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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to chromane and tetralin derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by
• metabotropic glutamate receptor 7 mGluR7
• mGluR7 is a Gai/ 0 coupled receptor with widespread CNS expression (13).
• L-Glutamate is the major neurotransmitter in the mammalian central nervous system and activates both ionotropic and metabotropic glutamate receptors.
• L- Glutamate plays a central role in numerous physiological functions such as learning and memory (1), sensory perception, development of synaptic plasticity, motor control, respiration and regulation of cardiovascular function.
• an imbalance in glutamatergic neurotransmission often underlies many neuropathological conditions.
• the metabotropic glutamate receptors are a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms and pharmacologic properties.
• Group I includes mGluRl and mGluR5 and these receptors have been shown to activate phospholipase C.
• Group II includes mGluR2 and mGluR3 whilst Group III includes mGluR4, mGluR6, mGluR7 and mGluR8.
• Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivity.
• mGluR7 is an inhibitory GPCR expressed pre-synaptically at the synaptic cleft on GABAergic and glutamatergic neurons. mGluR7 can influence neuronal excitability by modulating neurotransmitter release and is therefore an attractive target for many
• amyotrophic lateral sclerosis and multiple sclerosis amyotrophic lateral sclerosis and multiple sclerosis; bipolar disorder (6, 7); psychiatric diseases such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (1,4, 6, 8-1 1); and addiction. They may also be useful in treating age-related hearing loss/tinnitus (12).
• R represents hydrogen or halogen
• R 2 represents hydrogen, hydroxyl, C ⁇ -C6 alkyl, Ci-Ce haloalkyl, Ci-C 6 alkoxy, d-C 6 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ;
• R 3 represents hydrogen or C1-C3 alkyl
• R 4 represents cyano, hydroxyl, -N(R 9 ) 2 , d-C6 alkyl, C 3 -C 6 cycloalkyl, d-C 6 alkoxy, C 3 -C 6 cycloalkoxy, Ci-C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, Ci-C 6 alkoxycarbonyl, C 3 -C 6 cycloalkoxycarbonyl, -(CH 2 ) m R 10 , -0(CH 2 ) m R 10 or -NH(CH 2 ) m R 10 , wherein each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, Ikoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl
• R 5 represents hydrogen or halogen
• R 4 and R 5 together with the benzyl group to which they are attached form a 5- to 7- membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 6 alkyl, Ci-C 6 haloalkyl, d-C 6 alkoxy, d-C 6 haloalkoxy, -(CH 2 ) n R n and -0(CH2)nR n ;
• R 6 represents hydrogen, halogen, d-C 6 alkyl or Ci-C 6 haloalkyl
• R 7 independently represents hydrogen, d-C 6 alkyl, d-C 6 haloalkyl, C 4 -C 6 cycloalkyl, (C3-C6 cycloalkyl)methyl, 4- to 6-membered heterocycloalkyl, (3- to 6-membered
• heterocycloalkyl methyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, d-d haloalkyl, d-C 3 alkoxy and Ci-C 3
• R 8 represents d-d alkyl, d-C 6 cycloalkyl or (C3-C6 cycloalkyl)methyl
• R 9 independently represents methyl, C 3 -C 6 alkyl or d-C 6 haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, C1-C3 alkoxy and Ci-d haloalkoxy;
• R 10 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, d-d alkoxy and C1-C3 haloalkoxy;
• R 11 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein
• R 12 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy and - CON(R 13 ) 2 ;
• R 13 independently represents hydrogen or d-C 3 alkyl
• Z represents -CH 2 - or -0-;
• n 0, 1, 2 or 3;
• n 0, 1, 2 or 3.
• R 1 represents hydrogen or fluorine.
• R 2 represents hydrogen, hydroxyl, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, Ci-C 3 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ;
• R 7 independently represents hydrogen, Ci-C 3 alkyl, Ci-C 3 haloalkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-,
• 5- or 6-membered heterocyclic ring optionally comprising one, two or three further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-C 3 alkyl, Ci-C 3 haloalkyl, d-C 3 alkoxy and Ci-C 3 haloalkoxy; R 8 represents d-C 3 alkyl; R 12 represents a saturated or unsaturated 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or
• heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the
• carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, Ci-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy and - CON(R 13 ) 2 ; and R 13 independently represents hydrogen or d-d alkyl.
• R 3 represents hydrogen, methyl, or ethyl.
• R 4 represents hydroxyl, -N(R 9 ) 2 , C1-C3 alkyl, C 3 -C 6 cycloalkyl, C1-C3 alkoxy, C 3 -C 6 cycloalkoxy, C1-C3
• R 5 represents hydrogen or fluorine.
• R 4 and R 5 together with the benzyl group to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C4 alkyl, Ci-d haloalkyl, d-d alkoxy, Ci-d haloalkoxy, -(CH 2 ) n R n and -0(CH 2 )nR n ;
• R 11 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or
• R 6 represents hydrogen or halogen.
• the compound of formula (I) described herein is selected from:
• Various embodiments of the invention herein provide a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein which comprises reacting a compound of formula (II) or a salt thereof
• R 20 represents hydrogen, hydroxyl, Ci-Ce alkyl, d-C 6 haloalkyl, Ci-Ce alkoxy, Ci-C 6 haloalkoxy, -N(R 7 ) 2 , -S0 2 R 8 or -SR 8 , with a compound of formula (III) or a salt thereof
• Various embodiments of the invention herein provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.
• Various embodiments of the invention herein provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, for use in therapy.
• Various embodiments of the invention herein provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein for use in treating alcohol, drug or nicotine addiction.
• Various embodiments of the invention herein provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, for use in treating hearing loss or tinnitus.
• Various embodiments of the invention herein provide a compound of formula (I) or a
• Various embodiments of the invention herein provide a compound comprising the formula (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3 ,4-dihydro-2H- 1 - benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt thereof for use as a medicament for treatment of a disease, disorder, or condition associated with glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7 (mGluR7).
• mGluR7 metabotropic glutamate receptor 7
• the compound is a selective agonist of mGluR7.
• the compound has an EC 5 o within at least one range selected from the group of ranges consisting of about 1 nM to about 3 nM, about 2 nM to about 4 nM, about 3 nM to about 5 nM, about 4 nM to about 6 nM, and about 6 nM to about 8 nM.
• the compound has an EC 50 of 1.8+3.5 nM. In some embodiments, the compound has an EC 50 of 6.9+0.8 nM. In some embodiments, the compound is an allosteric agonist of mGluR7. In some embodiments, the compound is more selective for mGluR7 than for mGluR4 or mGluR8.
• Various embodiments of the invention herein provide a method of treating a subject for a disease, disorder, or condition associated with glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7
• (mGluR7) in a subject comprising: administering to the subject a therapeutically effective amount of compound (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3,4- dihydro-2H-l-benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt thereof, thereby selectively agonizing mGluR7 to treat the disease, disorder, or condition.
• the method further comprises modulating by the compound neurotransmitter release in the subject to treat the disease, disorder, or condition.
• the neurotransmitter is glutamate.
• the disease, disorder, or condition is selected from the group consisting of:
• the compound has a concentration selected from the ranges in the group consisting of: about 0.001 ⁇ to about 0.01 ⁇ , about 0.01 ⁇ to about 0.1 ⁇ , about 0.
• the compound has a concentration greater than about 0.001 ⁇ . In some embodiments of the method, the compound has a concentration selected from the group consisting of about 1 ⁇ , about 5 ⁇ , and about 10 ⁇ .
• compositions comprising the compound (2S)-2-(4-fluorophenyl)-N-((trans)-4- methanesulfonyl-3,4-dihydro-2H-l-benzopyran-3-yl)propanamide and a pharmaceutically acceptable excipient.
• Various embodiments of the invention herein provide a compound comprising the formula (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3,4-dihydro- 2H-l-benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, or a mixture of at least one enantiomer and at least one diastereoisomer thereof.
• Figure IB is a graph of the results of an impedance assay comparing the effects of pre- treatment with either the compound from Example 16 (CPDl) or AMN082 on the sample's response to tool compound, CPD A, a tool compound, which is a mGluR7 activator.
• AMN082 N,N'-dibenzhydrylethane-l,2-diamine dihydrochloride
• AMN082 is a known selective mGluR7 allosteric agonist.
• Figures 2 A-2D are graphs of the results from in vitro cAMP assays in CHO-CRE- luc cells stably expressing human mGluR7 to determine the mode of action of CPD1.
• Figure 2A provides the compound activity of non-selective agonist, L-AP4, with increasing concentrations of orthosteric antagonist, LY341495 (LY).
• Figure 2B provides the compound activity of a positive allosteric modulator (PAM) compound, VU0422288, for the same concentrations of LY as shown in Figure 2A.
• Figure 2C provides the compound activity of allosteric agonist, AMN082, for the same concentrations of LY as shown in Figure 2A.
• PAM positive allosteric modulator
• Figure 2D provides the compound activity of CPD 1 for the same concentrations of LY as shown in Figure 2A.
• Figure 3 A is a graph showing the results of a glutamate release assay for CPD1 in mouse synaptosomes.
• Figure 3B is a graph showing the results of a glutamate release potentiation assay.
• Figure 3C and Figure 3D provide graphs of electrophysiological recordings from the SC-CAl pathway in mouse hippocampal slices.
• Figure 3C is a graph comparing the changes in intracellular recordings of excitatory postsynaptic currents (EPSCs) as a result of contact with L-AP4 at a concentration of 0.5 mM, CPD 1 at a concentration of 1 ⁇ , and CPD 1 at a concentration of 5 ⁇ .
• Figure 3D is a graph comparing the changes in intracellular recordings of EPSCs in mice with wild-type (WT) mGluR7 and mice with an mGluR7 knock-out contacted with CPD 1 at a concentration of 5 ⁇ .
• WT wild-type
• a lack of selective compounds has limited investigation of the therapeutic potential of mGluR7 (14).
• agonists as exemplified by the compound in Example 16 (CPD 1), were tested in a range of assays (recombinant and native) to define their pharmacological profile.
• R represents hydrogen or halogen
• R 2 represents hydrogen, hydroxyl, d-C 6 alkyl, d-C 6 haloalkyl, Ci-C 6 alkoxy, d-C 6 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ;
• R 3 represents hydrogen or d-C 3 alkyl
• R 4 represents cyano, hydroxyl, -N(R 9 ) 2 , d-C 6 alkyl, C 3 -C 6 cycloalkyl, d-C 6 alkoxy, C 3 -C 6 cycloalkoxy, d-C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, Ci-C 6 alkoxycarbonyl, C 3 -C 6 cycloalkoxycarbonyl, -(CH 2 ) m R 10 , -0(CH 2 )mR 10 or
• each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, methylamino, dimethylamino, Ci-C 3 alkyl, Ci-C3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy;
• R 5 represents hydrogen or halogen
• R 4 and R 5 together with the benzyl group to which they are attached form a 5- to 7- membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 6 alkyl, d-C 6 haloalkyl, C 1 -C 6 alkoxy, d-C 6 haloalkoxy, -(CH 2 ) n R u and -0(CH 2 ) n R n ;
• R 6 represents hydrogen, halogen, d-C6 alkyl or d-C 6 haloalkyl
• R 7 independently represents hydrogen, d-C 6 alkyl, d-C 6 haloalkyl, C 4 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, 4- to 6-membered heterocycloalkyl, (3- to 6-membered
• heterocycloalkyl methyl or -COR 12 , or two.R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, Ci-C 3 alkoxy and d-d haloalkoxy;
• R 8 represents C1-C3 alkyl, C 3 -C 6 cycloalkyl or (C 3 -C 6 cycloalkyl)methyl;
• R 9 independently represents methyl, C3-C6 alkyl or d-C 6 haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, Ci-C3 haloalkyl, d-d alkoxy and d-d haloalkoxy;
• R 10 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, d-d alkoxy and d-d haloalkoxy;
• R 11 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, d-d alkoxy and d-d haloalkoxy;
• R 12 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, C1-C3 haloalkyl, Ci-C 3 alkoxy, C1-C3 haloalkoxy and - CON(R 13 ) 2 ;
• R 13 independently represents hydrogen or C1-C3 alkyl
• Z represents -CH2- or -0-
• n 0, 1, 2 or 3;
• n 0, 1, 2 or 3.
• an "alkyl" substituent group or an “alkyl” moiety in a substituent group may be linear or branched.
• Examples of Ci-C 6 alkyl groups/moieties include methyl, ethyl, propyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 2 -methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2- methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-pentyl, 3 -methyl- 1-pentyl, 4-methyl-l- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-buty
• a "cycloalkyl” substituent group or a “cycloalkyl” moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 ring carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• a "heterocycloalkyl” substituent group or a “heterocycloalkyl” moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 ring carbon atoms, in which one or more (e.g. one, two, three, four, five or six) ring carbon atoms are replaced by a corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
• a "3- to 6-membered heterocycloalkyl" substituent group or moiety has three, four, five or six ring atoms, at least one (e.g.
• a "4- to 6- membered heterocycloalkyl" substituent group or moiety has four, five or six ring atoms, at least one (e.g. one, two, three, four or five) of which is a ring carbon atom and at least one (e.g. one, two, three, four or five) of which is a ring heteroatom independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
• a "4- to 6- membered heterocycloalkyl" substituent group or moiety has four, five or six ring atoms, at least one (e.g. one, two, three, four or five) of which is a ring carbon atom and at least one (e.g. one, two, three, four or five) of which is a ring heteroatom independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen. Examples of
• heterocycloalkyl substituent groups or moieties include tetrahydrofuranyl (oxolanyl), piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl (oxanyl), oxazolidinyl, oxetanyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, dioxolanyl, 1 ,4-dioxanyl, azepanyl, morpholinyl, and thiomorpholinyl.
• halogen includes fluorine, chlorine, bromine and iodine.
• a "haloalkyl” or “haloalkoxy" substituent group/moiety comprises at least one halogen atom, e.g. one, two, three, four or five halogen atoms. Examples of such
• groups/moieties include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
• amino refers to a -NH 2 substituent group.
• methylamino refers to a -NH(CH 3 ) substituent group and the term “dimethylamino” refers to a -N(CH 3 ) 2 substituent group.
• oxo refers to an oxygen atom doubly bonded to the carbon atom to which it is attached to form the carbonyl of a ketone or aldehyde.
• a “saturated or unsaturated 4- to 7-membered heterocyclic ring” means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing four, five, six or seven ring atoms in which one or more (e.g. one, two, three, four, five or six) ring carbon atoms are replaced by a corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
• heterocyclic rings examples include tetrahydrofuranyl (oxolanyl), piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl (oxanyl), oxazolidinyl, oxetanyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, dioxolanyl, 1,4-dioxanyl, azepanyl, morpholinyl,
• thiomorpholinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, and tetrazinyl.
• substituent(s) may be attached to any suitable ring atom.
• a "saturated or unsaturated 3- to 7-membered carbocyclic ring” means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing three, four, five, six or seven ring carbon atoms. Examples of such carbocyclic rings include .
• cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopentadienyl, cyclohexadienyl, phenyl, cycloheptadienyl, and cycloheptatrienyl.
• the 5- to 7-membered carbocyclic or heterocyclic ring comprises at least one double bond and may optionally comprise one or two further double bonds, so that the ring may be partially unsaturated or fully unsaturated.
• a "5- to 7-membered carbocyclic or heterocyclic ring” means a hydrocarbyl group containing five, six or seven ring atoms in which one or more (e.g. one, two, three, four, five or six) ring carbon atoms are optionally replaced by a corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
• the invention does not encompass any unstable ring or other structures (e.g. >NCH 2 N ⁇ , >NCH 2 0- or aminal groupings of the type
• R 1 represents hydrogen or halogen. In a preferred embodiment of the invention, R 1 represents hydrogen, fluorine, chlorine or bromine. In another preferred embodiment, R 1 represents hydrogen, fluorine or chlorine. In another preferred embodiment, R 1 represents hydrogen or fluorine.
• R 2 may represent hydrogen, hydroxyl, d-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-Ce haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ; wherein
• R 7 independently represents hydrogen, d-Ce alkyl, Ci-C6 haloalkyl, C 4 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, 4- to 6-membered heterocycloalkyl, (3- to 6-membered heterocycloalkyl)methyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms (e.g.
• one, two, three, four or five further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), the heterocyclic ring being unsubstituted or substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, cyano, hydroxyl, oxo, amino,
• R 8 represents d-C 3 alkyl, C 3 -C 6 cycloalkyl or (C 3 -C 6 cycloalkyl)methyl;
• R 12 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three, four, five or six ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent (e.g.
• substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy and—
• R 13 independently represents hydrogen or d-C 3 alkyl.
• R 2 represents hydrogen, hydroxyl, d-Ce alkyl, d-C 6 haloalkyl, d-C 6 alkoxy, d-C 6 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ;
• R 7 independently represents hydrogen, Ci-Ce alkyl, d-C 6 haloalkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms (e.g. one, two, three, four or five further ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), the heterocyclic ring being unsubstituted or substituted with at least one substituent (e.g.
• substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy;
• R 8 represents d-C 3 alkyl
• R 12 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three, four, five or six ring heteroatoms) independently selected from nitrogen, Oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent (e.g.
• substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, d-C 3 alkoxy, C1-C3 haloalkoxy and - CON(R 13 ) 2 ; and
• R 13 independently represents hydrogen or d-C 3 alkyl.
• R 2 represents hydrogen, hydroxyl, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 ;
• R 7 independently represents hydrogen, d-C 3 alkyl, Ci-C 3 haloalkyl or - COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one, two or three further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-d alkyl, d-C 3 haloalkyl, d-d alkoxy and d-C 3 haloalkoxy;
• R 8 represents d-C 3 alkyl
• R 12 represents a saturated or unsaturated 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy and - CON(R 13 ) 2 ; and
• R 13 independently represents hydrogen or d-C 3 alkyl.
• R 2 represents hydrogen, hydroxyl, d-C 3 alkoxy, d-C 3 haloalkoxy, -N(R 7 ) 2 or -SO2R 8 ;
• R 7 independently represents hydrogen, d-C 3 alkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy;
• R 8 represents d-C 3 alkyl
• R 12 represents phenyl which is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy, d-C 3 haloalkoxy and
• R 13 independently represents hydrogen or d-C 3 alkyl.
• R 2 represents hydrogen, hydroxyl, d-C 3 alkyl, d-C 3 haloalkyl, C1-C3 alkoxy, d-C 3 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 .
• R 2 represents hydrogen, hydroxyl, d-d alkoxy, d-C 3 haloalkoxy, -N(R 7 ) 2 or -S0 2 R 8 .
• R 2 represents hydrogen, hydroxyl, d-d alkoxy, -N(R 7 ) 2 or -S0 2 R 8 .
• R 7 represents hydrogen, d-C 6 alkyl, d-C 6 haloalkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms (e.g. one, two, three, four or five further ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), the heterocyclic ring being unsubstituted or substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, cyano, hydroxyl, oxo, amino,
• substituent e.g. one, two, three, four, five, six or seven substituents
• R 7 represents hydrogen, d-C 3 alkyl, d-C 3 haloalkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one, two or three further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, C1-C3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy.
• R 7 represents hydrogen, d-C 3 alkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and Ci-C 3 haloalkoxy.
• R 7 represents hydrogen, d-C 2 alkyl or -COR 12 , or two R 7 together with the nitrogen atom to which they are attached form a saturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and Ci-C 3 haloalkoxy.
• two R 7 together with the nitrogen atom to which they are attached form an optionally substituted azetidine N
• two R 7 together with the nitrogen atom to which they are attached form an optionally substituted saturated or unsaturated 5-membered heterocyclic ring selected from:
• two R 7 together with the nitrogen atom to which they are attached form an optionally substituted saturated or unsaturated 6-membered heterocyclic ring selected from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein represents the bond by which the heterocyclic ring is attached to the rest of the molecule.
• R 8 represents C1-C3 alkyl. In another preferred embodiment, R 8 represents methyl or ethyl. In another preferred embodiment, R 8 represents methyl.
• R 12 represents a saturated or unsaturated 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6- membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, Ci-C 3 alkyl, Ci-C 3 haloalkyl, d-d alkoxy, d-d haloalkoxy and - CON(R 13 ) 2 .
• R 12 represents phenyl which is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, Ci-C 3 alkyl, Ci-C 3 haloalkyl, d-d alkoxy, d-d haloalkoxy and -CON(R 13 ) 2 .
• R 12 represents phenyl substituted with one or two substituents independently selected from halogen, hydroxyl, C1-C3 alkyl, d-d haloalkyl, C1-C3 alkoxy, d-d haloalkoxy and -CON(R 13 ) 2 .
• R 12 represents an optionally substituted saturated or unsaturated 5-membered heterocyclic ring selected from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-, preferably -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
• R 12 represents an optionally substituted saturated or unsaturated 6-membered heteroc scrap rin selected from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
• R 13 independently represents hydrogen, methyl or ethyl. In another preferred embodiment, R 13 independently represents hydrogen or methyl.
• R 4 may represent cyano, hydroxyl, -N(R 9 ) 2 , d-C 6 alkyl, C 3 -C 6 cycloalkyl, d-C 6 alkoxy, C 3 -C 6 cycloalkoxy, Ci-Ce alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, d-C 6
• alkoxycarbonyl d-Ce cycloalkoxycarbonyl, -(CH 2 ) m R 10 , -0(CH 2 ) ra R 10 or
• each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, cyano, hydroxyl, oxo, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy; wherein
• R 9 independently represents methyl, C 3 -C 6 alkyl or d-C 6 haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms (e.g. one, two, three, four or five further ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), the
• heterocyclic ring being unsubstituted or substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy;
• substituent e.g. one, two, three, four, five, six or seven substituents
• R 10 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three, four, five or six ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino,
• substituent e.g. one, two, three, four, five, six or seven substituents
• R 4 represents hydroxyl, -N(R 9 ) 2 , d-C 3 alkyl, C 3 -C 6 cycloalkyl, d-d alkoxy, C 3 -C 6 cycloalkoxy, d-C 3 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, C1-C3 alkoxycarbonyl, C 3 -C 6 cycloalkoxycarbonyl,
• each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, Ci-C 3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and O-C3 haloalkoxy; wherein
• R 9 independently represents methyl, C 3 -C 6 alkyl or Ci-Ce haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring" heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, Ci-C 3 alkoxy and Ci-C 3 haloalkoxy;
• R 10 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, C1-C3 haloalkyl, d-C 3 alkoxy and C1-C3 haloalkoxy; and
• n 0, 1 or 2.
• R 4 represents hydroxyl, -N(R 9 ) 2 , C1-C3 alkyl, C 3 -C 6 cycloalkyl, d-Cs alkoxy, C 3 -C 6 cycloalkoxy, -(CH 2 ) m R 10 , -0(CH 2 ) m R 10 or - NH(CH 2 ) m R 10 , wherein each of the alkyl, cycloalkyl, alkoxy and cycloalkoxy moieties is independently unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, Ci-Cs alkoxy and Ci-C 3 haloalkoxy; wherein
• R 9 independently represents methyl, C 3 -C 6 alkyl or Ci-Ce haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring
• heteroatoms independently selected from nitrogen and oxygen atoms, the. heterocyclic ring being unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, O-C3 haloalkyl, d-C 3 alkoxy and C1-C3 haloalkoxy;
• R 10 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, Ci-C 3 alkoxy and d-C 3 haloalkoxy; and
• n 0, 1 or 2.
• R 4 represents -N(R 9 ) 2 , C1-C3 alkyl, -(CH 2 ) m R 10 , -0(CH 2 ) m R 10 or -NH(CH 2 ) m R 10 , wherein the alkyl moiety is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, C 1 -C 3 alkoxy and d-C 3 haloalkoxy; wherein two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxy
• R 10 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and Ci-C 3 haloalkoxy; and
• n 0, 1 or 2.
• R 4 represents hydroxyl, - N(R 9 ) 2 , d-C 3 alkyl, C 3 -C 6 cycloalkyl, Ci-C 3 alkoxy, C 3 -C 6 cycloalkoxy, d-C 3
• alkylcarbonyl C 3 -C 6 cycloalkylcarbonyl, d-C 3 alkoxycarbonyl, C 3 -C 6 cycloalkoxycarbonyl, -(CH 2 )mR 10 , -0(CH 2 )mR 10 or -NH(CH 2 ) m R 10 , wherein each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and d-C 3 haloalkoxy.
• R 4 represents hydroxyl, -N(R 9 ) 2 , Ci-C 3 alkyl, C 3 -C 6 cycloalkyl, d-C 3 alkoxy, C 3 -C 6 cycloalkoxy, -(CH 2 ) m R 10 , -0(CH 2 ) m R 10 or - NH(CH 2 ) m R 10 , wherein each of the alkyl, cycloalkyl, alkoxy and cycloalkoxy moieties is independently unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, C1-C3 alkyl, d-d haloalkyl, d-d alkoxy and d-d haloalkoxy.
• R 4 represents -N(R 9 ) 2 , d-d alkyl, -(CH 2 ) m R 10 , -0(CH 2 ) m R 10 or -NH(CH 2 )mR 10 , wherein the alkyl moiety is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, methylamino, dimethylamino, Ci-C 3 alkyl, d-C 3 haloalkyl, d-C 3 alkoxy and C1-C3 haloalkoxy.
• R 4 represents -N(R 9 ) 2 , d-d alkyl (e.g.
• R 9 represents methyl, d-C 6 alkyl or Ci-C 6 haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, C1-C3 alkoxy and d-d haloalkoxy.
• R 9 represents methyl, d-C 6 alkyl or d-C 6 haloalkyl, or two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one or two substituents
• halogen independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, d-d haloalkyl, d-d alkoxy and C1-C3 haloalkoxy.
• two R 9 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring optionally comprising one or two further ring heteroatoms independently selected from nitrogen and oxygen atoms, the heterocyclic ring being unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino,
• two R 9 together with the nitrogen atom to which they are attached form an optionally substituted azetidine N wherein represents the bond by which the azetidine is attached to the rest of the molecule.
• two R 9 together with the nitrogen atom to which they are attached form an optionally substituted saturated or unsaturated 5-membered heterocyclic rin selected from:
• two R 9 together with the nitrogen atom to which they are attached form an optionally substituted saturated or unsaturated 6-membered heterocyclic ring selected from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein represents the bond by which the heterocyclic ring is attached to the rest of the molecule.
• R 10 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-Ca alkyl, d-C 3 haloalkyl, C1-C3 alkoxy and d-C3 haloalkoxy.
• R 10 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-C 3 alkyl, d-C 3 haloalkyl, Ci-C 3 alkoxy and C1-C3 haloalkoxy.
• R 10 represents an optionally substituted saturated or unsaturated 5-membered heterocyclic ring selected from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-, preferably -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
• R 10 represents an optionally substituted saturated or unsaturated 6-membered heterocyclic ring selected from:
• X is -NH-, -0- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
• n is 0, 1 or 2. In another preferred embodiment, m is 0 or 1. In another preferred embodiment, m is 1. In another preferred embodiment, m is 0.
• R 5 may represent hydrogen or halogen. In a preferred embodiment of the invention, R 5 represents hydrogen, fluorine, chlorine or bromine. In another preferred embodiment, R 5 represents hydrogen, fluorine or chlorine. In another preferred embodiment, R 5 represents hydrogen or fluorine. In another preferred embodiment, R 5 represents hydrogen. [0077] R 4 and R 5 together with the benzyl group to which they are attached may form a 5- to 7-membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g.
• one, two, three, four, five or six ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent (e.g.
• substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylammo, d-C 6 alkyl, Ci-C6 haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -(CH 2 ) n R n and -0(CH 2 ) n R n ; wherein
• R 11 represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three, four, five or six ring heteroatoms) independently selected from nitrogen, oxygen and sulphur atoms (in particular nitrogen and oxygen atoms), wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent (e.g.
• substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, d-d haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and
• n 0, 1, 2 or 3.
• R 4 and R 5 together with the benzyl group to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is
• R 11 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, d-d alkyl, d-d haloalkyl, Ci-C 3 alkoxy and d-d haloalkoxy; and
• n 0, 1, 2 or 3.
• R 4 and R 5 together with the benzyl group to which they are attached form a 6-membered heterocyclic ring, the heterocyclic ring comprising one or two ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocyclic ring is substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -(CH 2 ) n R n and -0(CH 2 ) contendR n ; wherein
• R 11 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one or two ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, d-C3 haloalkyl, C 1 -C 3 alkoxy and Ci-C 3 haloalkoxy; and
• n 0, 1, 2 or 3.
• R 4 and R 5 together with the benzyl group to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, d-C 4 alkoxy, C1-C4 haloalkoxy, -(CH 2 ) contendR n and -0(CH 2 ) contendR n .
• R 4 and R 5 together with the benzyl group to which they are attached form a 6-membered heterocyclic ring, the heterocyclic ring comprising one or two ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocyclic ring is substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -(CH 2 ) n R n and -0(CH 2 )nR u .
• R 4 and R 5 together with the benzyl group to which they are attached form an o d from:
• X is -NH-, -O- or -S-, preferably -NH- or -0-.
• R 4 and R 5 together with the benzyl group to which they are attached form an optionally substituted 6-membered heterocyclic ring selected from:
• X is -NH-, -0- or -S-, preferably -NH- or -0-.
• R 11 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6- membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, Ci-C 3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
• R 11 represents a saturated or unsaturated 3-, 4-, 5- or 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one or two ring heteroatoms
• carbocyclic or heterocyclic ring independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-C 3 alkyl, C1-C3 haloalkyl, d-C 3 alkoxy and C1-C3 haloalkoxy.
• R 11 represents an optionally substituted saturated or unsaturated -membered heterocyclic ring selected from:
• R 11 represents an optionally substituted saturated or unsaturated 6-membered heterocyclic ring selected from:
• X is -NH-, -0- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
• n is 0, 1 or 2. In another preferred embodiment, n is 0 or 1. In another preferred embodiment, n is i .
• R 6 represents hydrogen, halogen, Ci-C 6 alkyl or Ci-C 6 haloalkyl. In a preferred embodiment of the invention, R 6 represents hydrogen, halogen, d-C3 alkyl or
• R 6 represents hydrogen or halogen. In another preferred embodiment, R 6 represents hydrogen, fluorine, chlorine or bromine. In another preferred embodiment, R 6 represents hydrogen, fluorine or chlorine. In another preferred embodiment, R 6 represents hydrogen or fluorine. In another preferred embodiment, R 6 represents hydrogen.
• Z represents -0-. In another embodiment, Z represents -CH 2 -.
• Examples of compounds of the invention include:
• the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above, which comprises reacting a compound of formula (II) or a salt (e.g. hydrochloride salt) thereof
• R 20 represents hydrogen, hydroxyl, d-C 6 alkyl, d-C 6 haloalkyl, Ci-Ce alkoxy, Ci-C 6 haloalkoxy, -N(R 7 ) 2 , -S0 2 R 8 or -SR 8 , with a compound of formula (III) or a salt (e.g. hydrochloride salt) thereof
• HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-i]pyridinium 3-oxid hexafluorophosphate
• a solvent such as dichloromethane at room temperature to 60°C;
• R 20 may represents -SR 8 .
• -SR 8 may be converted into -S0 2 R 8 by treatment with, for example, meta-chloroperbenzoic acid in a solvent such as dichloromethane.
• a compound of formula (I), (II) or (III) may be converted into another compound of formula (I), (II) or (III) respectively.
• a hydroxyl substituent group (-OH) may be converted into:
• 3,3-difluoropyrrolidin-l-yl by treatment with, for example, methanesulfonic anhydride and triethylamine in a solvent such as tetrahydrofuran, followed by treatment with 3,3-difluoropyrrolidine hydrochloride and triethylamine;
• a bromine substituent group (-Br) may be converted into:
• the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate, hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g.
• the compounds of formula (I) are in the form of a hydrochloride salt.
• compounds of formula (I) may bear one or more radiolabels.
• radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom.
• radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
• any atom specified herein may also be an isotope of said atom.
• hydrogen encompasses 3 ⁇ 4 2 H and 3 H.
• carbon atoms are to be understood to include 12 C, 13 C and 14 C
• nitrogen atoms are to be understood to include 14 N and 15 N
• oxygen atoms are to be understood to include 16 0, 17 0 and 18 0.
• compounds of formula (I) may be isotopically labelled.
• an “isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
• Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention.
• Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
• Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
• the compound comprises the formula (2S)-2-(4- fluorophenyl)-N-((trans)-4-methanesulfonyl-3 ,4-dihydro-2H- 1 -benzopyran-3 -yl)propanamide or a pharmaceutically acceptable salt thereof.
• the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals and may be used in treating conditions or disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7.
• the present invention provides a compound of formula (I) or a
• the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the preparation of a medicament for the treatment of conditions associated with metabotropic glutamate receptor 7 (mGluR7).
• mGluR7 metabotropic glutamate receptor 7
• the present invention still further provides embodiments of a method of treating a condition associated with metabotropic glutamate receptor 7 which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• the compound is (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3,4-dihydro-2H-l- benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt thereof for use as a medicament for treatment of a disease, disorder, or condition associated with glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7 (mGluR7).
• mGluR7 metabotropic glutamate receptor 7
• a compound comprising the formula (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3,4-dihydro- 2H-l-benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt thereof for use as a medicament for treatment of a disease, disorder, or condition of the central nervous system.
• the compound is a selective agonist of mGluR7. In certain embodiments, the compound is more selective for mGluR.7 than for mGluR4 or mGluR8. In some embodiments, the compound has an EC 5 o within at least one range selected from the group of ranges consisting of about 1 nM to about 3 nM, about 2 nM to about 4 nM, about 3 nM to about 5 nM, about 4 nM to about 6 nM, and about 6 nM to about 8 nM. In certain embodiments, the compound has an EC 5 o of 1.8+3.5 nM. In certain embodiments, the compound has an EC50 of 6.9+0.8 nM. In some embodiments, the compound is an allosteric agonist of mGluR7. ⁇
• various embodiments of the invention herein include a method of treating a subject for a disease, disorder, or condition of the central nervous system in a subject, the method comprising: administering to the subject a therapeutically effective amount of compound (2S)-2-(4-fluorophenyl)-N-((trans)-4-methanesulfonyl-3,4-dihydro-2H- l-benzopyran-3-yl)propanamide or a pharmaceutically acceptable salt thereof, thereby selectively agonizing mGluR7 to treat the disease, disorder, or condition.
• the method further comprising modulating by the compound neurotransmitter release in the subject to treat the disease, disorder, or condition.
• the neurotransmitter is glutamate.
• the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
• the terms “therapeutic” and “therapeutically” should be construed accordingly.
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question.
• Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
• condition As used herein the terms “condition”, “disorder” and “disease” relate to any unhealthy or abnormal state.
• conditions associated with metabotropic glutamate receptor 7 includes conditions, disorders and diseases in which the modulation of mGluR7 may provide a therapeutic benefit, examples of which include:
• Nervous system disorders Parkinson's disease, including dementia associated with Parkinson's disease; Alzheimer's disease; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; bipolar disorder; and psychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (e.g. major depressive disorder);
• Hearing disorders hearing loss and/or tinnitus caused by age, noise or trauma;
• Schizophrenia is a debilitating psychiatric disorder characterised by a combination of negative symptoms (such as social withdrawal, anhedonia, avolition and apathy) and positive symptoms (including hallucinations, delusions and paranoia) as well as marked cognitive deficits (such as impairment of executive function).
• the executive function (EF) has been defined as "a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place.
• EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states" (Orellana G. and Slachevsky A., 2013. Executive Functioning in Schizophrenia. Front. Psychiatry, 4, 35).
• the present invention also provides a method of treating a negative symptom, a positive symptom and/or a cognitive deficit associated with a psychiatric disorder, especially schizophrenia, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
• the compound is
• the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the present invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the invention still further provides a process for the preparation of a
• composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
• compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
• the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers.
• parenteral as used herein includes subcutaneous,
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• suitable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
• compositions of the invention may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
• compositions of this invention may be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (percent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
• the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
• the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated.
• therapeutic agents may be selected from the following:
• anti-addiction drugs including, for example, acamprosate, disulfiram, naltrexone and nalmefene for alcohol dependency, and gabapentin, modafinil, topiramate, vigabatrin and baclofen for drug, particularly cocaine, addiction;
• antidepressants such as amitriptyline, amoxapine, bupropion, citalopram,
• clomipramine desipramine, doxepin duloxetine, elzasonan, escitalopram,
• antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszo
• anxiolytics including, for example, alnespirone, azapirones, benzodiazepines,
• Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, prazosin, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazep
• anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam and gabapentin, and equivalents and pharmaceutically active isomer(s) and or metabolite(s) thereof;
• Alzheimer's therapies including, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• Parkinson's therapies including, for example, L-dopa, ropinirole, pramipexole, monoamine oxidase type B (MAO-B) inhibitors such as deprenyl, selegiline, and rasagiline, catechol-O-methyl transferase (COMT) inhibitors such as entacapone or tolcapone, adenosine A-2 inhibitors, dopamine re-uptake inhibitors, NMDA antagonists, Nicotine agonists, and Dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• migraine therapies including, for example, almotriptan, amantadine, botulinum toxin A, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and zomitriptan, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• (ix) stroke therapies including, for example, abciximab, activase, citicoline,
• urinary incontinence therapies including, for example, darafenacin, duloxetine, falvoxate, mirabegron, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or
• neuropathic pain therapies including, for example, capsaicin, gabapentin, lidoderm, and pregabalin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, lorediplon, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ralmeteon, roletamide, suvorexant, triclofos, secobarbital, zaleplon, and Zolpidem, zopiclone and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
• (xv) 5HT1B ligands such as, for example, compounds disclosed in WO 99/05134 and WO 02/08212;
• alpha 7 nicotinic agonists such as, for example, compounds disclosed in
• chemokine receptor CCR1 inhibitors (xviii) chemokine receptor CCR1 inhibitors; and (xix) delta opioid agonists such as, for example, compounds disclosed in WO 97/23466 and WO 02/094794.
• Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
• composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum),
• mtracerebroventricular into the cerebral ventricles
• epicutaneous application onto the skin
• intradermal into the skin itself
• subcutaneous under the skin
• nasal administration
• compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier.
• the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired effect.
• the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
• the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
• split dosing regimens such as those described herein may be used.
• a "split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose.
• a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
• a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.
• the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject in split doses.
• EC50 within at least one range selected from the group of ranges consisting of about 1 nM to about 3 nM, about 2 nM to about 4 nM, about 3 nM to about 5 nM, about 4 nM to about 6 nM, and about 6 nM to about 8 nM.
• the compound has an EC50 of 1.8+3.5 nM.
• the compound has an EC50 of 6.9+0.8 nM.
• the compound is an allosteric agonist of mGluR7. In some
• the compound is more selective for mGluR7 than for mGluR4 or mGluR8.
• a method of treating a subject for a disease, disorder, or condition associated with glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7 (mGluR7) in a subject comprises
• the method further comprises modulating by the compound neurotransmitter release in the subject to treat the disease, disorder, or condition.
• the neurotransmitter is glutamate.
• the disease, disorder, or condition is selected from the group consisting of:
• the compound is formulated in a concentration selected from the ranges in the group consisting of: about 0.001 ⁇ to about 0.01 ⁇ , about 0.01 ⁇ to about 0.1 ⁇ , about 0. 1 ⁇ to about 1.0 ⁇ , and about 1.0 ⁇ to about 10 ⁇ . In some embodiments of the method, the compound has a concentration greater than about 0.001 ⁇ .
• the compound has a concentration selected from the group consisting of about 1 ⁇ , about 5 ⁇ , and about 10 ⁇ .
• NMR spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3 K, 298.2 K or 293 K unless otherwise stated; the chemical shifts ( ⁇ ) are reported in parts per million.
• Spectra were recorded using a Bruker (trade mark) 400 AVANCE instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE-III HD instrument fitted with a 5 mm BBFO smart probe or a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 3.2 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker Topspin 3.0 software or by a Bruker 300 MHz AVANCE II instrument fitted with a 5 mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software, or 5 mm BBFO probe controlled by Bruker Topspin 3.2 software, or by a JEOL
• Ultra Performance Liquid Chromatography with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters (trade mark) Acquity UPLC system equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1 mm id x 50 mm long) operated at 50 or 60 °C.
• Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid, 0.1% trifluoroacetic acid (TFA) or 0.025% ammonia.
• Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionisation.
• Preparative HPLC was performed using Agilent Technologies (trade mark) 1100 Series system or a Waters autopurification LC/MS system or a Shimadzu semi prep HPLC system, typically using Waters 19 mm id x 250 mm long CI 8 columns such as XBridge (trade mark) or SunFire (trade mark) 5 ⁇ materials at room temperature.
• Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless otherwise stated.
• SFC chiral separations were performed on a Waters prep30/MS system, using a flow rate of 30 mL/min, temperature of 40 °C and a pressure of 100 bar or on a Sepiatec prep 100 system, using a flow rate of 60 mL/min, temperature of 40 °C and pressure of 100 bar.
• Mobile phases typically consisted of supercritical C0 2 and a polar solvent such as methanol, ethanol or isopropanol. Column type and eluent are detailed for individual examples.
• 'Room temperature' as used in the present specification, means a temperature in the range from about 18 °C to about 25 °C.
• AIBN Azobisisobutyronitrile
• DIPEA N ⁇ V-Diisopropylethylamine
• HATU 1 - [Bis(dimethylamino)methylene] - 1 H- 1 ,2,3-triazolo [4,5
• NBS N-Bromosuccinamide
• TEA Triethylamine
• T3P Propylphosphonic anhydride
• Compound activities were determined in CHO-CRE-luc cells stably expressing hu/mo mGluR7, using a cAMP reporter gene assay (Steady Glo, Promega). Selectivity was assessed in stable CHO-mGluR4 cells (DiscoverX) and CHO-mGluR8 transients using an HTRF cAMP assay (Cisbio).
• L-2-amino-4-phosphonobutyric acid (herein "L-AP4") was a non-selective agonist used in the experiments herein.
• L-AP4 has the IUPAC name (2S)-2-amino-4- phosphonobutanoic acid and the CAS number 23052-81-5.
• LY341495 (also herein referred to as "LY") was a orthosteric antagonist used in the experiments herein.
• LY341495 has the IUPAC name 2-[(lS,2S)-2-carboxycyclopropyl]-
• VU0422288 was a positive allosteric modulator (PAM) compound used in the experiments herein.
• VU0422288 has the IUPAC name N-[3-Chloro-4-[(5-chloro-2- pyridinyl)oxy]phenyl]-2-pyridinecarboxamide and the CAS number 1630936-95-6.
• Cupric bromide (40.3 g, 180.4 mmol) in EtOAc (75 mL) was heated to reflux.
• a solution of 6-fluoro-3,4-dihydro-2H-l-benzopyran-4-one (15 g, 90 mmol) in chloroform (75 mL) was added dropwise to the hot cupric bromide solution and then stirred at reflux overnight.
• the mixture was allowed to cool to room temperature, filtered through a pad of diatomaceous earth, washing with EtOAc and concentrated in vacuo to afford the title compound.
• NBS 0.712 g, 4 mmol
• ethyl 2-[2-(2-ethoxy-2- oxoethyl)phenyl]acetate 1.00 g, 4 mmol
• AIBN 66 mg, 0.4 mmol
• the reaction mixture was filtered and the filtrate concentrated in vacuo to afford the title compound.
• Step (1) ethyl 2-(cyclopropylmethyl " )-3-oxo-l,2.3.4-tetrahvdroisoquinoline-l-carboxylate
• HATU (186 mg, 0.489 mmol) was added to a stirred solution of (lS)-2- (cyclopropyl-methyl)-3 -oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxylic acid (Intermediate E5, 100 mg, 0.408 mmol), (/rara)-3-amino-3,4-dihydro-2H-l-benzopyran-4-ol hydrochloride (Intermediate B, 67.3 mg, 0.408 mmol) and DIPEA (0.142 mL, 0.815 mmol) in DCM (2 mL) and stirred for 1 hour.
• Pivaloyl chloride (18.96 g, 158.01 mmol) was added dropwise over 30 minutes at 0 °C and then stirred for 1 hour at 0 °C.
• the benzyloxazolidinone solution was then transferred by cannula to the previously prepared anhydride solution at -70 °C and stirred for 30 minutes at -70 °C.
• the mixture was quenched with saturated NH 4 C1 solution, diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried (Na 2 S0 4 ) and concentrated in vacuo.
• the crude product was purified by column chromatography on silica, eluted with 0-7% ethyl acetate/hexane to afford the title compound.
• HATU (713 mg, 1.874 mmol) was added to a solution of (ds)-3-amino-3,4-. dihydro-2H-l-benzopyran-4-ol hydrochloride (Intermediate A, 258 mg, 1.562 mmol), (2S)- 2-(4-fluorophenyl)propanoic acid (Intermediate Fl, 263 mg, 1.562 mmol) and DIPEA (0.546 mL, 3.12 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1.5 hours. Saturated NaHC0 3 was added to the mixture. The phases were separated and the aqueous extracted with DCM.
• the reaction was stirred at 0 °C for 2 hours, then warmed to room temperature and stirred for 18 hours.
• the reaction was carefully quenched with sodium thiosulfate and the pH adjusted to pH 1 and extracted with EtOAc.
• the organic was collected, washed with brine, dried (Na 2 S0 4 ) and concentrated in vacuo.
• the aqueous was concentrated in vacuo and combined with the organic layer and purified by column chromatography on silica, eluted with 100% EtOAc with 1% AcOH to afford the title compound.
• Step ( ⁇ ) ethyl 2-(2,4-difluorophenvD-2-(2-oxo-l ,2-dihvdropyridin-l -vDacetate
• Methanesulfonic anhydride (221 mg, 1.268 mmol) was added as a solution in THF (2mL) to a dry ice/acetone cooled solution (2S)-2-(4-fluorophenyl)-N-((cw)-4-hydroxy-3,4- dihydro-2H-l-benzopyran-3-yl)propanamide (Intermediate F2, 200 mg, 0.634 mmol) and TEA (0.265 mL, 1.903 mmol) in THF (4 mL). The cooling bath was switched for an ice/water bath.
• Methyl iodide (1.173 ml, 18.75 mmol) was added to a suspension of tert-butyl N- ((trans)-4-hydroxy-3,4-dihydro-2H-l-benzopyran-3-yl)carbamate (Intermediate A3, 1.99 g, 7.50 mmol) and silver oxide (2.086 g, 9.00 mmol) in acetonitrile (40 ml). The reaction was stirred at room temperature for 2 days in a sealed flask in the dark.
• T3P 50 wt.% in EtOAc, 1.85 ml, 3.11 mmol was added dropwise to a mixture of (cw)-3-amino-3,4-dihydro-2H-l-benzopyran-4-ol hydrochloride (Intermediate A, 257 mg, 1.56 mmol) and (2S)-2-phenylpropanoic acid (245 mg, 1.63 mmol) in THF (20 mL). The mixture was stirred at room temperature for 5 minutes. TEA (1.73 mL, 12.4 mmol) was added dropwise. The mixture was stirred at room temperature overnight, then partitioned between EtOAc and saturated aq. NaHC0 3 .
• HATU (1198 mg, 3.15 mmol) was added to a solution of (5)-2-phenylpropanoic acid (451 mg, 3 mmol) and DIPEA (1.153 mL, 6.60 mmol) in DMF (5 mL). The mixture was stirred and allowed to stand for 5 minutes. 3-Aminochroman-4-one hydrochloride (599 mg, 3.00 mmol) was added and the reaction was stirred for 5 minutes. The mixture was diluted with EtOAc and washed with water. The organic phase was dried (MgS0 4 ) and concentrated in vacuo.
• Example 15 i5 -2-(cyclopropylmemylVN-(( ' tram 4-rnethoxy-3.4-dihydro-2H- 1 - benzopyran-3 -ylV3 -oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide
• Iodomethane (0.043 ml, 0.688 mmol) was added to a vial containing (1 S)-2- (cyclopropylmethyl)-N-((trafts)-4-hydroxy-3 ,4-dihydro-2H- 1 -benzopyran-3 -yl)-3 -oxo- 1, 2,3, 4-tetrahydroisoquinoline-l -carboxamide (Intermediate E, 135 mg, 0.344 mmol) and silver oxide (399 mg, 1.720 mmol) in acetonitrile (1.5 mL). The vial was sealed and wrapped in foil and stirred at room temperature for 4 days.
• Example 16 - 1 st eluting peak represents (2S)-2-(4-fluorophenyl)-N-((trans)-4- methanesulfonyl-3,4-dihydro-2H-l-benzopyran-3-yl)propanamide (CPD1 or Compound I).
• Example 25 2-(2,4-difluorophenyl -N-((/ra»>s ,' )-4-methoxy-3,4-dihydro-2H-l-benzopyran-3- yl)-2-[3-(triiluoromethoxy)azetid -l-yl]acetamide (diastereomer mixture)
• the crude material was purified by column chromatography on silica, eluted with 0-100% ethyl acetate/petroleum ether.
• the product was purified by chiral SFC (23%.MeOH, ID column) to afford the title compounds.
• Example 28 N-((trans)-4-meth.oxy-3.4-dihvdro-2H-l -benzopyran-3 -ylV2-[(oxan-4- yPmethyl] -3 -oxo- 1 ,2.3.4-tetrahydroisoquinoline- 1 -carboxamide
• T3P (50% in ethyl acetate, 0.231 mL, 0.389 mmol) was added to a suspension of 3 -oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)- 1 ,2,3 , 4-tetrahydroisoquinoline- 1 -carboxylic acid (Intermediate M, 0.075 g, 0.259 mmol), (tram)-4-methoxy-3,4-dihydro-2H-l-benzopyran- 3-amine hydrochloride (Intermediate S, 0.061 g, 0.285 mmol) and TEA (0.108 mL, 0.778 mmol) in DCM (2 mL).
• Methanesulfonic anhydride 110 mg, 0.634 mmol was added to a dry ice/acetone cooled solution of (2S)-2-(4-fluorophenyl)-iV-((cw)-4-hydroxy-3,4-dihydro-2H-l - benzopyran-3-yl)propanamide (Intermediate I, 100 mg, 0.317 mmol) and TEA (0.133 mL, 0.951 mmol) in THF (3 mL). The reaction mixture was stirred at this temperature for 10 minutes. The cooling bath was switched for an ice bath. After 30 minutes, pyrrolidine (0.132 mL, 1.586 mmol) was added.
• reaction was stirred in the ice bath for 30 minutes and then allowed to warm to room temperature and stirred for 24 hours.
• the reaction mixture was partitioned between DCM and water and the organic phase was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to afford the title compound.
• Methanesulfonic anhydride 110 mg, 0.634 mmol was added to a dry ice/acetone cooled solution of (2S)-2-(4-fluorophenyl)-N-((c/5)-4-hydroxy-3,4-dihydro-2H-l- benzopyran-3-yl)propanamide (Intermediate I, 100 mg, 0.317 mmol) and TEA (0.133 mL, 0.951 mmol) in THF (3 mL). The reaction mixture was stirred at this temperature for 10 minutes. The cooling bath was switched for an ice bath.
• Example 40 Biological efficacy shown by a mGluR7 assay
• test compounds were assessed in a CRE-directed luciferase reporter gene assay, using a stable CHO cell line expressing the CRE-luc reporter and human mGluR7 genes. In this cell line, production of cAMP stimulated the transcription of the luciferase gene and luciferase activity was then measured in a luminescent enzyme assay (Steady Glo assay; Promega E2550). Activation of mGluR7 decreased the forskolin stimulated luminescence signal.
• the growth media was removed from the cell plate and replaced with 15 ⁇ Opti-MEM I, followed by a 5 ⁇ addition from the 5x compound plate and a fifteen minute incubation (37 °C).
• Forskolin (Sigma F3917) was then added to the wells (5 ⁇ of 2.5 ⁇ ) and the plate was incubated for five hours (37 °C). During this incubation, the Steady Glo Substrate reagent was warmed to 37 °C. Aliquots (11ml; stored at -20 °C) of this reagent were prepared by dissolving the contents of 1 vial of lyophilised substrate in 100 ml Steady-Glo buffer.
• Luminescence was then measured using the EnVision Multilabel Reader (Perkin Elmer). [00406] Compound activity was examined using a 10-point, half log concentration- response range and each concentration was tested in duplicate wells. Luminescence values were normalised to 'maximum' (forskolin alone) and 'minimum' (forskolin in the presence of tool mGluR7 agonist) controls. EC 50 values were derived from this data using non-linear regression and a four parameter curve fit. The EC 50 values for the compounds of the
• Example 42 Selectivity and desensitization profile of the compound in Example 16
• Example 43 In vitro mode of action for the compound of Example 16
• Example 16 The mode of action of the compound in Example 16 was determined by testing activity in the presence of the orthostenc antagonist LY341495 (LY). Whereas increasing LY concentrations reduced the potency of an orthosteric antagonist as shown in Figure 2A and the Emax of a PAM as shown in Figure 2B, no effect was seen on an allosteric agonist (see Figure 2C). CPDl activity was unaffected by LY as shown in Figure 2D, suggesting it is also an allosteric agonist.
• LY341495 LY341495
• CPDl is a potent (low nM) and selective (vs mGluR4, 8) mGluR7 agonist, which, like AMN082, acts allosterically. In contrast to AMN082, in vitro desensitization effects were not observed for CPDl . In native tissue, CPDl modulated neurotransmitter release and synaptic activity with a similar profile to L-AP4 (non-selective agonist). Unlike L-AP4, the effects of CPDl on synaptic activity were observed to be entirely mGluR7 specific.
• Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease. J Pharmacol Exp Ther., 332 (3), 1064-71.

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