NZ774642B2 - Azabenzimidazoles and their use as ampa receptor modulators - Google Patents
Azabenzimidazoles and their use as ampa receptor modulators Download PDFInfo
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- NZ774642B2 NZ774642B2 NZ774642A NZ77464216A NZ774642B2 NZ 774642 B2 NZ774642 B2 NZ 774642B2 NZ 774642 A NZ774642 A NZ 774642A NZ 77464216 A NZ77464216 A NZ 77464216A NZ 774642 B2 NZ774642 B2 NZ 774642B2
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- cycloalkyl
- haloalkyl
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- 102000003678 AMPA Receptors Human genes 0.000 title claims 7
- 108090000078 AMPA Receptors Proteins 0.000 title claims 7
- 150000001875 compounds Chemical class 0.000 claims abstract 23
- 150000001204 N-oxides Chemical class 0.000 claims abstract 5
- 150000003839 salts Chemical class 0.000 claims abstract 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 4
- 239000012453 solvate Substances 0.000 claims abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims 52
- -1 -CH -pyrazinyl Chemical group 0.000 claims 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims 20
- 125000001188 haloalkyl group Chemical group 0.000 claims 20
- 125000005843 halogen group Chemical group 0.000 claims 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 16
- 125000002393 azetidinyl group Chemical group 0.000 claims 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 14
- 125000004076 pyridyl group Chemical group 0.000 claims 14
- 125000003545 alkoxy group Chemical group 0.000 claims 10
- 201000010099 disease Diseases 0.000 claims 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims 8
- 125000003566 oxetanyl group Chemical group 0.000 claims 8
- 201000000980 schizophrenia Diseases 0.000 claims 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 8
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims 7
- 101150065749 Churc1 gene Proteins 0.000 claims 7
- 102100038239 Protein Churchill Human genes 0.000 claims 7
- 125000002541 furyl group Chemical group 0.000 claims 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 7
- 125000001544 thienyl group Chemical group 0.000 claims 7
- 208000035475 disorder Diseases 0.000 claims 6
- 230000001404 mediated effect Effects 0.000 claims 6
- 125000002757 morpholinyl group Chemical group 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 5
- 206010029216 Nervousness Diseases 0.000 claims 4
- 208000002193 Pain Diseases 0.000 claims 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 4
- 208000010877 cognitive disease Diseases 0.000 claims 4
- 206010015037 epilepsy Diseases 0.000 claims 4
- 208000020016 psychiatric disease Diseases 0.000 claims 4
- 206010061811 demyelinating polyneuropathy Diseases 0.000 claims 3
- 125000004193 piperazinyl group Chemical group 0.000 claims 3
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- 208000030507 AIDS Diseases 0.000 claims 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 2
- 208000019901 Anxiety disease Diseases 0.000 claims 2
- 208000020925 Bipolar disease Diseases 0.000 claims 2
- 201000006474 Brain Ischemia Diseases 0.000 claims 2
- 206010058019 Cancer Pain Diseases 0.000 claims 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims 2
- 208000000094 Chronic Pain Diseases 0.000 claims 2
- 208000016192 Demyelinating disease Diseases 0.000 claims 2
- 208000020401 Depressive disease Diseases 0.000 claims 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims 2
- 206010019196 Head injury Diseases 0.000 claims 2
- 208000023105 Huntington disease Diseases 0.000 claims 2
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 claims 2
- 208000019695 Migraine disease Diseases 0.000 claims 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims 2
- 208000008238 Muscle Spasticity Diseases 0.000 claims 2
- 206010028570 Myelopathy Diseases 0.000 claims 2
- 206010069350 Osmotic demyelination syndrome Diseases 0.000 claims 2
- 208000018737 Parkinson disease Diseases 0.000 claims 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims 2
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 208000011235 central nervous system lupus Diseases 0.000 claims 2
- 208000010353 central nervous system vasculitis Diseases 0.000 claims 2
- 208000009885 central pontine myelinolysis Diseases 0.000 claims 2
- 206010008118 cerebral infarction Diseases 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 206010014599 encephalitis Diseases 0.000 claims 2
- 125000006379 fluoropyridyl group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 206010027599 migraine Diseases 0.000 claims 2
- 201000006417 multiple sclerosis Diseases 0.000 claims 2
- 230000004770 neurodegeneration Effects 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- 208000008795 neuromyelitis optica Diseases 0.000 claims 2
- 201000006292 polyarteritis nodosa Diseases 0.000 claims 2
- 208000028173 post-traumatic stress disease Diseases 0.000 claims 2
- 201000000306 sarcoidosis Diseases 0.000 claims 2
- 208000018198 spasticity Diseases 0.000 claims 2
- 208000020431 spinal cord injury Diseases 0.000 claims 2
- 239000003053 toxin Substances 0.000 claims 2
- 231100000765 toxin Toxicity 0.000 claims 2
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 claims 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims 1
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical group OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000000750 progressive effect Effects 0.000 claims 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof, [formula (I) should be inserted here]. Also provided herein are pharmaceutical compositions comprising compounds of Formula (I) and methods of using compounds of Formula (I).
Claims (27)
1. A compound of Formula (I): 5 wherein X is N or CR ; R is a member selected from the group consisting of: -C alkyl, -C haloalkyl, -C alkoxy, -(CH ) C(=O)OCH , -(CH ) OH, -(CH ) O-C 1-5 1-5 1-5 2 2 3 2 1-3 2 1-2 1- alkyl, -CH(CH )OCH , -C(CH ) OCH , -CH SO CH , -C(=O)H, -NH-C alkyl, -N(C 5 3 3 3 2 3 2 2 3 1-5 1- 10 alkyl) , -C(=O)N(H)C alkyl, -C(=O)N(C alkyl) , -C cycloalkyl, -(CH )-C 5 2 1-5 1-5 2 3-8 2 3- cycloalkyl, -CH(CH )-C cycloalkyl, -NH-C cycloalkyl, -C(=O)NH-cyclopropyl,- 8 3 3-8 3-8 C(=O)-NH-phenyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, azetidinyl, phenyl, benzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH -pyrazinyl, furanyl, thienyl, and pyridinyl, wherein the -C3-8cycloalkyl, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 15 tetrahydropyranyl, pyridinyl, -CH -pyrazinyl, furanyl and thienyl rings are each independently optionally substituted with 1-3 substituents selected from the group consisting of: halo, -C alkyl, -C haloalkyl, -C haloalkoxy, -OH, and -C(=O)OC 1-5 1-5 1-5 1- alkyl; R is: 20 ; wherein R is optionally substituted with a member selected from the group consisting of: H, halo, -C alkyl, -C alkenyl, -CN, -OH, CH=CHCH OH, C(=O)OC 1-5 1-5 2 1- alkyl, and phenyl; R is selected from the group consisting of: H, halo, -C alkyl, -S-C alkyl, -C haloalkyl, -C 1-5 1-5 1-5 1- 3a 3b alkoxy, -NR R , -OH, -(CH ) OH, -CH=CHCH OH, -C cycloalkyl, piperidinyl, 5 2 1-3 2 3-8 piperazinyl, morpholinyl, and pyridyl; 3a 3b each R and R are independently selected from the group consisting of H and C alkyl; 5 R is selected from the group consisting of: H, halo, -CH , and -CF ; R is selected from the group consisting of: H, -OH, -C alkyl, -C alkoxy, -C haloalkyl, -C 1-5 1-5 1-5 1- 5a 5b 5a 5b haloalkoxy, -NR R , azetidinyl, and morpholinyl; each R and R are independently selected from the group consisting of: -C alkyl, and -C haloalkyl; and 1-5 1-5 R is selected from the group consisting of: H, -OH, -CHF , and -Br; 10 or a pharmaceutically acceptable salt, N-oxide, or solvate thereof.
2. The compound of claim 1, wherein X is N.
3. The compound of claim 1, wherein X is CR .
4. The compound of claim 1, wherein R is H.
5. The compound of claim 1, wherein R is -C alkyl, -C haloalkyl, -C alkoxy, - 1-5 1-5 1-5 (CH ) C(=O)OCH , -(CH ) -OH, -C(CH ) OCH , -(CH ) -O-C alkyl, -CH(CH )OCH , - 2 2 3 2 3 3 2 3 2 1-2 1-5 3 3 20 CH SO CH , -NH-C alkyl, -N(C alkyl) , -C(=O)N(H)C alkyl, or -C(=O)N(C alkyl) . 2 2 3 1-5 1-5 2 1-5 1-5 2
6. The compound of claim 1, wherein R is -C alkyl, -C haloalkyl, -C alkoxy, -(CH ) -OH, - 1-5 1-5 1-5 2 3
7. (CH ) -O-C alkyl, -C(CH ) OCH , or -CH(CH )OCH . 2 1-2 1-5 3 2 3 3 3 25 7. The compound of claim 1, wherein R is -C cycloalkyl, -(CH )-C cycloalkyl, -CH(CH )-C 3-8 2 3-8 3 3- cycloalkyl, NH-C cycloalkyl, -C(=O)NH-cyclopropyl, -C(=O)-NH-phenyl, -C(=O)- 8 3-8 azetidinyl, -C(=O)-pyrrolidinyl, azetidinyl, phenyl, benzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH -pyrazinyl, furanyl, thienyl, or pyridinyl, wherein the -C cycloalkyl, 2 3-8 phenyl, oxetanyl, azetidinyl, and pyridinyl rings are each independently optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, -C alkyl, -C 1-5 1- 5 haloalkyl, -C haloalkoxy, -OH, and -C(=O)OC alkyl. 5 1-5 1-5
8. The compound of claim 1, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- fluorocyclopropyl, 3-fluorocyclobutyl, cyclopropanol, 2-furyl, 3-methyloxetanyl, 2- tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, cyclopentylmethyl, pyrazinylmethyl, - 10 C(=O)NH-cyclopropyl, -C(=O)-NH-phenyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, or NH- cyclohexyl.
9. The compound of claim 1, wherein R is -C cycloalkyl, phenyl, -CH -phenyl, or pyridyl, 3-8 2 wherein each phenyl, -CH -phenyl, or pyridyl is optionally substituted with 1-3 substituents 15 independently selected from the group consisting of: halo, -C alkyl, -C haloalkyl, -C 1-5 1-5 1- haloalkoxy, and -OH.
10. The compound of claim 1, wherein R is phenyl, 2-chlorophenyl, 4-fluorophenyl, 4- (difluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-fluoromethyl- 20 phenyl, p-tolyl, m-tolyl, pyridyl, 2-chloropyridyl, 2-bromopyridyl, 2-fluoropyridyl, 2- 19 18 [ F]fluoropyridyl, 2-[ F]fluoropyridyl, 5-fluoropyridyl, 6-fluoropyridyl, or pyridin
11. The compound of claim 1, wherein R is -C alkyl, -C ,haloalkyl, or -C cycloalkyl, wherein 1-5 1-5 3-8 25 the -C cycloalkyl is optionally substituted with halo.
12. The compound of claim 1, wherein R is optionally substituted with a member selected from the group consisting of: halo, -C alkyl, -C alkenyl, -CN, -OH, CH=CHCH OH, C(=O)OC 1-5 1-5 2 1- alkyl, and phenyl. 5
13. The compound of claim 1, wherein R is 1H-indolyl. is H, halo, -C alkyl, -C haloalkyl, -OCH , -NH , -
14. The compound of claim 1, wherein R 1-5 1-5 3 2 N(CH ) , or -OH.
15. The compound of claim 1, wherein R is H, fluoro or -CH .
16. The compound of claim 1, wherein R is H, -OH, -C alkyl, -C haloalkyl, or -C haloalkoxy. 1-5 1-5 1-5 15
17. The compound of claim 1, wherein R is H.
18. A pharmaceutical composition comprising: (A) an effective amount of at least one compound of Formula (I): 20 wherein X is N or CR ; R is a member selected from the group consisting of: -C alkyl, -C haloalkyl, -C alkoxy, -(CH ) C(=O)OCH , -(CH ) OH, -(CH ) O-C 1-5 1-5 1-5 2 2 3 2 1-3 2 1-2 1- alkyl, -CH(CH )OCH , -C(CH ) OCH , -CH SO CH , -C(=O)H, -NH-C alkyl, -N(C 5 3 3 3 2 3 2 2 3 1-5 1- alkyl) , -C(=O)N(H)C alkyl, -C(=O)N(C alkyl) , -C cycloalkyl, -(CH )-C 5 2 1-5 1-5 2 3-8 2 3- cycloalkyl, -NH-C cycloalkyl, -C(=O)NH-cyclopropyl,-C(=O)-NH-phenyl, -C(=O)- 8 3-8 5 azetidinyl, -C(=O)-pyrrolidinyl, azetidinyl, phenyl, benzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH -pyrazinyl, furanyl, thienyl, and pyridinyl, wherein the -C cycloalkyl, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, - CH -pyrazinyl, furanyl and thienyl rings are each independently optionally substituted with 1-3 substituents selected from the group consisting of: halo, -C alkyl, -C 1-5 1- 10 haloalkyl, -C haloalkoxy, -OH, and -C(=O)OC alkyl; 5 1-5 1-5 R is: ; wherein R is optionally substituted with H, halo, -C alkyl, -C alkenyl -CN, 1-5 1-5 -OH, CH=CHCH OH, C(=O)OC alkyl, and phenyl; 2 1-5 R is selected from the group consisting of: H, halo, -C alkyl, -S-C alkyl, -C haloalkyl, -C 1-5 1-5 1-5 1- 3a 3b 15 alkoxy, -NR R , -OH, -(CH ) OH, -CH=CHCH OH, -C cycloalkyl, piperidinyl, 5 2 1-3 2 3-8 piperazinyl, morpholinyl, and pyridyl; 3a 3b each R and R are independently selected from the group consisting of H and C alkyl; R is selected from the group consisting of: H, halo, -CH , and -CF ; R is selected from the group consisting of: H, -OH, -C1-5alkyl, -C1-5alkoxy, -C1-5haloalkyl, -C1- 5a 5b 5a 5b 20 haloalkoxy, -NR R , azetidinyl, and morpholinyl; each R and R are independently selected from the group consisting of: -C alkyl, and -C haloalkyl; and 1-5 1-5 R is selected from the group consisting of: H, -OH, -CHF , and -Br; or a pharmaceutically acceptable salt, N-oxide or solvatethereof; and (B) at least one pharmaceutically acceptable excipient.
19. Use of a compound of Formula (I) in the manufacture of a medicament for treatment of a disease, disorder, or medical condition mediated by AMPA receptor activity: wherein 5 X is N or CR ; R is a member selected from the group consisting of: -C alkyl, -C haloalkyl, -C alkoxy, -(CH ) C(=O)OCH , -(CH ) OH, -(CH ) O-C 1-5 1-5 1-5 2 2 3 2 1-3 2 1-2 1- alkyl, -CH(CH )OCH , -C(CH ) OCH , -CH SO CH , -C(=O)H, -NH-C alkyl, -N(C 5 3 3 3 2 3 2 2 3 1-5 1- alkyl) , -C(=O)N(H)C alkyl, -C(=O)N(C alkyl) , -C cycloalkyl, -(CH )-C 5 2 1-5 1-5 2 3-8 2 3- 10 cycloalkyl, -NH-C cycloalkyl, -C(=O)NH-cyclopropyl,-C(=O)-NH-phenyl, -C(=O)- 8 3-8 azetidinyl, -C(=O)-pyrrolidinyl, azetidinyl, phenyl, benzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH -pyrazinyl, furanyl, thienyl, and pyridinyl, wherein the -C cycloalkyl, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, - CH2-pyrazinyl, furanyl and thienyl rings are each independently optionally substituted 15 with 1-3 substituents selected from the group consisting of: halo, -C alkyl, -C 1-5 1- haloalkyl, -C haloalkoxy, -OH, and -C(=O)OC alkyl; 5 1-5 1-5 R is: ; wherein R is optionally substituted with H, halo, -C alkyl, -C alkenyl -CN, 1-5 1-5 -OH, CH=CHCH OH, C(=O)OC alkyl, and phenyl; 2 1-5 20 R is selected from the group consisting of: H, halo, -C alkyl, -S-C alkyl, -C haloalkyl, -C 1-5 1-5 1-5 1- 3a 3b alkoxy, -NR R , -OH, -(CH ) OH, -CH=CHCH OH, -C cycloalkyl, piperidinyl, 5 2 1-3 2 3-8 piperazinyl, morpholinyl, and pyridyl; 3a 3b each R and R are independently selected from the group consisting of H and C alkyl; R is selected from the group consisting of: H, halo, -CH , and -CF ; R is selected from the group consisting of: H, -OH, -C alkyl, -C alkoxy, -C haloalkyl, -C 1-5 1-5 1-5 1- 5a 5b 5a 5b haloalkoxy, -NR R , azetidinyl, and morpholinyl; each R and R are independently selected from the group consisting of: -C alkyl, and -C haloalkyl; and 1-5 1-5 5 R is selected from the group consisting of: H, -OH, -CHF , and -Br; or a pharmaceutically acceptable salt, N-oxide or solvate thereof.
20. The use of claim 19, wherein the AMPA receptor mediated disease, disorder, or medical condition is selected from cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, 10 Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy, Guillain Barre syndrome, chronic inflammatory 15 demyelinating polyneuropathy, multiple sclerosis, Marchiafava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, a secondary demyelinating disorder, CNS lupus erythematodes, polyarteritis nodosa, Sjogren syndrome, sarcoidosis, isolated cerebral vasculitis, schizophrenia, prodromal schizophrenia, cognitive disorder, depression, anxiety disorders, anxious depression, 20 and bipolar disorder.
21. The use of claim 20, wherein the AMPA receptor mediated disease, disorder or condition is depression, post-traumatic stress disorder, epilepsy, schizophrenia, prodromal schizophrenia, or a cognitive disorder.
22. Use of a pharmaceutical composition of claim 18 in the manufacture of a medicament for treatment of a disease, disorder, or medical condition mediated by AMPA receptor activity.
23. The use of claim 22, wherein the AMPA receptor mediated disease, disorder, or medical condition is selected from cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease,
24. Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance 5 by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy, Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchiafava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal 10 leucoencephalopathy, a secondary demyelinating disorder, CNS lupus erythematodes, polyarteritis nodosa, Sjogren syndrome, sarcoidosis, isolated cerebral vasculitis, schizophrenia, prodromal schizophrenia, cognitive disorder, depression, anxiety disorders, anxious depression, and bipolar disorder. 15 24. The use of claim 23, wherein the AMPA receptor mediated disease, disorder or condition is depression, post-traumatic stress disorder, epilepsy, schizophrenia, prodromal schizophrenia, or a cognitive disorder.
25. A compound of Formula (I) or a pharmaceutically acceptable salt, N-oxide, or solvate thereof 20 as claimed in any one of claims 1-17 substantially as herein described and with reference to any example thereof.
26. A pharmaceutical composition as claimed in claim 18 substantially as herein described and with reference to any example thereof.
27. A use as claimed in any one of claims 19-24 substantially as herein described and with reference to any example thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562154313P | 2015-04-29 | 2015-04-29 | |
| NZ736057A NZ736057B2 (en) | 2016-04-28 | Azabenzimidazoles and their use as ampa receptor modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ774642A NZ774642A (en) | 2024-09-27 |
| NZ774642B2 true NZ774642B2 (en) | 2025-01-07 |
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