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JP-7856644-B2 - MAGL inhibitors

JP7856644B2JP 7856644 B2JP7856644 B2JP 7856644B2JP-7856644-B2

Inventors

  • ウィーナー，ジョン，ジェイ．エム．
  • グライス，シェリル，エー．
  • バザード，ダニエル，ジェイ．
  • チーサシュ，ジャスティン，エス．
  • ウェバー，オリビア，デー．
  • アラン，エイミー
  • ラファエル，ニコラス
  • ムーディー，ジェーン，ブイ．
  • シャガフィ，マイケル，ビー．

Assignees

  • ハー・ルンドベック・アクチエゼルスカベット

Dates

Publication Date
20260511
Application Date
20211112
Priority Date
20201113

Claims (17)

  1. Equation (I): (In the formula, R1 represents -C(O)NHR2, -C(O)N( CH3 )R2, -C(O)NR3R4, -C(O) NHCH2R2 , or -C(O)NHC(O)R2; R2 represents a phenyl or a five- or six-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S; a six-membered heterocycle having one or two heteroatoms independently selected from N or O; a C3 - C7 cycloalkyl; or a seven-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O; R3 and R4, together with the N to which they are bonded , form a nine-membered or ten-membered bicyclic heterocycle having one to four heteroatoms independently selected from N or O, or a six-membered heterocycle having one or two heteroatoms independently selected from N or O; Each phenyl, five- or six-membered heteroaryl, six-membered heterocycle, C3 - C7 cycloalkyl, seven-membered bicyclic heterocycle, or nine- or ten-membered bicyclic heterocycle is unsubstituted or substituted with halogens, C1 - C3 alkyl, C1 - C3 haloalkyl, C3 - C6 cycloalkyl, C1 - C3 alkoxy, cyano, -NHC(O) CH3 , -C(O) NH2 , -C(O) NHCH3 , five-membered heteroaryl having one or two heteroatoms independently selected from N or O , -NHSO2CH3 , -P(O)( CH3 ) 2 , and -OCH2COOH ) compounds or pharmaceutically acceptable salts thereof.
  2. Equation (Ia): (In the formula, R1 represents -C(O)NHR2, -C(O)N( CH3 )R2, -C(O)NR3R4, -C(O) NHCH2R2 , or -C(O)NHC(O)R2; R2 represents a phenyl or a five- or six-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S; a six-membered heterocycle having one or two heteroatoms independently selected from N or O; a C3 - C7 cycloalkyl; or a seven-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O; R3 and R4, together with the N to which they are bonded , form a nine-membered or ten-membered bicyclic heterocycle having one to four heteroatoms independently selected from N or O, or a six-membered heterocycle having one or two heteroatoms independently selected from N or O; Each phenyl, five- or six-membered heteroaryl, six-membered heterocycle, C3 - C7 cycloalkyl, seven-membered bicyclic heterocycle, or nine- or ten-membered bicyclic heterocycle is unsubstituted or substituted with halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C3 - C6 cycloalkyl, C1 - C3 alkoxy, cyano, -NHC(O) CH3 , -C(O) NH2 , -C(O) NHCH3 , five-membered heteroaryl having one or two heteroatoms independently selected from N or O , -NHSO2CH3 , -P(O)( CH3 ) 2 , and -OCH2COOH , is a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein R1 represents -C(O)NHR2.
  4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R2 represents a five- or six-membered heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyridadinyl, pyrimidyl, pyrazolyl, thiazolyl, and isoxazolyl, and the five- or six - membered heteroaryl is unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, cyclopropyl, C1 - C3 alkoxy , cyano, -NHC(O) CH3 , -C(O) NH2 , -C(O)NHCH3, one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)( CH3 ) 2 , and -OCH2COOH .
  5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R2 represents a six-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, and R2 is either unsubstituted or substituted with a single substituent selected from the group consisting of C1-C3 alkyl, C3 -C6 cycloalkyl, and cyano.
  6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2 represents a six-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, and R2 is unsubstituted.
  7. Formula (Ic): (In the formula, R5 represents a phenyl or a five- or six-membered heteroaryl, a six-membered heterocycle, a C3 - C7 cycloalkyl, or a seven-membered bicyclic heterocycle having one or two heteroatoms independently selected from N, O, and S; R6 represents hydrogen or methyl; W is -CH₂- or -C(O)-; n is either 0 or 1; Each compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, having a structure (where each phenyl, five - membered or six-membered heteroaryl, six -membered heterocycle, C3 - C7 cycloalkyl, or seven- membered bicyclic heterocycle is unsubstituted or substituted with halogen, C1 -C3 alkyl, C1- C3 haloalkyl, C3-C6 cycloalkyl, C1 - C3 alkoxy, cyano , -NHC(O) CH3 , -C(O) NH2 , -C(O) NHCH3 , a five - membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)( CH3 )2, and -OCH2COOH).
  8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  9. The compound according to any one of claims 7 to 8 or a pharmaceutically acceptable salt thereof, wherein R5 represents a five- or six-membered heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyridadinyl, pyrimidyl, pyrazolyl, thiazolyl, and isoxazolyl, and the five- or six - membered heteroaryl is unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1 - C3 alkyl, C1 -C3 haloalkyl, cyclopropyl, C1-C3 alkoxy , cyano , -NHC(O) CH3 , -C(O) NH2 , -C(O)NHCH3, one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)( CH3 ) 2 , and -OCH2COOH .
  10. The compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein R5 represents a six-membered heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyridadinyl, and pyrimidyl, and the six-membered heteroaryl is unsubstituted.
  11. The compound according to any one of claims 7 to 8 or a pharmaceutically acceptable salt thereof, wherein R5 represents a six-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, and R5 is either unsubstituted or substituted with one substituent selected from the group consisting of C1-C3 alkyl, C3 - C6 cycloalkyl, and cyano.
  12. A compound according to any one of claims 7 to 11, or a pharmaceutically acceptable salt thereof, wherein R5 is unsubstituted.
  13. 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyridine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(methyl(pyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(isoxazole-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-(trifluoromethyl)pyrimidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(dimethylphosphoryl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyridine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(1H-pyrazole-1-yl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(methylcarbamoyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-methoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((5-fluoropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(methyl(pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(methyl(pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyridine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyrazine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((5-chloropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(trifluoromethyl)pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(((6-(trifluoromethyl)pyridine-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((pyridine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyrimidine-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-(trifluoromethyl)pyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-methylpyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-methylpyridazine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(pyridazine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((5-methylpyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((1-methylpiperidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((1-methyl-1H-pyrazole-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(thiazole-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((1-methyl-1H-pyrazole-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(thiazole-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate: 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((pyrimidine-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((pyridazine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((2-Oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-Azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-cyclopropylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-isopropoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-acetamidopyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-carbamoylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(isoxazole-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-((6-(methylsulfonamide)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; (±) 2-((5-(6-(((1,1,1,3,3,3-hexafluoropropane-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octan - 1-carboxamide)pyridine-2-yl)oxy)acetic acid; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(±)1-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; A compound according to claim 1, selected from the group consisting of 1,1,1,3,3,3-hexafluoropropan-2-yl(±)1-(methyl(pyridazine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; and 1,1,1,3,3,3-hexafluoropropan-2-yl(±)1-((6-cyanopyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, or a pharmaceutically acceptable salt thereof.
  14. 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyridine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(methyl(pyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(methyl(pyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(isoxazole-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(isoxazole-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-(trifluoromethyl)pyrimidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-(trifluoromethyl)pyrimidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(dimethylphosphoryl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(dimethylphosphoryl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyridine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(1H-pyrazole-1-yl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(1H-pyrazole-1-yl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(methylcarbamoyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(methylcarbamoyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-methoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-methoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((5-fluoropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((5-fluoropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(methyl(pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(methyl(pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(methyl(pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(methyl(pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyridine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyrazine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyrazine-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((5-chloropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((5-chloropyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(trifluoromethyl)pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(trifluoromethyl)pyridine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(((6-(trifluoromethyl)pyridine-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(((6-(trifluoromethyl)pyridine-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-methylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-(trifluoromethyl)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((pyridine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((pyridine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyrimidine-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyrimidine-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-(trifluoromethyl)pyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-(trifluoromethyl)pyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-methylpyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-methylpyrimidine-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-methylpyridazine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-methylpyridazine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(pyridazine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazine-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((5-methylpyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((5-methylpyrazine-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((1-methylpiperidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((1-methylpiperidine-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((1-methyl-1H-pyrazole-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((1-methyl-1H-pyrazole-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(thiazole-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(thiazole-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((1-methyl-1H-pyrazole-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((1-methyl-1H-pyrazole-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(thiazole-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(thiazole-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((pyrimidine-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((pyrimidine-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((pyridazine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((pyridazine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((2-Oxaspiro[3,3]heptan-6-yl)carbamoyl)-6-Azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((2-Oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-Azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-cyclopropylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-cyclopropylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-isopropoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-isopropoxypyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-acetamidopyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-acetamidopyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-carbamoylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-carbamoylpyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-(isoxazole-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(isoxazole-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(R)-1-((6-(methylsulfonamide)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-((6-(methylsulfonamide)pyridine-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of (R)-2-((5-(6-(((1,1,1,3,3,3-hexafluoropropane-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxamide)pyridine-2-yl)oxy)acetic acid; and (S)-2-((5-(6-(((1,1,1,3,3,3-hexafluoropropane-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxamide)pyridine-2-yl)oxy)acetic acid.
  15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.
  16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.
  17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(isoxazole-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

Description

This invention relates to compounds that are monoacylglycerol lipase (MAGL) inhibitors. Another aspect of the invention relates to pharmaceutical compositions comprising the compounds, and to the use of the compounds for treating diseases and disorders related to the modulation of endogenous cannabinoid signaling activity. MAGL is a member of the serine hydrolase superfamily. MAGL is expressed throughout the brain, including in neurons, microglial cells, astrocytes, and oligodendrocytes. MAGL is the key enzyme that regulates the breakdown of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol. 2007; Nomura et al. Science. 2011). 2-AG is the most abundant endogenous cannabinoid ligand in the brain, where it functions as a retrograde messenger that reduces excessive neurotransmission through activation of presynaptic CB1 receptors (Kano et al. Physiol Rev. 2009; Katona and Freund. Physiol Rev. 2009), modulates the immune response through activation of microglial cell CB2 receptors (Turcotte et al. Cell Mol Life Sci. 2016), and promotes neuroprotection, for example, by influencing oligodendrocyte production and survival (Ilyasov et al. Front Neurosci. 2018). AA is one of the most abundant fatty acids in the brain and is a major precursor to prostanoids and eicosanoids such as leukotrienes, which are known as inflammatory mediators. MAGL lies at the crossroads between the endogenous cannabinoid and eicosanoid signaling systems. Inhibiting the action or activation of MAGL is a promising therapeutic approach for the prevention or treatment of brain disorders, including those characterized by hypertransmission, neuroinflammation, or neurodegeneration, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, epilepsy, pain, migraines, addiction, anxiety, depression, and other stress-related disorders (Grabner et al. Pharmacol Ther. 2017; Mulvihill et al. Life Sci. 2013; Gil-Ordonez et al. Biochem Pharmacol. 2018). International Publication No. 2019/046318 discloses spirocyclic compounds that are MAGL inhibitors. International Publication No. 2019/046330 discloses spirocyclic compounds that are MAGL inhibitors. Despite advances in MAGL research, there is still a shortage of potent, effective, and selective inhibitors of MAGL that are beneficial for treating neurological and psychiatric disorders associated with diseases or disorders that benefit from inhibiting MAGL activation. The object of the present invention is to provide a compound that inhibits MAGL. Therefore, the present invention relates to formula (I), (In the formula, R1 represents -C(O)NHR2, -C(O)N( CH3 )R2, -C(O)NR3R4, -C(O) NHCH2R2 , or -C(O)NHC(O)R2; R2 represents a phenyl or a five- or six-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S; a six-membered heterocycle having one or two heteroatoms independently selected from N or O; a C3 - C7 cycloalkyl; or a seven-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O; R3 and R4, together with the N to which they are attached, form a nine-membered or ten-membered bicyclic heterocycle having one to four heteroatoms independently selected from N or O, or a six-membered heterocycle having one or two heteroatoms independently selected from N or O; The present invention provides compounds of each phenyl, five- or six-membered heteroaryl, six-membered heterocycle, C3 - C7 cycloalkyl, seven-membered bicyclic heterocycle, or nine- or ten-membered bicyclic heterocycle that are unsubstituted or substituted with halogens, C1 - C3 alkyl, C1 - C3 haloalkyl, C3 - C6 cycloalkyl, C1 - C3 alkoxy, cyano, -NHC(O) CH3 , -C(O) NH2 , -C (O) NHCH3 , five-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3 , -P(O)( CH3 ) 2 , and -OCH2COOH , or pharmaceutically acceptable salts thereof. In a further aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents. In a further aspect of the present invention, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the treatment of diseases or disorders selected from pain, epilepsy/paroxysmal disorders, Alzheimer's disease, Huntington's disease, Huntington's disease, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia. A further aspect of the present invention provides a method for treating neurological and/or psychiatric disorders selected from pain, epilepsy/paroxysmal disorders, Alzheimer's disease, Huntington's disease, Huntington's disease, multiple sclerosis, obsessive-compulsive disorder, Parkinson