyl acetate 10:2. A white solid (0.07 g, 45%) was recovered as desired product. EIMS 361.0 [M+H]+.
Step 7
2-Methoxy-9-(4-methoxypyridin-3-yl)-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine
2-Methoxy-9-(4-methoxypyridin-3-yl)-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2-e]pyrazine was synthesized in a manner similar to Example 12, starting with l-bromo-8-
methoxy-4-methyl-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (0.12 g, 0.33 mmol) (Scheme 6, step 6) and 4-methoxy-5-pyridineboronic acid (0.18 g, 1.0 mmol) The crude was purified by flash chromatography on silica gel in ethyl acetate. A white solid was recovered (0.04 g) 31 % yield. MS (ES) m/z 390.1 [M+ 1]+
Example 35
9-(2,5-Dichlorophenyl)-2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine
9-(2,5-Dichlorophenyl)-2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with l-bromo-8-methoxy-4- methyl-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (0.12 g, 0.33 mmol) and 2,5- dichlorophenylboronic acid (0.22 g, 1.0 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2 : 1. A white solid was recovered (0.06 g) 45% yield. MS (ES) m/z 427.0 [M+l]+
Example 36
4-Fluoro-3-[2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-9- yljbenzamide
4-Fluoro-3-[2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-9- yl]benzamide was synthesized in a manner similar to Example 12, starting with l-bromo-8-methoxy- 4-methyl-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (0.12 g, 0.33 mmol) and [5- carbamoyl-2-fluorophenyl]boronic acid (0.14 g, 0.66 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.08 g) 58% yield. MS (ES) m/z 420.1 [M+l]+
Example 37
2-Methoxy-6-methyl-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine
2-Methoxy-6-methyl-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l ,5- a]pyrido[3,2- e]pyrazine was synthesized in a manner similar to Example 12, starting with l-bromo-8-methoxy-4- methyl-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (Example 33, step 6) (0.12 g, 0.33 mmol) and 2-methylphenylboronic acid (0.16 g, 0.1 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.04 g) 32% yield. MS (ES) m/z 373.1 [M+ 1]+
Scheme 7 shows a synthetic method that was used in the preparation of Examples 38-39.
Scheme 7
Scheme 6
R = 2-methylphenyl
Example 38 2-Methoxy-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5-fl]pyrido[3,2-e]pyrazin-6-amine
Step l l-Bromo-4-ch loro-8-meth oxy-3-trifluorom ethyl-2, 5, 9, 9b-tetraaza-cyclopen ta[a]n aph th alen e
4-Chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraazacyclopenta[a]naphthalene (Scheme 6, , Step 4) (0.10 g, 0.33 mmol) was suspended in acetonitrile (3 niL). N-bromosuccinimide (0.09 g, 0.5 mmol) was then added and the reaction protected from light and stirred for 16 hrs at room temperature. The reaction was then poured into aqueous sodium sulfite and extracted with ethyl acetate 2x. The organic layers were separated and combined then washed with water, brine and dried over MgSO4. The solution was filtered and solvent was removed under reduced pressure. A white solid (0.1 g, 79%) was recovered as desired product. EIMS 380.0 [M+H]+.
Step 2 l-Bromo-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaz(i-cyclopenta[a]naphthalen-4-ylamine l-Bromo-4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene (Scheme 7, Step 1) (0.50 g, 1.3 mmol) was suspended in dioxane (3 mL). Ammonia 7M/methanol (3 mL) was then added and the reaction sealed and heated to 50 0C overnight. The reaction was let cool the filtered and the solids collected. A white solid (0.1 g, 20%) was recovered as desired product. EIMS 362.0 [M+H]+.
Step 3
2-Methoxy-7-methyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6-amine
2-Methoxy-7-methyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6-amine was synthesized in a manner similar to Example 12, starting with l-bromo-8-methoxy-3-trifluoromethyl- 2,5,9,9b-tetraaza-cyclopenta[a]naphthalen-4-ylamine (0.10 g, 0.27 mmol) (scheme 7 step 2) and 2- methylphenylboronic acid (0.11 g, 0.8 mmol) The crude was purified by flash chromatography on silica gel in hexane/ethyl acetate 2:1. A white solid was recovered (0.06 g) 59% yield. MS (ES) m/z 374.1 [M+ 1]+
Example 39 N-[2-Methoxy-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl] methanesulf onamide
6-Chloro-2-methoxy-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2- e]pyrazine (Scheme 7, step 2) (0.14 g, 0.37 mmol) was suspended in pyridine (3 mL). To this was added methylsulfonyl chloride (0.09 mL, 1.1 mmol). The reaction was sealed and heated to 50 0C overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated and washed with dilute HCl then water, brined and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in hexane/ ethyl acetate 2:1. A yellow solid was recovered (0.01 g) 6% yield. MS (ES) m/z 452.0 [M+l].
Scheme 8 shows a synthetic method that was used in the preparation of Example 40.
Scheme 8
[C] [D] [E]
Example 40 9-(2,5-Dichlorophenyl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile
Step 1
6-Methoxy-2-(4-methyl-lH-imidazol-l-yl)-3-nitropyridine
To a N,N-dimethylformamide (500 mL) solution of 4-methylimidazole (8.5 g, 103 mmol) was added freshly powdered KOH (6.72 g, 120 mmol) in two portions under N2 at 0 0C, followed by addition of 2-chloro-6-methoxy-3-nitropyridine (18.9 g, 100 mmol). The resulting solution was warmed to room temperature and stirred for 2 hours. Majority of solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate three times. The organic layer was combined and washed two more times with water to remove additional Λ^Λ^-dimethylformamide and dried over magnesium sulfate. Solvent was evaporated under vacuum and the residue was purified by column (15-25% gradient eluent of ethyl acetate in dichloromethane) to provide a yellow oil (21.9 g, 93% yield) which becomes yellow solid after standing on bench. The ratio of two regioisomers was determined by NOE studies of intermediate B.
Step 2 6-Methoxy-2-(4-methyl-lH-imidazol-l-yl)pyridin-3-amine
To a mixture of 6-methoxy-2-(4-methyl-lH-imidazol-l-yl)-3-nitropyridine (21.4 g, 91.5 mmol) and 10% Pd/C (5.12 g, 4.58 mmol) in a 1 L RB flask (connected with a condenser) was loaded 240 mL THF, followed by slow addition of 240 mL MeOH under N2 with stirring. HCOONH4 (34.75 g, 503.25 mmol) was added in two portions into the stirring mixture and the final mixture was stirred at room temperature for 10 min (gas released) and then warmed to 50 0C for 1 hr. The reaction was cooled to room temperature and filtered through celite. Solvent was evaporated under vacuum to dryness to provide clean product as an off-white powder (18.6 g, 99% yield). NMR indicated a 4 : 1 ratio mixture of two regioisomers with the major one as the desired regioisomer (confirmed by NOE studies).
Step 3 2-Methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6(5H)-one
A mixture of 6-methoxy-2-(4-methyl-lH-imidazol-l-yl)pyridin-3-amine (8.56 g, 41.8 mmol) and urea (35.8 g, 596.7 mmol) was heated to 140 0C for 10 min (solid melted) and then heated to 160 0C for 2 hours. Glacial acetic acid (6 mL) was added and stirred at 120 0C for additional 2 hours before cooling to 70 0C. 80 mL water was added and the mixture was stirred at 70 0C for 30 min, then agitation was stopped. The precipitate was filtered and washed with water (2 x 25 mL) and dried in oven overnight to provide an off-white solid (3.2 g, 33% yield). NMR indicated some acyclic byproduct presented.
Step 4 6-Chloro-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine
A suspension of 2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (1.6 g, 6.8 mmol) in 20 mL POCI3 was stirred at 108 0C for 5 hours, then cooled to room temperature. POCI3
was removed using toluene as co-solvent (2 x 50 mL) under vacuum. The residue was added water and dichloromethane. The mixture was agitated for 15 min. The aqueous phase was extracted with dichloromethane and the organic layer was washed with brine and dried over magnesium sulfate. Evaporation under vacuum to dryness provided clean product as an offwhite solid (280 mg, —20% yield).
Step 5 2-Methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile
To a suspension of 6-chloro-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine (1.0 g, 4.27 mmol)in 10 mL DMSO was added tetramethylammonium cyanide (1.2 g, 4.17 mmol) under N2 at 0 0C. The resulting mixture was stirred at 75 0C for 2 hours. The mixture was poured into water extracted with chloroform. The organic phase was dried over magnesium sulfate. Evaporation under vacuum and purification by ISCO (20% ethyl acetate in dichloromethane) provided the product as a yellow solid (965 mg).
Step 6 9-Bromo-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile
To a mixture of 2-methoxy-7-methylimidazo[l,5-α]pyrido[3,2-e]pyrazine-6-carbonitrile (800 mg, 3.48 mmol) and NBS (619 mg, 3.48 mmol) was added anhydrous CH3CN (20 mL) under N2. The resulting solution was stirred in dark for 24 hours. The reaction was concentrated to dryness and the residue was dissolved in 30 mL ethyl acetate. The solution was washed twice with brine (2 x 30 mL), saturated Na2SO3 solution (20 mL) and brine (20 mL). All aqueous phase were combined and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and dried over magnesium sulfate. Evaporation under vacuum and purification by ISCO (20% ethyl acetate in dichloromethane) provided the product as a yellow solid (860 mg).
Example 40
A flask containing the mixture of 9-bromo-2-methoxy-7-methylimidazo[l,5-α]pyrido[3,2- e]pyrazine-6-carbonitrile, 200 mg, 0.65 mmol), 2,5-dichlorophenylboronic acid (123 mg, 0.65 mmol), K2CO3 (267 mg, 1.94 mmol) and Pd(PPh3 )4 ( 15 mg, 0.013 mmol) was vacuumed and refilled with nitrogen, followed by the addition of dioxane and H2O (V/V 3:1). The final mixture was stirred at 90 0C for 1 hour and cooled to room temperature. The reaction was quenched with saturated NH4CI, extracted with ethyl acetate. Organic solution was washed with brine and dried over magnesium sulfate. Column chromatography using 20% ethyl acetate in dichloromethane as eluent provided the desired coupling product as a white solid (102 mg).
Scheme 9 shows a synthetic method that was used in the preparation of Examples 41-45.
Scheme 9
Example 41
6-Chloro-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
4-Methyl-2-(3,3,3-trifluoropropyl)-lH-imidazole A solution of 4,4,4-trifluorobutanal (6.3 g, 50 mmol) in ethanol (25 niL) was treated with ammonium hydroxide (30%, 25 mL) and heated to 55 0C. 2-Oxopropanal (40% in H2O, 11.25 g, 62.5 mmol) was added dropwise and the resulting mixture was stirred at 60 0C overnight. The reaction mixture was poured into water, extracted with ethyl acetate and dried over magnesium sulfate. Column purification using ethyl acetate as eluent provided the product as a yellow solid (5.8 g, 65% yield). EIMS 179.1 [M+H]+.
Step 2 6-Methoxy-2-(4-methyl-2-(3,3,3-trifluoropropyl)-lH-imidazol-l-yl)-3-nitropyridine
To a solution of 4-methyl-2-(3,3,3-trifluoropropyl)-lH-imidazole (1 g, 5.6 mmol) in DMF (25 mL) was added freshly powdered KOH (366 mg, 6.54 mmol) at 0 0C under nitrogen, followed by addition of 2-chloro-6-methoxy-3-nitropyridine (1.03 g, 5.45 mmol). The resulting brown solution was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was extracted with ethyl acetate, washed with brine and dried over MgSO4. Column purification using 10-25% ethyl acetate in hexane as eluent provided the product as a yellow powder (1.46 g, 82% yield). EIMS 331.0 [M+H]+.
Step 3 6-Methoxy-2-(4-methyl-2-(3,3,3-trifluoropropyl)-lH-imidazol-l-yl)pyridin-3-amine
To a mixture of 6-methoxy-2-(4-methyl-2-(3,3,3-trifluoropropyl)-lH-imidazol-l-yl)-3- nitropyridine (8.1 g, 24.5 mmol) and 10% Pd/C (1.38 g, 1.22 mmol) in a 250 mL RB flask (connected with a condenser) was loaded 80 mL THF, followed by slow addition of 80 mL MeOH with stirring. HCOONH4 (9.31 g, 134.75 mmol) was added in three portions into the stirring mixture and the final mixture was stirred at room temperature for 10 min (gas released) and then warmed to 50 0C for 1 hr. The reaction was cooled to room temperature and filtered through celite. Solvent was evaporated by rotovap and the residue was partitioned between water (—100 mL) and ethyl acetate (—150 mL).
Aqueous phase was extracted with ethyl acetate (3 X 50 mL). The combined organic phase was dried over MgSO4. Solvent was evaporated to provide clean product as an offwhite powder (7.22 g, 98% yield). EIMS 301.0 [M+H]+.
Step 4
2-Methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6(5H)-one
A mixture of 6-methoxy-2-(4-methyl-2-(3,3,3-trifluoropropyl)-lH-imidazol-l-yl)pyridin-3- amine (6.87 g, 22.9 mmol) and urea (19.8 g, 330 mmol) was heated to 160 0C for 4 hours, then 5 mL of glacial acetic acid was added. The mixture was stirred at 120 0C for additional 2 hours, cooled to 70 0C and added 100 mL water. Stirring was continued for 30 minutes and the reaction was cooled to room temperature overnight. The precipitate was collected and washed with water (2 x 25 mL), dried in oven for 2 hours. The product was obtained as an off-white solid (6.9 g, 92% yield). EIMS 327.1 [M+H]+.
Step 5
6-Chloro-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
A mixture of 2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-6(5H)-one (6.9 g, 21.1 mmol) in 40 mL OfPOCl3 was refluxed at 120 0C for 4 hours, then cooled to room temperature. The solvent was removed under vacuum. Cold water was added very slowly, followed by addition of dichlorom ethane. The mixture was stirred for 15 minutes and extracted with dichloromethane, dried over magnesium sulfate. Column purification using 10-20% ethyl acetate in dichloromethane as eluent provided the product as an off-white powder (4.93 g, 68% yield). EIMS 345.0 [M+H]+.
Example 42
2-Methoxy-6,7-dimethyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
To a solution of 6-Chloro-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5- a]pyrido[3,2-e]pyrazine (172 mg, 0.5 mmol) in tetrahydrofuran (3 niL) was added MeMgBr (3.0 M in ethyl ether, 0.6 mL, 2.0 mmol) dropwise at 0 0C. The resulting solution was stirred at room temperature overnight. The mixture was cooled to 0 0C and quenched with saturated NH4CI aqueous solution very carefully. Extraction with dichloromethane and column purification using 50% ethyl acetate in hexane as eluent provided the product as a yellow powder (145 mg, 90% yield). EIMS 325.0 [M+H]+.
Example 43 6-Azetidin-l-yl-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2- e]pyrazine
To a suspension of 6-Chloro-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5- a]pyrido[3,2-e]pyrazine (172 mg, 0.5 mmol) in 1 mL of ethanol was added azetidine (0.1 mL, 1.5 mmol) at room temperature. The resulting mixture was stirred under microwave (150 0C) for 10 minutes. Solvent was removed under vacuum. Column purification using 20% ethyl acetate in dichloromethane as eluent provided the product as a white powder (146 mg, 80% yield). EIMS 366.1 [M+H]+.
Example 44 2-Methoxy-7-methyl-9-(3,3,3-trifluor opropyl)imidazo [1,5-a] pyrido [3,2-e] pyrazin-6-amine
To a mixture of 6-Chloro-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5- a]pyrido[3,2-e]pyrazine (1.78 g, 5.1 mmol) in ethanol (12 mL) was added ammonium in methanol (7 N, 12 mL) quickly. The resulting mixture was stirred in a sealed tube at 100 0C for 3 days, cooled to room temperature. The precipitate was collected to provide clean product as an off-white powder (1.33 g, 80% yield). EIMS 326.1 [M+H]+.
Example 45
Λ/-[2-Methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl] methanesulf onamide To a mixture of 2-Methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-6-amine (1.31 g, 4.0 mmol) in pyridine (30 mL) was added MeSC^Cl (1.0 mL, 12.0 mmol). The resulting mixture was stirred at 40 0C for 2 days. Pyridine was removed under vacuum. The residue was dissolved in dichloromethane and water, extracted with dichloromethane, dried over magnesium sulfate. Column purification using 10-25% ethyl acetate in dichloromethane as eluent provided the desired product as an off-white powder (700 mg, 44%). EIMS 404.1 [M+H]+.
Example 46 6,7-Dimethyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one
To a solution of 2-methoxy-6,7-dimethyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine (270 mg, 1 mmol) in 4 niL of dichloromethane was added BBr3 (0.48 niL, 5 mmol) dropwise at 0 0C, then slowly warmed to 40 0C for 1 hour and refluxed at 50 0C for another 1 hour. The reaction was added K2CO3 aqueous solution at 0 0C. Solvent was removed under vacuum and the residue was purified by column using 5% methanol in dichloromethane as eluent to provide the product as a white powder (100 mg, 40% yield). EIMS 257.1 [M+H]+.
General Experimental for Suzuki Coupling
A vial or RB flask containing the mixture of bromide 5B (I equivalent), aryl boronic acid (1.5-2 equivalent), K2CO3 (3 equivalent) and Pd(PPh3)4 (0.05 equivalent) was vacuumed and refilled with nitrogen, followed by the addition of dioxane and H2O (concentration = 0.05 molar, V/V 3:1). The final mixture was stirred at 90 0C for 1—4 hours and cooled to room temperature. The reaction was quenched with saturated NH4CI, extracted with ethyl acetate. Organic solution was washed with brine and dried over magnesium sulfate. Column chromatography using 20-50% ethyl acetate in dichloromethane as eluent provided the desired coupling product.
Example 47
9-(2,5-Dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (800 mg, 2.61 mmol), 2,5-dichlorophenylboronic acid (600 mg, 3.14 mmol), K2CO3 (1.08 g, 7.83 mmol) and Pd(PPh3 )4 (60 mg, 0.0522 mmol) provided the coupling product as a white powder (770 mg, 80% yield). EIMS 372.8 [M+H]+.
Example 48 9-(3-Chlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (60 mg, 0.19 mmol), 3-chlorophenylboronic acid (33.8 mg, 0.21 mmol), K2CO3 (80 mg, 0.57 mmol) and Pd(PPh3)4 (11.6 mg, 0.01 mmol) provided the coupling product as a white powder (41 mg, 64% yield). EIMS 338.9 [M+H]+.
Example 49 2-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-cyanophenylboronic acid (63.2 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and
Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the hydrolyzed product as a yellow powder (45 mg, 33% yield). EIMS 348.1 [M+H]+.
Example 50 2-Methoxy-6,7-dimethyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-methylphenylboronic acid (58.5 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and
Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as a yellow powder (122 mg, 98% yield). EIMS 319.1 [M+H]+.
Example 51
2-Methoxy-6,7-dimethyl-9-[2-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-trifluoromethylphenylboronic acid (81.7 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (142 mg, 98% yield). EIMS 373.1 [M+H]+.
Example 52 2-Methoxy-9-(2-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-methoxyphenylboronic acid (65.3 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (130 mg, 100% yield). EIMS 335.1 [M+H]+.
Example 53
2-Methoxy-6,7-dimethyl-9-[2-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-trifluoromethoxyphenylboronic acid (88.5 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (143 mg, 95% yield). EIMS 389.1 [M+H]+.
Example 54 9-(2-Isopropoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-isopropoxyphenylboronic acid (77.4 mg, 0.43 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (140 mg, 99% yield). EIMS 363.2 [M+H]+.
Example 55 2-Methoxy-9-(4-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 4-methoxyphenylboronic acid (54.7 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3 )4 (18.5 mg, 0.016 mmol) provided the coupling product as an off-white powder (82 mg, 77% yield). EIMS 335.2 [M+H]+.
Example 56
2-Methoxy-6,7-dimethyl-9-(3-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 3-thienylboronic acid (62 mg, 0.48 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3)4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (90 mg, 75% yield). EIMS 311.1 [M+FTJ+.
Example 57 2-Methoxy-6,7-dimethyl-9-(3-methyl-2-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 3-methyl-2-thienylboronic acid (68 mg, 0.48 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (74 mg, 59% yield). EIMS 325.1 [M+H]+.
Example 58 9-(3-Furyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 3-furylboronic acid (54 mg, 0.48 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3)4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (68 mg, 60% yield). EIMS 295.1 [M+H]+.
Example 59 2-Methoxy-6,7-dimethyl-9-(4-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 4-methylphenylboronic acid (49 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3 )4 (18.5 mg, 0.016 mmol) provided the coupling product as an off-white powder (77 mg, 75% yield). EIMS 319.2 [M+H]+.
Example 60 9-(2-Furyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 2-furylboronic acid (54 mg, 0.48 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3)4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (89 mg, 77% yield). EIMS 295.1 [M+H]+.
Example 61 9-(3,5-Dimethylisoxazol-4-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (120 mg, 0.39 mmol), 3,5-dimethylisoxazolboronic acid (68 mg, 0.48 mmol), K2CO3 (162.8 mg, 1.18 mmol) and Pd(PPh3 )4 (22.6 mg, 0.0196 mmol) provided the coupling product as an off-white powder (30 mg, 24% yield). EIMS 324.1 [M+H]+.
Example 62
2-Methoxy-9-(3-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 3-methoxyphenylboronic acid (54.7 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3 )4 (18.5 mg, 0.016 mmol) provided the coupling product as a light yellow powder (59 mg, 55% yield). EIMS 335.2 [M+H]+.
Example 63 2-Methoxy-6,7-dimethyl-9-[3-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 3-trifluoromethoxyphenylboronic acid (74.2 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3 )4 (18.5 mg, 0.016 mmol) provided the coupling product as an off-white powder (100 mg, 80% yield). EIMS 389.2 [M+H]+.
Example 64 2-Methoxy-6,7-dimethyl-9-[4-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 4-trifluoromethoxyphenylboronic acid (74.2 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol)
and Pd(PPh3 )4 (18.5 mg, 0.016 mmol) provided the coupling product as a light yellow powder (82 mg, 66% yield). EIMS 389.2 [M+H]+.
Example 65 2-Methoxy-6,7-dimethyl-9-(3-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-methylphenylboronic acid (40 mg, 0.29 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4
(6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (52 mg, 63% yield).
EIMS 319.1 [M+H]+.
Example 66
2-Methoxy-6,7-dimethyl-9-[3-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-trifluoromethylphenylboronic acid (57 mg, 0.29 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (76 mg, 79% yield). EIMS 373.1 [M+H]+.
Example 67 2-Methoxy-6,7-dimethyl-9-[4-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-trifluoromethylphenylboronic acid (57 mg, 0.29 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (54 mg, 56% yield). EIMS 373.1 [M+H]+.
Example 68
2-Methoxy-6,7-dimethyl-9-(2-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 2-thienylboronic acid (46 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3)4 (7.5 mg, 0.0064 mmol) provided the coupling product as an off-white powder (58 mg, 58% yield). EIMS 311.1 [M+H]+.
Example 69 2-Methoxy-6,7-dimethyl-9-(4-methyl-3-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), 4-methyl-3-thienylboronic acid (52 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and
Pd(PPh3 )4 (7.5 mg, 0.0064 mmol) provided the coupling product as an off-white powder (68 mg, 66% yield). EIMS 325.1 [M+H]+.
Example 70
9-Biphenyl-2-yl-2-methoxy-6,7-dimethylimidazo [1,5-a] pyrido [3,2-e] pyr azine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), biphenyl-2-ylboronic acid (72 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3)4 (7.5 mg, 0.0064 mmol) provided the coupling product as an off-white powder (74 mg, 61% yield). EIMS 381.1 [M+H]+.
Example 71 9-Biphenyl-3-yl-2-methoxy-6,7-dimethylimidazo [1,5-a] pyrido [3,2-e] pyr azine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), biphenyl-3-ylboronic acid (72 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3)4
(7.5 mg, 0.0064 mmol) provided the coupling product as an off-white powder (79 mg, 65% yield).
EIMS 381.1 [M+FTJ+.
Example 72
9-Biphenyl-4-yl-2-methoxy-6,7-dimethylimidazo [1,5-a] pyrido [3,2-e] pyr azine
Following the general Suzuki coupling procedure, reaction of bromide 5B (100 mg, 0.32 mmol), biphenyl-4-ylboronic acid (72 mg, 0.36 mmol), K2CO3 (135.2 mg, 0.98 mmol) and Pd(PPh3)4 (7.5 mg, 0.0064 mmol) provided the coupling product as an off-white powder (73 mg, 60% yield).
EIMS 381.1 [M+FTJ+.
Example 73 3-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzonitrile Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-cyanophenylboronic acid (48 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (55 mg, 65% yield). EIMS 330.1 [M+FTJ+.
Example 74
4-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzonitrile
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-cyanophenylboronic acid (48 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (62 mg, 72% yield). EIMS 330.1 [M+FTJ+.
Example 75 2-Methoxy-6,7-dimethyl-9-(phenylethynyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
To a pre-dried flask was charged with bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol) and phenylacetylene (33 mg, 0.32 mmol) under nitrogen, followed by addition of Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol). The mixture was stirred at 85 0C for 2 hours and cooled to room temperature. The reaction was poured into saturated NH4CI aqueous solution, extracted with ethyl acetate and dried over magnesium sulfate. Column purification using 20-50% ethyl acetate in dichloromethane as eluent provided the coupling product as a light yellow powder (82 mg, 96% yield). EIMS 329.1 [M+H]+.
Example 76
9-[(4-Fluorophenyl)ethynyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the procedure of preparing Example 75, reaction of bromide 5B 80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 4-fluorophenylacetylene (38.4 mg, 0.32 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (40 mg, 44% yield). EIMS 347.1 [M+H]+.
Example 77 2-Methoxy-9-[(4-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 4-methoxyphenylacetylene (42.2 mg, 0.32 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (32 mg, 34% yield). EIMS 359.1 [M+H]+.
Example 78
9-(2-Chloro-5-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (60 mg, 0.196 mmol), 2-chloro-5-methylphenylboronic acid (40 mg, 0.235 mmol), K2CO3 (80 mg, 0.588 mmol) and Pd(PPh3 )4 (5 mg, 0.0039 mmol) provided the coupling product as a white powder (63 mg, 92% yield). EIMS 353.1 [M+FTJ+.
Example 79 9-(5-Chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 5-chloro-2-methylphenylboronic acid (53 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (92 mg, 100% yield). EIMS 353.1 [M+H]+.
Example 80 9-(4-Chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-chloro-2-methylphenylboronic acid (53 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (85 mg, 92% yield). EIMS 353.1 [M+H]+.
Example 81 9-(5-Fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 5-fluoro-2-methylphenylboronic acid (48 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and
Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (83 mg, 95% yield).
EIMS 337.1 [M+FTJ+.
Example 82
9-(4-Fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-fluoro-2-methylphenylboronic acid (48 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (67 mg, 77% yield).
EIMS 337.1 [M+FTJ+.
Example 83 9-(5-Fluoro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide5B (80 mg, 0.26 mmol), 5-fluoro-2-methoxyphenylboronic acid (53 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (89 mg, 98% yield). EIMS 353.1 [M+FTJ+.
Example 84
9-(5-Chloro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 5-chloro-2-methoxyphenylboronic acid (58 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (96 mg, 100% yield). EIMS 369 [M+H]+.
Example 85 4-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-aminocarbonylphenylboronic acid (52 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (76 mg, 84% yield). EIMS 348.1 [M+H]+.
Example 86
9-(4-Fluoro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-fluoro-2-methoxyphenylboronic acid (53 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and
Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (62 mg, 67% yield).
EIMS 353.1 [M+FTJ+.
Example 87
9-(3-Chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-chloro-2-methylphenylboronic acid (53 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (73 mg, 79% yield).
EIMS 353.0 [M+H]+.
Example 88 9-(3-Fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-fluoro-2-methylphenylboronic acid (48 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (65 mg, 75% yield). EIMS 337.1 [M+FTJ+.
Example 89
9-(2,3-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 2,3-dichlorophenylboronic acid (60 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (82 mg, 85% yield). EIMS 373.0 [M+H]+.
Example 90 9-(4-Chloro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-chloro-2-methoxyphenylboronic acid (58 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (78 mg, 81% yield). EIMS 369.2 [M+H]+.
Example 91
9-[4-Chloro-2-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 4-chloro-2-trifluoromethylphenylboronic acid (70 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (55 mg,
52% yield). EIMS 407.2 [M+H]+.
Example 92
9-(5-Chloro-2-thienyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 5-chloro-2-thienylboronic acid (126 mg, 0.78 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a yellow powder (75 mg, 84% yield). EIMS 345.2 [M+H]+.
Example 93 3-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-aminocarbonylphenylboronic acid (52 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a white powder (80 mg, 89% yield). EIMS 348.1 [M+FTJ+.
Example 94
2-Methoxy-9-[(3-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 3-methoxyphenylacetylene (42.2 mg, 0.32 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (78 mg, 84% yield). EIMS 359.1 [M+H]+.
Example 95 9-(Cyclohexylethynyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), cyclohexylacetylene (140 mg, 1.3 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (28 mg, 32% yield). EIMS 335.1 [M+H]+.
Example 96 9-[(2-Chlorophenyl)ethynyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 2-chlorophenylacetylene (107 mg, 0.78 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (82 mg, 87% yield). EIMS 363.1 [M+H]+.
Example 97
9-(Cyclopropylethynyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), cyclopropylacetylene (172 mg, 2.6 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (34 mg, 45% yield). EIMS 293.1 [M+H]+.
Example 98 2-Methoxy-9-[(2-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 2-methoxyphenylacetylene (42.2 mg, 0.32 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (25 mg, 27% yield). EIMS 359.1 [M+H]+.
Example 99 2-Methoxy-6,7-dimethyl-9-[(2-methylphenyl)ethynyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine
Following the procedure of preparing Example 75, reaction of bromide 5B (80 mg, 0.26 mmol), DMF (3 mL), Et3N (0.11 mL, 0.78 mmol), 2-methylphenylacetylene (37 mg, 0.32 mmol), Pd(PPh3 )2C12 (3.6 mg, 0.0052 mmol) and CuI (2 mg, 0.0104 mmol) provided the coupling product as a light yellow powder (78 mg, 88% yield). EIMS 343.1 [M+H]+.
Example 100 3-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-Λ/-methylbenzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(methylcarbamoyl)phenylboronic acid (56 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a light yellow powder (40 mg, 43% yield). EIMS 362.1 [M+H]+.
Example 101 Λ/-Ethyl-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(ethylcarbamoyl)phenylboronic acid (60 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as a light yellow powder (52 mg, 53% yield). EIMS 376.1 [M+H]+.
Example 102 Λ/-Methoxy-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(methoxycarbamoyl)phenylboronic acid (62 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (65 mg, 66% yield). EIMS 378.0 [M+H]+.
Example 103
Λ/-Isopropyl-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(isopropylcarbamoyl)phenylboronic acid (65 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (66 mg, 65% yield). EIMS 390.1 [M+H]+.
Example 104 3-(2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-ΛyV-dimethylbenzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(dimethylcarbamoyl)phenylboronic acid (60 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (98 mg, 100% yield). EIMS 376.1 [M+H]+.
Example 105 2-Methoxy-6,7-dimethyl-9-[3-(piperidin-l-ylcarbonyl)phenyl]imidazo[l,5-a]pyrido[3,2- e]pyrazine
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 3-(piperidine-l-carbonyl)phenylboronic acid (72 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (108 mg, 100% yield). EIMS 416.1 [M+H]+.
Example 106 4-Fluoro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 5-carbamoyl-2-fluorophenylboronic acid (58 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (89 mg, 93% yield). EIMS 366.1 [M+H]+.
Example 107
4-Fluoro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-Λ/- methylbenzamide
Following the general Suzuki coupling procedure, reaction of bromide 5B (80 mg, 0.26 mmol), 2-fluoro-5-(methylcarbamoyl)phenylboronic acid (62 mg, 0.32 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(PPh3 )4 (6 mg, 0.0052 mmol) provided the coupling product as an off-white powder (98 mg, 99% yield). EIMS 380.0 [M+H]+.
Examples 108-128 were prepared according to the processes described in this application or U.S. Application Serial Nos. 11/753,207 and 11/753,260.
Table 1: Examples 108-128
Examples 129-132 were prepared according to the method described in Example 47.
Table 2: Examples 129-132
The symbol u" -\ ^ »" shows the point where substituent R is attached to the tricyclic ring system
Example 133 (2-Methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)acetonitrile Scheme 11 shows a synthetic method that was used in the preparation of compounds of Example 133.
Scheme 11
MeO ' P NΛrNYV + K-2CO3" Me0 f Ni" N,"xV
CN
Following the General Experimental for Suzuki Coupling as shown in Scheme 11, the above named compound was obtained as an off-white powder. [M+H]+ 268.1 (ESI).
Examples 134-151 were prepared according to Scheme 12.
Scheme 12
9-Bromo-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one (8B)
To a mixture of substrate 5B (306 mg, 1 mmol) in 10 mL dichloroethane was added BBr3 (0.8 mL, 8 mmol) dropwise at 0 0C. The resulting mixture was stirred at 80 0C overnight and then cooled to room temperature, poured into a solution of 2 g K2CO3 in 20 mL ice water. The crude product precipitated and was filtered, which was purified by column using 5% methanol in dichloromethane as eluent to provide 160 mg (55% yield) of product 8B as a yellow powder. [M+H]+ 292.9 (ESI).
9-Bromo-2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine (9B) To a mixture of substrate 8B (160 mg, 0.54 mmol) and Cs2CO3 (266 mg, 0.82 mmol) in 5 mL
DMF was added cyclopropylmethyl bromide (0.08 mL, 0.82 mmol). The resulting mixture was warmed to 100 0C overnight, cooled to room temperature and diluted with water. Standard workup followed by column purification provided 156 mg (84% yield) of product 9B as a yellow solid. [M+H]+ 347.0 (ESI).
Table 3: Examples 134-151
The symbol „ % » shows the point where substituent R is attached to the tricyclic ring system
Examples 123 and 152-158 were prepared according to Scheme 13.
Scheme 13
152
Example 152 6,7-Dimethyl-9-o-tolylimidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one The procedure to prepare compound 8B in Scheme 12 was followed to prepare Example 152, which was isolated as a yellow powder (82% yield). [M+H]+ 305.1 (ESI).
Table 4: Examples 123 and 153-158
6,7-Dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one was prepared according to Scheme 13. It was isolated as a yellow powder. 1H NMR (400MHz, DMSO) δ ppm 10.98 (s, br, IH), 8.50 (d, IH), 8.43 (s, IH), 8.01 (d, IH), 7.33 (d, IH), 6.76 (d, IH), 2.75 (s, 3H), 2.71 (s, 3H), 2.02 (s, 3H). [M+H]+ 306.1 (ESI).
Example 160 2-Methoxy-6,7-dimethyl-9-(3-methylpyridin-4-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine
Compound was made according to Example 5. A white solid was recovered (0.06 g) 48% yield. MS (ES) m/z 320.1 [M+l]+
Example 161 2-Methoxy-9-(3-methoxypyridin-4-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine
Compound was made according to Example 5. A white solid was recovered (0.06 g) 46% yield. MS (ES) m/z 336.1 [M+l]+
Compound was made according to Example 5. A white solid was recovered (0.1 g) 80% yield. MS (ES) m/z 320.2 [M+l]+
Scheme 14 shows a synthetic method that was used in the preparation of Intermediate 1 used in the preparation of Example 163.
Scheme 14
PaIIaCIiUm(II)-CH2CI2
Intermediate 1: 2-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2Jdioxaborolan-2-yl)-pyridine
3-Bromo-2-pinnacol (Ig, 5.8 mmol) was dissolved in DMF (20 mL). To this was added potassium acetate (2g, 20.3 mmol) followed by 4,4,5,5,4',4',5',5'-octamethyl- [2,2']bi[[l,3,2]dioxaborolanyl] (1.9 g, 7.5 mmol)and [1,1- bis(diphenylphosphino)ferrocene]palladium(II) bis methylene chloride (0.47g, 10%mol). The reaction was heated to 80 0C for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and brined then dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in ethyl acetate. A greenish/black oil 0.2 g was recovered.
Example 163
2-Methoxy-6,7-dimethyl-9-(2-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine
Compound was made according to Example 5 using intermediate 1 (2-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridine).
A white solid was recovered (0.15 g) 73% yield. MS (ES) m/z 320.1 [M+l]+ 1H NMR (400 MHz, DMSO) δ ppm 8.50 (m, IH), 8.10 (d, IH), 7.75 (dxd, IH), 7.35 (m, IH), 6.15 (d, IH), 3.05 (s, IH), 2.75 (s, 3H), 2.70 (s, 3H), 2.15 (s, 3H).
Example 164 9-Bromo-2-methoxy-7-(trifluoromethyl)imidazo[l,5-fl]pyrido[3,2-e]pyrazine-6-carbonitrile.
A mixture of imidazo[l,5-α]pyrido[3,2-e]pyrazine, 9-bromo-6-chloro-2-methoxy-7- (trifluoromethyl) (5.0 g, 13.1 mmol), DMSO (100 mL) and tetraethylammonium cyanide (2.0 g, 13.1 mmol) was stirred at 75 ° C for 10 hours. The mixtrure was poured into water and extracted with CH2CI2. The organic extracts were dried over MgSO4. Evaporation and purification by ISCO (eluting solvent CH2Cl2/EtOAc 3/1) afforded 9-bromo-2-methoxy-7-(trifluoromethyl)imidazo[l,5- α]pyrido[3,2-e]pyrazine-6-carbonitrile as a yellow solid (3.85 g, 79% yield); MS m/s 317(M+)
Examples 111, 112, and 165-172 were prepared according to Example 40.
Intermediate F (9-bromo-2-methoxy-7-methylimidazo[l,5-α]pyrido[3,2-e]pyrazine-6- carbonitrile) of Scheme 7 was coupled with the corresponding boronic acids or boronic acid pinacol esters under palladium catalyzed conditions.
Table 5: Examples 111, 112, and 165-172
The symbol „" % ^ »" shows the point where substituent R is attached to the tricyclic ring system
Examples 173-191 were prepared according to Example 47.
Intermediate E (9-bromo-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine) of Scheme 9 was coupled with the corresponding boronic acids or boronic acid pinacol esters under palladium catalyzed conditions.
Table 6: Examples 173-191
The symbol " ^ " shows the point where substituent R is attached to the tricyclic ring system
Example 191 2-Methoxy-6,7-dimethyl-9-(l,3,5-trimethyl-lH-pyrazol-4-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine
1H NMR (400 MHz, DMSO) δ ppm 8.00 (d, IH), 7.85 (d, IH), 3.65 (s, 3H), 3.35 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H), 2.00 (s, 3H), 1.85 (s, 3H).
Example A
Inhibition of PDElO
Method A
Phosphodiesterase isoenzyme 10 (PDElO) activity was determined in preparations of human recombinant PDElOA and PDElO from pig striatum, respectively. The DNA of PDEl OAl (AB 020593, 2340 bp) was synthesized and cloned into the vector pCR4.TOPO (Entelechon GmbH, Regensburg, Germany). The gene was than inserted into a baculovirus vector, ligated with the baculovirus DNA. The enzyme-protein was expressed in SF21- cells. The enzyme was isolated from these cells by harvesting the cells by a centrifugation at 200 g to collect the cells. The cells were resuspended in 50 mM Tris-HCl/5 mM MgCl2 buffer (pH=7.4) and lysed by a sonication of the cells. The cytosolic PDElOA was obtained by a centrifugation at 48000 g for 1 h in the supernatant and stored at -70 0C.
Striatum from male hybrid pigs (150kg) were collected and frozen at -700C. At the day of preparation 0.5 g striatum was homogenised in 10 ml 50 mM Tris/Mg-buffer at 4°C and centrifuged for one hour at 100000 g. The supernatant was removed and the pellet was resuspended in the same buffer, but containing l%Triton and incubated for 45 min at 4°C. The membrane fraction was applied onto a 5 ml Hi TrapTM QHP column at the Akta-FPLC. After washing the column the bound PDE protein was eluted with an increasing sodium chloride gradient (0 mM-500 mM sodium chloride) in 50 mM Tris/Mg-buffer at 4°C in the presence of 1% Triton. The eluted and collected fractions were tested with 100 nM [3H]-cAMP for PDElO-activity in the presence and without a specific PDE -Inhibitor at a concentration, were a 100% inhibition is expected. The fractions with PDE 10 -activity were pooled and frozen in aliquots until use at -200C.
PDElO activity was determined in a one step procedure in microtiterplates. The reaction mixture of 100 μl contained 50 mM Tris-HCl/5 mM MgC12 buffer (pH=7.4) (Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) 0.1 μM [3H]-cAMP (Amersham, Buckinghamshire, UK) and the enzyme. Nonspecific activity was tested without the enzyme. The reaction was initiated by addition of the substrate solution and was carried out at 37 0C for 30 minutes. Enzymatic activity was
stopped by addition of 25 μl YSi-SPA-beads (Amersham-Pharmacia). One hour later the mixture was measured in a liquid scintillation counter for microtiterplates (Microbeta Trilux). To pipette the incubation mixture a robot Biomek (Fa. Beckman) is used. The determined Km-values for the substrate cAMP is 88 nM for pig striatum and 130 nM for human recombinant PDElOA respectively. The optimal amount of enzyme in the assay has been determined and optimised for each enzyme preparation before using the enzyme in compound testing. For determination of IC50 values the Hill- plot, 2-parameter-model, was used. Specific inhibitors of other PDE-Subtypes do not inhibit the PDElO preparation significantly. Papaverine was used as the most common PDElO inhibitor and inhibits the PDElO with IC50 values of 89 nM and 103 nM for PDElO from human recombinant PDE 1 OA and PDE 10 from striatum of pig respectively.
Method B
The phosphodiesterase isoenzyme 10 (PDElO) activity was determined in preparations of rat, pig and guinea pig striatum respectively. Striatum from male Wistar rats (180-200 g), male hybrid pigs (150 kg) and male guinea pigs (CRL (HA), 500 g) respectively were collected and frozen at - 700C.
At the day of preparation 0.5 g striatum was homogenized in 10 ml 50 mM Tris/Mg-buffer at 4°C and centrifuged for one hour at 100000 g. The supernatant is called the cytosolic fraction and was removed and stored on ice. The pellet was resuspended in the same buffer, but containing 1 %Triton and incubated for 45 min at 4°C. Both fractions were independently applied onto a 5ml Hi TrapTM QHP column at the Akta-FPLC. After washing the columns the bound PDE protein was eluted with an increasing sodium chloride gradient (0 mM-500 mM sodium chloride) in 50 mM Tris/Mg-buffer at 4°C for the cytosolic fraction and in the presence of 1% Triton for the membrane fraction. The eluted and collected fractions were tested with 100 nM [3H] -cAMP for PDElO-activity in the presence and without a specific PDE-Inhibitor at a concentration, were a 100% inhibition is expected. The fractions with PDE 10 -activity were pooled and frozen in aliquots until use at -200C.
The eluted fractions from the FPLC were additionally characterized by Western blot (Fig. 1).
It was shown, that the PDElOA containing pooled fractions include a great number of other proteins. Nevertheless PDElO was detected with specific antibodies by Western blot clearly. The protein was proven in the preparation of the striatum of the rat, the pig and the guinea pig. The main part of protein was found in the membrane fraction (Fig. 2).
In the prepared brain areas gene segments containing the catalytic domain of the PDE 10 were amplified and the sequence determined.
Therefore the RNA from the frozen striatum of the different animals was isolated according to the instructions of the RNeasy kit (Qiagen; Hilden; Germany) and transcribed into cDNA using Oligo-Primer provided with the 1st strand cDNA synthese kit for RT-PCR (Roche; Mannheim; Germany). These cDNA was used as template for the PCR-reaction to amplify the catalytic domain of
the PDElO. For the PCR reaction Taq-Polymerase (Promega; Mannheim; Germany) was used. Therefore it was possible to clone the amplificates directly by TA-cloning in the pCR2.1 vector (Invitrogen; Karlsruhe; Germany). The cloning vector was transformed into E.coli's (XL-2), replicated within the cells, prepared and the included gene sequence determined for the pig and the guinea pig.
The following primers were used for the PCR-reaction:
Pl : tgcatctacagggttaccatggagaa (SEQ ID NO: 1) P2: tatccctgcaggccttcagcagaggctct (SEQ ID NO: 2)
P3 : ttcacatggatatgcgacggtaccttct (SEQ ID NO: 3)
P4: ctgtgaagaagaactatcggcgggttcctta (SEQ ID NO: 4).
For the pig the priming was successful with Pl and P2. The following sequence (SEQ ID NO: 5) was identified:
tgcatctacagggttaccatggagaagctgtcctaccacagcatttgtaccgcggaagagtggcaaggcctcatgcgcttcaaccttcc cgtccgtctttgcaaggagattgaattgttccacttcgacattggtccttttgaaaacatgtggcctggaatctttgtctatatggttcatcgcttctgtggg acggcctgctttgagcttgaaaagctgtgtcgttttatcatgtctgtgaagaagaactatcgtcgggttccttaccacaactggaagcacgcggtcacg gtggcacactgcatgtacgccatcctccagaacagccacgggctcttcaccgacctcgagcgcaaaggactgctaatcgcgtgtctgtgccacga cctggaccacaggggcttcagcaacagctacctgcagaaattcgaccaccccctggccgctctctactccacgcccaccatggagcagcaccact tctcccagaccgtgtccatcctccagttggaagggcacaacatcttctccaccctgagctccagtgagtacgagcaggtgcttgagatcatccgcaa agccatcattgccacagacctcgctttgtactttggaaacaggaaacagttggaggagatgtaccagaccggatcgctaaaccttaataaccagtca catagagaccgcgtcattggtttgatgatgactgcctgtgatctctgttccgtgacaaaactgtggccagtaacaaaactgacggcaaatgatatatat gcggaattctgggccgagggcgatgaggtgaagaagctgggaatacagcctattcccatgatggacagagacaagaaggacgaagtcccacaa ggccagctcggattctacaacgcggtagctatcccctgctacaccaccctcacccagatcttcccgcccacagagcctcttctgaaggcctgcagg gata
For the guinea pig the priming was successful with P4 and P2 as well as for P2 and P3. The following sequence (SEQ ID NO: 6) was identified with P4 and P2: ctgtgaagaagaactatcggcgggttccttaccacaactggaagcatgcagtcacggtggcgcactgcatgtacgccatacttcaaaac aacaatggcctcttcacagaccttgagcgcaaaggcctgctaattgcctgtctgtgccatgacctggaccacaggggcttcagtaacagctacctgc agaaattcgaccaccccctggctgcgttgtactccacctccaccatggagcaacaccacttctcccagacggtgttcatcctccagctggaaggaca caacatcttctccaccctgagctccagcgagtacgagcaggtgctggagatcatccgcaaagccatcatcgccactgacctcgcactgtactttggg aacaggaagcagttggaggagatgtaccagacagggtcgctgaacctcaataaccagtcccatcgagaccgcgtcatcggcttgatgatgactgc ctgcgatctttgctctgtgacgaaactatggccagttacaaaattgacagcaaatgatatatatgcagagttctgggctgagggggatgagatgaaga agttggggatacagcccatccctatgatggacagagacaagaaggatgaagtccctcaaggacagcttggattctacaatgctgtggccatcccct gctataccaccctgacgcagatcctcccacccacagagcctctgctgaaggcctgcagggata
The following sequence (SEQ ID NO: 7) was identified with P2 and P3: tagagcctctgctgaaggcctgcagggataacctcaatcagtgggagaaggtaattcgaggggaagagacagcaatgtggatttcag gcccagcaactagcaaaagcacatcagggaagccgaccaggaaggtcgatgactgatcctgaggtgatgtctgcctagcaactgactcaacctg cttctgtgacttcgttctttttatttttatttttttaacggggtgaaaacctctctcagaaggtaccgtcgcatatccatgtgaa
An alignment of the sequences showed a nearly complete accordance between the rat (published gene number NM-022236 3437 bp; coding sequence: 281-2665; catalytic domain 1634- 2665) and the guinea pig. More differences were detected between rat and pig. For the alignment the coding areas are used only. The gene alignment is shown in Fig. 3.
This results in the following differences in the protein sequences within the catalytic domain as shown in a protein alignment (Fig. 4).
PDElO activity was determined in a one step procedure in microtiterplates. The reaction mixture of 100 μl contained 50 mM Tris-HCI/5 mM MgCl2 buffer (pH=7.4) (Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) 0.1 pM [3H]-cAMP (Amersham, Buckinghamshire, UK) and the enzyme. Nonspecific activity was tested without the enzyme. The reaction was initiated by addition of the substrate solution and was carried out at 37°C for 30 minutes. Enzymatic activity was stopped by addition of 25 μl YSi-SPAbeads (Amersham-Pharmacia). One hour later the mixture was measured in a liquid scintillation counter for microtiterplates (Microbeta Trilux). To pipette the incubation mixture a robot Biomek (Fa. Beckman) is used. The determined Km-values for the substrate cAMP is 78 nM for PDElO from rat striatum, 88 nM for pig striatum and 66.7 nM for guinea pig striatum respectively. cGMP is the second substrate for PDElO, the Km values are 1800 nM, 2200 nM and 1700 nM for PDElO from these species. For the test with cGMP 500 nM of this substrate was used. The optimal amount of enzyme in the assay has been determined and optimized for each enzyme preparation and substrate separately before using the enzyme in compound testing. For determination of IC50 values the Hill-plot, 2-parameter-model, was used. Specific inhibitors of other PDE-Subtypes do not inhibit the PDElO preparation significantly. Papaverine was used as the most common PDElO inhibitor and inhibits the PDElO with IC50 values of 142 nM, 110 nM and 77 nM for PDElO from striatum of rat, pig and guinea pig respectively.
See Table 7, Table 8, and Table 9 for PDElO IC50 values for select compounds of the invention.
Example B Compound Data
The compounds of formula (I) are potent inhibitors of PDElO. A substance is considered to effectively inhibit PDElO if it has an IC50 of less than 10 μM, e.g., less than 1 μM. IC50 values for select compounds are provided in Tables 7, 8, and 9, where "+" indicates that the IC50 value is less than or equal to 10 nM; "++" indicates that the IC50 value is between 10 -100 nM; and "+++" indicates that the IC50 value is equal to or greater than 100 nM.
Table 7: Analytical and assay data for select Examples
Table 8: Analytical and assay data for select Examples
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and journal literature, cited in the present application is incorporated herein by reference in its entirety.
Claims
1. A compound of Formula (I):
R1 Is:
Ci_8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C1.3 alkyl, cyano, and a cyclic radical; aryl, heteroaryl, C3_s cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Ci_3 alkylamino, nitro, C1.5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Ci_3 haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, a cyclic radical, and C3.8 cyclo(hetero)alkyl; or two adjacent O- CiJ alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group;
R2 is Ci-S alkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with halo, OH, O-Cu alkyl, or a cyclic radical;
NR6R7, (CO)OR6, (CO)NR6R7, NR5(CO)OR6, NR5(CO)R6, NR5(C=O)-NR6R7, or NR5(SO2R6), wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci-8 alkyl, O- Ci-5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl, wherein Ci-8 alkyl, O-C1.5 alkyl, C3_6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci.5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R is halo, R , or OR wherein R is: H,
Ci-S alkyl or C3.6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-Cu alkyl, C2-8 alkynyl, and a cyclic radical; aryl-Ci-5 alkyl or heteroaryl-Ci.5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is Ci-S alkyl optionally mono- or polysubstituted with halo.
3. The compound of claim 2, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is propyl optionally mono- or polysubstituted with fluoro.
4. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is C2_8 alkynyl optionally mono- or polysubstituted with a cyclic radical.
5. The compound of claim 4, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is C2 alkynyl monosubstituted with C3.8 cycloalkyl.
6. The compound of claim 5, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is C2 alkynyl monosubstituted with cyclopropyl or cyclohexyl.
7. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is C2 alkynyl monosubstituted with aryl, and said aryl is optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, O-Cu alkyl, cyano, and Cu haloalkyl.
8. The compound of claim 7, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is C2 alkynyl monosubstituted with phenyl optionally mono- or polysubstituted with substitents independently selected from fluoro, methyl, and OCH3.
9. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl or heteroaryl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, -(C=O)-NR6R7, and a cyclic radical.
10. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl optionally mono- or polysubstituted with substitents independently selected from halo, Ci-3 alkyl, O-Ci_3 alkyl, cyano, Ci-3 haloalkyl, O-Ci_3 haloalkyl, -(C=O)-NR6R7, and a cyclic radical.
11. The compound of claim 10, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with a cyclic radical.
12. The compound of claim 11, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with phenyl.
13. The compound of claim 11 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with morpholino.
14. The compound of claim 10, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with -(C=O)-NR6R7, and said R6 and R7 are independently selected from H, Ci-S alkyl, and O-Ci_5 alkyl.
15. The compound of claim 14, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with -(C=O)-NR6R7, and R6 and R7 are independently selected from H, methyl, and OCH3.
16. The compound of claim 15, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl mono-substituted with -(C=O)-NR6R7, and said R6 and R7 together with the nitrogen atom to which they are attached form a 5-6 membered cycloheteroalkyl group.
17. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO2NR6R7.
18. The compound of claim 17, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is aryl optionally mono- or polysubstituted with substitents independently selected from COOH and SO2NH2.
19. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 5- or 6-membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, Ci_5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, and a cyclic radical.
20. The compound of claim 19, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 5- or 6-membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
21. The compound of claim 19, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
22. The compound of claim 20, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 5- membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
23. The compound of claim 22, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is furan or thiophene.
24. The compound of claim 22, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyrrole or pyrazole, each optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, cyano, and Cu haloalkyl.
25. The compound of claim 24, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyrazole optionally mono- or polysubstituted with C1-5 alkyl.
26. The compound of claim 25, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyrazole mono-substituted with methyl.
27. The compound of claim 25, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyrazole polysubstituted with methyl.
28. The compound of claim 27, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is l,3,5-trimethyl-lH-pyrazole-4-yl.
29. The compound of claim 27, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 3,5-dimethyl-lH-pyrazole-4-yl.
30. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 6-membered heteroaryl optionally mono- or polysubstituted with substitents independently selected from halo, C1.5 alkyl, amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, cyano, Cu haloalkyl, and a cyclic radical.
31. The compound of claim 30, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from amino, Cu alkylamino, di-Cu alkylamino, O-Cu alkyl, and a cyclic radical.
32. The compound of claim 30, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine or pyrimidine, each optionally mono- or polysubstituted with substitents independently selected from halo, C1-5 alkyl, cyano, and Cu haloalkyl.
33. The compound of claim 32, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine optionally mono- or polysubstituted with substitents independently selected from halo and Ci-5 alkyl.
34. The compound of claim 33, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine optionally mono- or polysubstituted with substitents independently selected from fluoro, chloro, and methyl.
35. The compound of claim 33, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine mono-substituted with methyl.
36. The compound of claim 35, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is 4-methylpyridin-3-yl or 2-methylpyridin-3-yl.
37. The compound of claim 31 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R1 is pyridine optionally mono-substituted with di-methylamino, OCH3, or morpholino.
38. The compound of any one of claims 1-37, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R2 is Ci_8 alkyl optionally mono- or polysubstituted with halo.
39. The compound of claim 38, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R2 is methyl.
40. The compound of any one of claims 1-39, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R3 is Ci_8 alkyl, Ci_8 haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical.
41. The compound of claim 40, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R3 is Ci_8 alkyl or Ci_8 haloalkyl.
42. The compound of claim 41, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R3 is CH3.
43. The compound of any one of claims 1 -39, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R3 is cyano.
44. The compound of any one of claims 1 -43, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OR8, and said R8 is Ci_8 alkyl optionally mono- or polysubsituted substitents independently selected from with halo, OH, O-Ci_3 alkyl, and a cyclic radical.
45. The compound of claim 44, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OR8, and said R8 is methyl optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical.
46. The compound of claim 45, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OCH3.
47. The compound of claim 45, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OR8, and said R8 is methyl mono- or polysubsituted with cyclopropyl.
48. The compound of claim 44, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OR8, and said R8 is ethyl optionally mono- or polysubsituted with halo.
49. The compound of claim 48, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OCH2CH2F, OCH2CHF2, or OCH2CF3.
50. The compound of any one of claims 1 -43, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R4 is OR8, wherein said R8 is aryl-Ci.5 alkyl or heteroaryl-Ci.5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, and O-Ci.3 alkyl.
51. The compound of claim 50, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R8 is benzyl optionally mono- or polysubstituted with fluoro.
52. The compound of claim 50, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R8 is pyridinyl.
53. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein the compound has Formula (I):
R1 is:
Ci-S alkyl, C2_8 alkenyl, or C2_8 alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, cyano, and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci.5 alkyl, or heteroaryl-Ci.5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, C1.5 alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Cu haloalkyl, COOH, -(C=O)-NR6R7, SO2NR6R7, and a cyclic radical; or two O-Cu alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group;
R is Ci-8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
R3 is: cyano;
Ci_8 alkyl or Ci-S haloalkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C1.3 alkyl, and a cyclic radical;
(CO)NR6R7, wherein R6 and R7 are selected from H, a cyclic radical, Ci-8 alkyl, O-C1.5 alkyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and R4 is R8 or OR8, wherein R8 is Ci_8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, C2-s alkynyl, and a cyclic radical.
54. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein:
R1 is:
Ci-S alkyl, C2-s alkenyl, or C2-s alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Ci_3 alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Ci_3 haloalkyl, -(C=O)-NR6R7, and a cyclic radical; or two O-Cu alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group;
R2 is Ci-8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo and a cyclic radical;
R3 is: cyano;
Ci-8 alkyl or Ci-S haloalkyl each optionally mono- or polysubstituted with halo, OH, O-Cu alkyl, or a cyclic radical;
(CO)NR6R7, wherein R6 and R7 are selected from H, a cyclic radical, Ci-8 alkyl, O-Ci-5 alkyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R4 is R8 or OR8, wherein R8 is Ci-8 alkyl optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical.
55. The compound of claim 1 , or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein:
R1 is aryl or heteroaryl, each optionally mono- or polysubstituted with substitents independently selected from halo, Cu alkyl, and O-Cu alkyl; each of R2 and R3 is independently Ci-8 alkyl; and
R4 is Ci-8 alkyl or Q-Ci-8 alkyl.
56. A compound of Formula (I):
R1 Is:
Ci-S alkyl, C2-s alkenyl, C2-s alkynyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical; aryl, heteroaryl, C3.8 cyclo(hetero)alkyl, aryl-Ci_5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Ci_3 alkylamino, nitro, Cu alkyl, O-Cu alkyl, cyano, Cu haloalkyl, O-Ci_3 haloalkyl, -(C=O)-NR6R7, and a cyclic radical; or two adjacent O-Ci_3 alkyl groups, together with the atoms to which they are attached, form a 5-7 membered cycloheteroalkyl group; and
R2 is Ci-S alkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Cu alkyl, and a cyclic radical;
R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical;
NR6R7, (CO)OR6, (CO)NR6R7, NR5(CO)OR6, NR5(CO)R6, NR5(C=O)-NR6R7, or NR5(Sθ2R6), wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, O- Ci-5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci-5 alkyl, wherein said Ci-S alkyl, O-Ci_5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci_5 alkyl are optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-Ci_3 alkyl, and a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group; and
R4 is halo, R , or OR , wherein R8 is: H, Ci-8 alkyl or C3.6 cyclo(hetero)alkyl, each optionally mono- or polysubsituted with substitents independently selected from halo, OH, O-C1.3 alkyl, and a cyclic radical; aryl-Ci.5 alkyl or heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, amino, Cu alkylamino, di-Cu alkylamino, nitro, Cu alkyl, O-C1.3 alkyl, and a cyclic radical; or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
57. The compound of claim 56, or N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein:
R3 is: cyano;
Ci-S alkyl, Ci-S haloalkyl, C3.8 cyclo(hetero)alkyl, aryl-Ci-5 alkyl, heteroaryl-Ci_5 alkyl, each optionally mono- or polysubstituted with substitents independently selected from halo, OH, O-C1.3 alkyl, and a cyclic radical;
(CO)OR6 or (CO)NR6R7, wherein R5, R6, and R7 are independently selected from H, a cyclic radical, Ci-S alkyl, O-C1.5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci_5 alkyl, wherein Ci-S alkyl, O-C1.5 alkyl, C3.6 cycloalkyl, aryl-Ci-5 alkyl, and heteroaryl-Ci_5 alkyl are optionally mono- or polysubstituted substitents independently selected from with halo, OH, O-C1.3 alkyl, and a cyclic radical; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4-7 membered cycloheteroalkyl group.
58. The compound of claim 1 selected from: 2-ethoxy-6,7-dimethyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(2-chlorophenyl)-2-ethoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(3-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(3,5-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(3,4-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(2,4-difluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(6-fluoropyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 2-methoxy-6,7-dimethyl-9-pyridin-3-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 2-methoxy-6,7-dimethyl-9-pyridin-4-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 9-(2-chloro-4-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 9-(4-chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 9-(2-fluoro-4-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 9-(2-fluoro-3-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 9-(2-chloro-4-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 9-(4-chloro-2-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(2-chloro-4-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(2-chloro-5-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[ 1 ,5-a]pyrido[3,2- e]pyrazine;
9-[2-chloro-4-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine;
9-(2-fluoro-5-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(2-chloro-5-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-[2-chloro-5-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine;
9-[2-chloro-5-(trifluoromethoxy)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine;
4-chloro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl)benzonitrile;
9-(2-chloro-5-ethoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-6,7-dimethyl-9-pyrimidin-5-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-9-(6-methoxypyridin-3 -yl)-6,7-dimethylimidazo[ 1 ,5 -a]pyrido [3 ,2- e]pyrazine;
2-methoxy-9-(2-methoxypyridin-3 -yl)-6,7-dimethylimidazo[ 1 ,5 -a]pyrido [3 ,2- e]pyrazine;
2-methoxy-9-(4-methoxypyridin-3 -yl)-6,7-dimethylimidazo[ 1 ,5 -a]pyrido [3 ,2- e]pyrazine;
9-(6-fluoro-2-methylpyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5- a]pyrido[3,2- e]pyrazine;
2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(6-fluoro-5-methylpyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-α]pyrido[3,2- e]pyrazine;
2-methoxy-9-(4-methoxypyridin-3-yl)-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2-e]pyrazine;
9-(2,5-dichlorophenyl)-2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine;
4-fluoro-3-[2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-9- yl]benzamide;
2-methoxy-6-methyl-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5- a]pyrido[3,2- e]pyrazine;
2-methoxy-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5-α]pyrido[3,2-e]pyrazin-6- amine;
N-[2-methoxy-9-(2-methylphenyl)-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl]methanesulfonamide;
9-(2,5-dichlorophenyl)-2-methoxy-7-methylimidazo[l,5-α]pyrido[3,2-e]pyrazine-6- carbonitrile;
2-methoxy-6,7-dimethyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine; 6-azetidin-l-yl-2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6-amine;
N-[2-methoxy-7-methyl-9-(3,3,3-trifluoropropyl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl]methanesulfonamide;
4-fluoro-3-[2-methoxy-6-methyl-7-(trifluoromethyl)imidazo[l,5-a]pyrido[3,2- e]pyrazin-9- yl]benzamide;
9-(2,5-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3-chlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
2-methoxy-6,7-dimethyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[2-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-9-(2-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[2-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2-isopropoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-9-(4-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(3-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(3-methyl-2-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3-fιuyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(4-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2-fιuyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3,5-dimethylisoxazol-4-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-9-(3-methoxyphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[3-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[4-(trifluoromethoxy)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(3-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[3-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[4-(trifluoromethyl)phenyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(2-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(4-methyl-3-thienyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-biphenyl-2-yl-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-biphenyl-3 -yl-2-methoxy-6,7-dimethylimidazo[ 1 ,5 -a]pyrido [3 ,2-e]pyrazine;
9-biphenyl-4-yl-2-methoxy-6,7-dimethylimidazo[ 1 ,5 -a]pyrido [3 ,2-e]pyrazine;
3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzonitrile;
4-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzonitrile;
2-methoxy-6,7-dimethyl-9-(phenylethynyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9- [(4-fluorophenyl)ethynyl] -2-methoxy-6,7-dimethylimidazo [ 1 ,5 -a]pyrido [3 ,2-e]pyrazine; 2-methoxy-9-[(4-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2-chloro-5-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(5-chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(4-chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(5-fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(4-fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(5-fluoro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(5 -chloro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo [ 1 ,5-a]pyrido [3 ,2-e]pyrazine;
4-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
9-(4-fluoro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3-chloro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3-fluoro-2-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2,3-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(4-chloro-2-methoxyphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-[4-chloro-2-(trifluoromethyl)phenyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(5-chloro-2-thienyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
2-methoxy-9-[(3-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(cyclohexylethynyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-[(2-chlorophenyl)ethynyl]-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(cyclopropylethynyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-9-[(2-methoxyphenyl)ethynyl]-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[(2-methylphenyl)ethynyl]imidazo[l,5-a]pyrido[3,2-e]pyrazine;
3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-Λ^-methylbenzamide;
Λ^-ethyl-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
Λ^-methoxy-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
Λ^-isopropyl-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-ΛyV- dimethylbenzamide;
2-methoxy-6,7-dimethyl-9-[3-(piperidin-l-ylcarbonyl)phenyl]imidazo[l,5-a]pyrido[3,2- e]pyrazine;
4-fluoro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
4-fluoro-3-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-JV- methylbenzamide;
N-(9-cyclohexyl-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl)methanesulfonamide; 2-methoxy-7-methyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carboxamide;
9-cyclohexyl-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile;
9-(2-chlorophenyl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile;
9-(2,4-dichlorophenyl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6- carbonitrile;
9-(2,4-dichlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-benzyl-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
4-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-3,5-dimethylisoxazole;
9-(2-fluoro-3-methylphenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
6-(difluoromethyl)-2-methoxy-7-methyl-9-propylimidazo[ 1 ,5 -a]pyrido [3 ,2-e]pyrazine;
9-(benzo[d][l,3]dioxol-5-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
N-(9-cyclohexyl-2-(cyclopropylmethoxy)-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl)methanesulfonamide;
9-(2-fluorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
N-(9-(2-fluorophenyl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl)methanesulfonamide;
N-(9-cyclohexyl-2-(cyclopropylmethoxy)-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6-yl)- N-(cyclopropylmethyl)methanesulfonamide;
2-(cyclopropylmethoxy)-6,7-dimethyl-9-o-tolylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2-chlorophenyl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-propylimidazo[l,5-a]pyrido[3,2-e]pyrazine 8-oxide; and
N-(9-cyclohexyl-7-methyl-2 -oxo-1, 2-dihydroimidazo[l,5-a]pyrido[3,2-e]pyrazin-6- yl)methanesulfonamide;
9-cyclohexyl-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6-amine; and
9-(2-chlorophenyl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazin-6-amine, or N-oxide thereof, or pharmaceutically acceptable salts thereof.
59. The compound of claim 1 selected from:
3-fluoro-5-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
2-fluoro-5-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
2-chloro-5-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
2-chloro-4-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)benzamide;
(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)acetonitrile;
9-(5-chloro-2-methylphenyl)-2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-(cyclopropylmethoxy)-9-(4-fluoro-2-methylphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine; 2-(cyclopropylmethoxy)-9-(3-fluoro-2-methylphenyl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-[4-chloro-2-(trifluoromethyl)phenyl]-2-(cyclopropylmethoxy)-6,7- dimethylimidazo[l,5- a]pyrido[3,2-e]pyrazine;
9-(2-chloro-4-fluorophenyl)-2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-(cyclopropylmethoxy)-9-(6-methoxypyridin-3-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-(cyclopropylmethoxy)-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-(cyclopropylmethoxy)-9-(6-fluoro-2-methylpyridin-3-yl)-6,7- dimethylimidazo[ 1 ,5- a]pyrido[3,2-e]pyrazine;
4-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl]benzamide;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl]benzamide;
5-(2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-2- fluorobenzamide;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]- 5- fluorobenzamide;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]- 4- methylbenzoic acid;
4-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]-3- methylbenzoic acid;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9- yl]benzenesulfonamide;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]- 4- methylbenzamide;
4-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]-3- methylbenzamide;
3-[2-(cyclopropylmethoxy)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl]- 4- fluorobenzamide;
6,7-dimethyl-9-o-tolylimidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one;
2-(2,2-difluoroethoxy)-6,7-dimethyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-(2-fluoroethoxy)-6,7-dimethyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
6,7-dimethyl-9-(2-methylphenyl)-2-(2,2,2-trifluoroethoxy)imidazo[l,5-e]pyrazine;
6,7-dimethyl-9-(2-methylphenyl)-2-(prop-2-yn-l-yloxy)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-[(4-fluorobenzyl)oxy]-6,7-dimethyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2- e]pyrazine; 6,7-dimethyl-9-(2-methylphenyl)-2-(pyridin-4-ylmethoxy)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
6,7-Dimethyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazin-2(lH)-one;
2-methoxy-6,7-dimethyl-9-(3-methylpyridin-4-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-9-(3-methoxypyridin-4-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-6,7-dimethyl-9-(6-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-6,7-dimethyl-9-(2-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-Bromo-2-methoxy-7-(trifluoromethyl)imidazo[l,5-α]pyrido[3,2-e]pyrazine-6-carbonitrile;.
2-methoxy-7-methyl-9-(2-methylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile;
3-(6-cyano-2-methoxy-7-methylimidazo [ 1 ,5 -a]pyrido [3 ,2-e]pyrazin-9-yl)-4-fluorobenzamide;
3-(6-cyano-2-methoxy-7-methylimidazo [ 1 ,5 -a]pyrido [3 ,2-e]pyrazin-9-yl)benzamide;
5-(6-cyano-2-methoxy-7-methylimidazo [ 1 ,5 -a]pyrido [3 ,2-e]pyrazin-9-yl)-2-fluorobenzamide;
2-methoxy-7-methyl-9-(4-methylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine-6- carbonitrile;
2-methoxy-7-methyl-9-pyridin-4-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile;
2-methoxy-7-methyl-9-pyridin-3-ylimidazo[l,5-a]pyrido[3,2-e]pyrazine-6-carbonitrile;
9-(6-fluoro-2-methylpyridin-3-yl)-2-methoxy-7-methylimidazo[l,5-a]pyrido[3,2-e]pyrazine- 6-carbonitrile;
9-(3,5-dimethyl-lH-pyrazol-4-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2- e]pyrazine;
9-(2-fluoropyridin-4-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(2-fluoropyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(3-chloropyridin-4-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(lH-indol-5-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
5-(2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazin-9-yl)-N,N-dimethylpyridin-2- amine;
2-methoxy-6,7-dimethyl-9-(lH-pyrazol-4-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(l-methyl-lH-pyrazol-4-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-( 1 H-pyrrol-3 -yl)imidazo [ 1 ,5-a]pyrido [3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[l-(2-methylpropyl)-lH-pyrazol-4-yl]imidazo[l,5-yl}imidazo[l,5- a]pyrido[3,2-e]pyrazine;
9-(2,4-dimethyl- 1 ,3-thiazol-5-yl)-2-methoxy-6,7-dimethylimidazo[ 1 ,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-9-(5-methoxypyridin-3-yl)-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(l-methyl-lH-pyrrol-2-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
9-(4-chloropyridin-3-yl)-2-methoxy-6,7-dimethylimidazo[l,5-a]pyrido[3,2-e]pyrazine; 2-methoxy-6,7-dimethyl-9-(6-moφholin-4-ylpyridin-3-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine;
2-methoxy-6,7-dimethyl-9-(3-moφholin-4-ylphenyl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-(l-propyl-lH-pyrazol-4-yl)imidazo[l,5-a]pyrido[3,2-e]pyrazine;
2-methoxy-6,7-dimethyl-9-[l-(2-moφholin-4-ylethyl)-lH-pyrazol-4-yl]imidazo[l,5- a]pyrido[3,2-e]pyrazine; and
2-methoxy-6,7-dimethyl-9-(l,3,5-trimethyl-lH-pyrazol-4-yl)imidazo[l,5-a]pyrido[3,2- e]pyrazine; or N-oxide thereof, or pharmaceutically acceptable salt thereof.
60. A pharmaceutical composition comprising a compound of any one of claims 1 to 59, or N- oxide thereof, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
61. The composition of claim 60 further comprising at least one pharmaceutically active compound useful in the treatment of central nervous system disorders.
62. The composition of claim 60 wherein said the treatment is not based on PDE 10 inhibition.
63. A method of treating or preventing disorders caused by, associated with and/or accompanied by phosphodiesterase 10 hyperactivity and/or disorders in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound or composition of any claim of claims 1-62, or N-oxide thereof, or pharmaceutically acceptable salt thereof.
64. A method of treating or preventing central nervous system disorders in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound or composition of any claim of claims 1-62, or N-oxide thereof, or pharmaceutically acceptable salt thereof.
65. The method of claim 63 or 64 wherein the disorders are selected from neurological disorders and psychiatric disorders; schizophrenia and other psychotic disorders; mood disorders; neurotic, stress-related and somatoform disorders; anxiety disorders; eating disorders; sexual dysfunction; excessive sexual drive; disorders of adult personality and behavior; disorders usually first diagnosed in infancy, childhood or adolescence; mental retardation; disorders of psychological development; disorders comprising the symptom of cognitive deficiency in a mammal, and factitious disorders.
66. The method of claim 63 or 64 wherein the disorders are movement disorders with malfunction of basal ganglia selected from focal dystonias; multiple-focal or segmental dystonias; torsion dystonias; hemispheric, generalised and tardive dyskinesias; akathisias; dyskinesias; Huntington's disease; Parkinson's disease; Lewis body disease; restless leg syndrome; and PLMS.
67. The method of claim 63 or 64 wherein the disorders are organic disorders selected from symptomatic mental disorders; organic delusional (schizophrenia-like) disorders; presenil or senile psychosis associated with dementia; psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; and personality and behavioural disorders due to brain disease, damage and dysfunction.
68. The method of claim 63 or 64 wherein the disorders are selected from mental and behavioural disorders due to psychoactive compounds, more particular to the treatment of psychotic disorders and residual and late-onset psychotic disorders induced by alcohol, opioids, cannabinoids, cocaine, hallucinogens, other stimulants, including caffeine, volatile solvents and other psychoactive compounds.
69. The method of claim 63 or 64 further improving learning and memory capacities in a mammal.
70. The method of claim 65 wherein the neurological disorders are selected from neurodegenerative disorders; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; and neurodegeneration associated with neurotoxic poisoning or multi-system atrophy.
71. The method of claim 70 wherein said neurodegenerative disorders are selected from Parkinson's disease, Huntington's disease, and dementia.
72. The method of claim 70 wherein the dementia is selected from Alzheimer's disease, multi- infarct dementia, AIDS-related dementia, and fronto temperal dementia.
73. The method of claim 65 wherein the schizophrenia and other psychotic disorders are selected from continuous or episodic schizophrenia of different types; schizotypal disorders; persistent delusional disorders; acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different types; puerperal psychosis, and other nonorganic psychosis.
74. The method of claim 65 wherein the mood disorders are selected from manic episodes associated with bipolar disorder and single manic episodes; hypomania; mania with psychotic symptoms; bipolar affective disorders; depressive disorders; single episode or recurrent major depressive disorder; depressive disorder with postpartum onset; depressive disorders with psychotic symptoms; persistent mood disorders; cyclothymia; dysthymia; and premenstrual dysphoric disorder.
75. The method of claim 65 wherein the neurotic, stress-related and somatoform disorders are selected from phobic anxiety disorders; agoraphobia and social phobia related to psychosis; anxiety disorders; panic disorders; general anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders; post traumatic stress disorder; dissociative disorders; neurotic disorders; and depersonalisation-derealisation syndrome.
76. The method of claim 65 wherein the disorders of adult personality and behaviour are selected from specific personality disorders of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; mixed personality disorders; habit and impulse disorders; and disorders of sexual preference.
77. The method of claim 65 wherein the disorders usually first diagnosed in infancy, childhood or adolescence are selected from hyperkinetic disorders; attentional deficit/hyperactivity disorder (AD/HD); conduct disorders; mixed disorders of conduct and emotional disorders; nonorganic enuresis; nonorganic encopresis; stereotyped movement disorder; and specified behavioural emotional disorders; attention deficit disorder without hyperactivity; excessive masturbation; nail-biting; nose- picking and thumb-sucking; disorders of psychological development; schizoid disorder of childhood; pervasive development disorders; and psychotic episodes associated with Asperger's syndrome.
78. The method of claim 65 wherein the disorders of psychological development are selected from developmental disorders of speech and language; developmental disorders of scholastic skills; specific disorder of arithmetical skills; reading disorders and spelling disorders and other learning disorders, which disorders are predominantly diagnosed in infancy, childhood or adolescence.
79. The method of claim 65 wherein the disorders comprising as a symptom cognitive deficiency are selected from cognitive deficits related to psychosis; age -associated memory impairment; Parkinson's disease; Alzheimer's disease; multi infarct dementia; Lewis body dementia; stroke; frontotemporal dementia; progressive supranuclear palsy Huntington's disease and in HIV disease; cerebral trauma; drug abuse; and mild cognitive disorder.
80. A method of treating or preventing obesity, type 2 diabetes, metabolic syndrome, or glucose intolerance comprising administering to a patient in need a therapeutically effective amount of a compound or composition of any one of claims 1-62, or pharmaceutically acceptable salt thereof.
81. The method of claim 80 wherein said patient is overweight or obese.
82. The method of claim 80 wherein the compound is a selective PDElO inhibitor.
83. The method of claim 80 further comprising administering a further therapeutic agent.
84. The method of claim 83 wherein said further therapeutic agent is an anti-obesity agent.
85. A method of reducing body fat or body weight in a patient comprising administering to said patient in need a therapeutically effective amount of a compound or composition of any claim of claims 1 -62, or pharmaceutically acceptable salt thereof.
86. The method of claim 85 wherein said patient is overweight or obese.
87. The method of claim 85 wherein the compound is a selective PDElO inhibitor.
88. The method of claim 85 further comprising administering a further therapeutic agent.
89. The method of claim 85 wherein said further therapeutic agent is an anti-obesity agent.
90. A method of treating pain conditions and disorders in a patient comprising administering to said patient in need a therapeutically effective amount of a compound or composition of any claim of claims 1 -62, or pharmaceutically acceptable salt thereof.
91. The method of claim 90 wherein the pain conditions and disorders are selected from inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatory pain, neuropathic pain, peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain.
92. The method of claims 90 wherein the compound or composition, or pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents effective for treating pain.
93. The method of claim 92 wherein the agents are selected from analgesics, non-steroidal antiinflammatory drugs (NSAIDs), opiods and antidepressants.
94. The method of claim 92 wherein the agents are selected from the group consisting of buprenorphine, naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol (LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide, carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram, acamprosate, topiramate, ondansetron, sertraline, bupropion, amantadine, amiloride, isradipine, tiagabine, baclofen, propranolol, tricyclic antidepressants, desipramine, carbamazepine, valproate, lamotrigine, doxepin, fluoxetine, imipramine, moclobemide, nortriptyline, paroxetine, sertraline, tryptophan, venlafaxine, trazodone, quetiapine, Zolpidem, zopiclone, zaleplon, gabapentin, memantine, pregabalin, cannabinoids, tramadol, duloxetine, milnacipran, naltrexone, paracetamol, metoclopramide, loperamide, clonidine, lofexidine, and diazepam.
95. A process for preparing a compound of any one of claims 1-59, or N-oxide thereof, or pharmaceutically acceptable salt thereof, the process comprising reacting a compound of Formula (E)
(E) wherein L1 is halogen; with R1 -X, wherein X is a leaving group; to prepare said compound of Formula (I).
96. The process of claim 95 wherein said compound of Formula (E) is prepared by the process comprising reacting a compound of Formula (D):
(D) with a halogenating reagent to prepare said compound of Formula (E).
97. The process of claim 96 wherein said compound of Formula (D) is prepared by the process comprising: a) reacting said compound of Formula (A)
(A); with a reducing agent to prepare a compound of Formula (B)
to prepare a compound of Formula (C)
(C); and c) reacting said compound of Formula (C) with a cyclizing reagent to prepare said compound of Formula (D).
98. The process of claim 96 wherein said compound of Formula (D) is prepared by the process comprising: a) reacting a compound of Formula (G)
(G), wherein R is C1.4 alkyl; with a reducing agent to prepare a compound of Formula (H)
(H); b) reacting a compound of Formula (H) with a halogenating reagent to produce a compound of Formula (J)
(J); wherein L3 is halogen; and c) reacting a compound of Formula (J) with an alkylating reagent R3Y , wherein Y is a leaving group; to prepare said compound of Formula (D).
99. A process for preparing a compound of any one on claims 1-59, or N-oxide thereof, or pharmaceutically acceptable salt thereof, the process comprising: a) reacting a compound of Formula (D):
(D) with a halogenating reagent to prepare a compound of Formula (E):
(E) wherein L1 is a halogen; and b) reacting a compound of Formula (E) with R!-X, wherein X is a leaving group; to prepare said compound of formula (I).
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US20090143361A1 (en) | 2009-06-04 |
AR069509A1 (en) | 2010-01-27 |
CL2008003577A1 (en) | 2009-11-27 |
TW200927119A (en) | 2009-07-01 |
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