Therapeutic compounds

(Cross-reference of related applications) This application is a non-provisional patent application 37 CFR §1.53 (b), filed 60 / 777,332 on February 28, 2006 and filed on February 16, 2007 in the US provisional patent application. Claim the priority of 37 CFR § 119 (e) over No. 60 / 890,455, the full disclosure of which is expressly incorporated herein by reference.

(Background of invention) Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-dependent metabolic enzyme important for the oxidative deamination of both endogenous amine neurotransmitters and heterologous amines. There are two reported forms of MAO, MAO-A and MAO-B, which arise from two independent genes (Bach, et. Al., Proc. Natl. Acad. Sci. 1988, 85, 4934- 4938). Both forms of MAO are distributed in varying amounts in different tissues throughout the body; MAO-B is more abundant than MAO-A in the human brain (Saura, et. Al., Neuroscience, 1996, 70, 755-774).

MAO-A has a high selectivity for serotonin and adrenaline, MAO-B is selective for tyramine and phenethylamine, and both isoforms metabolize dopamine. Studies have shown that levels of MAO-B activity in the brain increase with age (Fowler, et.al., J. Neural Transm., 1980, 49, 1-20). The process of oxidative deamination produces both peroxides and aldehydes as by-products and is associated with increased oxidative damage to the brain, especially to dopaminergic neurons, and nerves associated with diseases such as Alzheimer's disease and Parkinson's disease. Potentially exacerbates degeneration. It has also been reported that the levels of MAO-B activity present are higher in patients with Alzheimer's disease who may be associated with increased cognitive impairment in patients with Alzheimer's disease (Dostert, et. Al, Biochem. Pharmacol., 1989, 38, 555-561; and Emilsson, et.al., Neuroscience Letters, 2002, 326, 56-60). This relationship between oxidative stress and the progression of nerve damage suggests that inhibition of MAO-B minimizes the degenerative effects of both of these diseases, presumably by interfering with monoamine metabolism in the brain. In addition, relative increases in dopamine levels due to metabolic inhibition may have an effect on downstream regulation of plasticity-related cognitive function and may help repair rather than inhibit the progression of these diseases.

The use of selective MAO-B inhibitors for neurological disorders has been previously known (Bentue-Ferrer, et.al., CNS Drugs, 1996, 6, 217-236). The earliest MAO inhibitors in the treatment of depression were irreversible inhibitors with minimal MAO-B vs. MAO-A selectivity. This means that irreversible inhibitors may not be able to effectively metabolize dietary amines associated with cardiovascular events (cheese effects) and drug-drug interactions with other drugs metabolized by MAO-B. It can be a problem because of the potential side effects associated with both of the potentials of. More recent drugs, including ceregylin and rasagiline, are still irreversible inhibitors, but have a higher selectivity for MAO-B and a good side effect profile (Chen & Swope, J Clin Pharmacol. 2005 45, 878-94). Currently, there is a need for compounds that are useful in enhancing cognitive function and treating cognitive deterioration in Parkinson's and Alzheimer's diseases, as well as compounds that can generally improve cognition in normal, diseased, and aging subjects. Preferably, such agents have higher efficacy and / or fewer side effects than current therapeutic agents.

(Gist of the invention) The present invention provides, for example, MAO-B inhibitory compounds useful for enhancing cognitive function in animals (eg, humans). Accordingly, the present invention provides a method of inhibiting one or more MAO enzymes in an animal, comprising administering to the animal an effective amount of a compound of formula I that inhibits MAO.

Aspects listed The present invention provides the following listed aspects: 1. Equation I: <img file="JP2009528362A_D0001.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is aryl or heteroaryl; X is -C (= O), -C (= S), -C (R)⁴)₂, -C (OH)-, or -S (O)_ZIs; Each z is independently 0, 1, or 2; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_aR_{b b}, Het, or Het (C₁~ C₆) One or more Rs selected from the group consisting of alkyl_dUnreplaced or replaced with; or Two Rs with bonded atoms⁴The groups are aryl, Het, or carbon atoms and optionally O, S (O)._z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more additional heteroatoms selected from, each ring system optionally having one or more. R_dReplaced by; Each R_aAnd R_{b b}Independently hydrogen or (C₁~ C₆) Alkyl; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gPiperidino ring, pyrrolidino ring, morpholino ring or thiomorpholino ring shape and form, one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl; If X is -C (= O), then Y is not H) A method of inhibiting one or more MAO enzymes in an animal, comprising administering to the animal an MAO inhibitory effective amount of the compound or a pharmaceutically acceptable salt thereof.

2. The method of aspect 1, wherein B is a 6-12 member monocyclic or bicyclic heteroaryl.

3. The method according to any of the above embodiments, wherein B is a heteroaryl having more than one heteroatom.

4. The method according to any of the above embodiments, wherein B is aryl.

5. A method for improving cognitive function in an animal in need of treatment, comprising the step of administering to the animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments.

6. The method according to any of the above aspects, wherein the animal is a healthy animal.

7. The method according to any of the above aspects, wherein the animal is an aging animal.

8. Activate the CREB pathway in animals in need of treatment, including the step of administering to the animal an effective amount of CREB pathway activation effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments. how to.

9. Age-related memory impairment, cognitive impairment, in animals in need of treatment, comprising the step of administering to the animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments. How to treat Alzheimer's disease or Parkinson's disease.

10. The method according to any of the above aspects, wherein the animal has a mental disorder.

11. The method of any of the above embodiments, wherein the animal has a psychotic disorder, a neurological disorder, or a neurotic disorder.

12. The method according to any of the above embodiments, wherein the animal has a disorder of the central nervous system.

13. The method of any of the above embodiments, wherein the animal has head trauma, brain trauma, or cerebrovascular disease.

14. The method according to any of the above aspects, wherein the animal has attention deficit disorder.

15. The method according to any of the above aspects, wherein the psychotic disorder is schizophrenia.

16. The method according to any of the above aspects, wherein the animal has an affect disorder.

17. The method according to any of the above aspects, wherein the cerebrovascular disease is vascular dementia.

18. The method of any of the above embodiments, wherein cognitive impairment is associated with depression.

19. A method for treating a psychiatric disorder in an animal, comprising the step of administering to an animal in need of treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments.

20. The method according to any of the above aspects, wherein the psychiatric disorder is a psychotic disorder, a neurological disorder, or a neurotic disorder.

21. The method according to any of the above aspects, wherein the psychiatric disorder is a disorder of the central nervous system.

22. The method according to any of the above aspects, wherein the disorder of the central nervous system is age-related memory impairment, mild cognitive impairment, Alzheimer's disease or Parkinson's disease.

23. The method of any of the above embodiments, wherein the psychiatric disorder is associated with head trauma, brain trauma or cerebrovascular disease.

24. The method according to any of the above aspects, wherein the psychiatric disorder is attention deficit disorder.

25. The method according to any of the above aspects, wherein the psychotic disorder is schizophrenia.

26. The method according to any of the above aspects, wherein the mental disorder is an affect disorder.

27. The method according to any of the above embodiments, wherein the cerebrovascular disease is vascular dementia.

28. The method according to any of the above aspects, wherein the mental disorder is depressed.

29. The method according to any of the above embodiments, wherein the animal is a healthy animal.

30. The method according to any of the above embodiments, wherein the animal is an aging animal.

31. R¹Is (C₁~ C₆) Alkyl (C)₁~ C₆) Haloalkyl, or phenyl, halo, cyano, nitro, azide, (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) The method of any of the above embodiments, wherein the method is optionally substituted with one or more substituents independently selected from alkanoyloxy.

32. R¹The method of any of the above embodiments, wherein is trifluoromethyl, phenyl, methyl, or isopropyl.

33. R²The method of any of the above embodiments, wherein is absent.

34. R³The method of any of the above embodiments, wherein is absent.

35. R²Is (C₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, aryl, Het, or Het (C)₁~ C₆) The method according to any one of the above aspects, which is alkyl.

36. R²Describes any of the above embodiments, wherein is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, cyclopentyl, 2-pyridyl, 2-morpholinoethyl, 2,2,2-trifluoroethyl, or 2-hydroxyethyl. the method of.

37. R³Is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, aryl, Het, aryl (C)₁~ C₆) Alkyl, or Het (C₁~ C₆) The method according to any one of the above aspects, which is alkyl.

38. R³Hydrogen, methyl, ethyl, propyl, isopropyl, 2-pyridyl, cyclopentyl, phenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,2,2-trifluoroethyl, The method according to any one of the above embodiments, which is 2-hydroxyethyl, 4-chlorophenyl, benzyl, 4-nitrophenyl, 2-morpholinoethyl, or cyclohexyl.

39. The method of any of the above embodiments, wherein B is a benzene ring, a thiophene ring, or a pyridine ring.

40. The method of any of the above embodiments, wherein B is a thiophene ring.

41. The method of any of the above embodiments, wherein X is -C (= O).

42. Each R⁴Independently, H, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_{b b}R_c, Het, or Het (C₁~ C₆) The method according to any one of the above aspects, which is alkyl.

43. Each R⁴Independently, hydrogen, methyl, ethyl, butyl, propyl, isopropyl, 2-fluorophenethyl, 2-pyrrolidinoethyl, 2-furylmethyl, 4-methylbenzyl, cyclopropylmethyl, cyclohexylmethyl, 4-methoxybenzyl, 4-Fluorobenzyl, 4-pyridylmethyl, 4-chlorobenzyl, cyclohexyl, benzyl, 4-methylphenyl, 3-pyrrolidin-1-ylpropyl, 3-chlorobenzyl, 3,5-dimethylbenzyl, 2- (ethylthio) Ethyl, isobutyl, allyl, 2-hydroxyethyl, phenyl, 3-fluoro-6-methylbenzyl, 3-pyridylmethyl, 4-fluorophenethyl, 2-phenoxyethyl, 5-methyl-flu-2-ylmethyl, 2,2 , 2-Trifluoroethyl, 2-methoxyethyl, 2-methylbutyl, 2-imidazol-4-ylethyl, phenethyl, 2-morpholinoethyl, 3-methylbutyl, 2-piperidinoethyl, 3-methoxypropyl, 3-chlorobenzyl, 2 -Frillmethyl, 3,5-difluorobenzyl, 2- (2-furyl) ethyl, 3-imidazol-1-ylpropyl, 2-cyanoethyl, 2-ethylbutyl, 2-pyrid-3-ylethyl, S-α-hydroxy -β-Methylphenethyl, S-α-methylphenethyl, 4,4-dimethoxybutyl, 3- (2-oxopyrrolidin-1-yl) propyl, 2,2-dimethoxyethyl, 4-methylphenethyl, cyanomethyl, 3- Ethoxypropyl, 3- (N, N-dimethylamino) propyl, 3-morpholinopropyl, 2-hydroxypropyl, 2-methylpropyl, ethoxycarbonylmethyl, 2-methylphenyl, 2-hydroxyphenyl, tetrahydrofuran-2-ylmethyl, One of the above embodiments, which is R-tetra-2-ylmethyl, S-tetra-2-ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine, or N-piperidinyl. the method of.

44. Each R⁴Is independently hydrogen or (C₁~ C₆) The method according to any one of the above aspects, which is alkyl.

45. Both Rs with the bonding atom⁴Is a carbon atom and optionally O, S (O)_z, And NR_cForm a saturated or partially unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic or spiro ring system containing one or more additional heteroatoms selected from: The ring system is optionally one or more R_dReplaced by; z is 0, 1, or 2; Each R_cIndependently, hydrogen, aryl, amide, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, NR_fR_g, And (C₁~ C₆) Selected from alkanoyloxy; Each R_fAnd R_gIndependently hydrogen or (C₁~ C₆) Alkyl; or R with attached nitrogen_fAnd R_gIs the method of any of the above embodiments, wherein is the piperidino ring, the pyrrolidino ring, the morpholino ring, or the thiomorpholino ring.

46. Both Rs with the bonding atom⁴Are aziridine, morpholine, piperidine, 4-methylpiperidine, 2-hydroxymethylpyrrolidin, pyrrolidine, azetidine, 3-pyrrolin, 4- (4-fluorophenyl) piperidine, 3,5-dimethylmorpholin, 4- (2-hydroxy) Ethyl) piperidine, 3,5-dimethylpiperidine, indolin, R-3-hydroxypyrrolidin, 1,4-dioxa-8-aza-spiro [4.5] decane, 1,2,3,4-tetrahydroisoquinoline, 2,3 , 4,5,6,7-Hexahydroazepine, 4-hydroxymethylpiperidine, 4- (N, N-dimethylamino) piperidine, 4- (1-pyrrolidinyl) piperidine, 4-phenylpiperidine, 4-hydroxy-4 -Phenylpiperidin, 4- (carboxamide) piperidine, 4-hydroxypiperidine, 4-phenylpiperidine, 4-acetylpiperazine, 3-carboxamide piperidine, 2-carboxypiperidine, 4-trifluoromethylpiperidine, 3-trifluoromethylpiperidine Perhydroazotin, 3,6-dimethylpiperazine, 4-aminopiperidine, 4-hydroxy-4-trifluoromethylpiperidine, 4-methylhomopiperidin, thiomorpholin 1,1 dioxide, 4- (2'-pyridyl) piperidine , 4- (2'-methoxy) ethyl piperidine, 4-t-butoxycarbonylamino piperidine, perhydro-1,2-thiazine 1,1-dioxide, 3-amino piperidine, hexahydro-pyridazine, 4-difluoromethylene-piperidine, 3-Hydroxypiperidine, 4-ethylpiperazine, 4-fluoropiperidine, 4,4-difluoropiperidine, 3-fluoropiperidine, 3,3-difluoropiperidine, 4-isopropylpiperazine, 4-t-butoxycarbonylpiperazine, or 4- The method of any of the above embodiments, wherein benzylpiperidine is formed.

47. Both Rs with the bonding atom⁴Form a piperidine ring and optionally halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) Substituted with one or more of alkyl, any phenyl can optionally be one or more R_dReplaced by; each R_dIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; as well as each R_fAnd R_gIndependently hydrogen or (C₁~ C₆) Alkyl; or R with attached nitrogen_fAnd R_gIs the method of any of the above embodiments, wherein is the piperidino ring, the pyrrolidino ring, the morpholino ring, or the thiomorpholino ring.

48. Both Rs with bonding atoms⁴The method of any of the above embodiments, wherein the piperidine ring is formed.

49. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula II.<img file="JP2009528362A_D0002.tif" />

50. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula III.<img file="JP2009528362A_D0003.tif" />

51. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula IIIa.<img file="JP2009528362A_D0004.tif" />

52. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula IV.<img file="JP2009528362A_D0005.tif" />

53. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula IVa.<img file="JP2009528362A_D0006.tif" />

54. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula V.<img file="JP2009528362A_D0007.tif" />

55. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula Va.<img file="JP2009528362A_D0008.tif" />

56. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula Vb.<img file="JP2009528362A_D0009.tif" />

57. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VI.<img file="JP2009528362A_D0010.tif" />

58. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VIa.<img file="JP2009528362A_D0011.tif" />

59. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VIb.<img file="JP2009528362A_D0012.tif" />

60. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VII.<img file="JP2009528362A_D0013.tif" />

61. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VIIa.<img file="JP2009528362A_D0014.tif" />

62. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VIIIa.<img file="JP2009528362A_D0015.tif" />

63. The method of any of the above embodiments, wherein the compound of formula I is a compound of formula VIIIb.<img file="JP2009528362A_D0016.tif" />

64. Expression I:<img file="JP2009528362A_D0017.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is aryl or heteroaryl; X is -C (= O), -C (= S), -C (R)⁴)₂, Or -S (O)_zIs; Each z is independently 0, 1, or 2; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_aR_{b b}, Het, or Het (C₁~ C₆) Selected from the group consisting of alkyl, each alkyl, aryl, or Het is one or more R_dUnsubstituted or substituted with; or two Rs with an attached atom⁴Groups are aryl, Het, or carbon atoms and optionally O, S (O)_z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more additional heteroatoms selected from, each ring system optionally having one or more. R_dReplaced by; Each R_aAnd R_{b b}Independently hydrogen or (C₁~ C₆) Alkyl; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl (cabonyl) or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C_I~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl; B is thiophene and R¹Is trifluoromethyl and R²Is methyl and R³And R⁶Does not exist and R⁵Is H, X is C (= O), and Y is N (R)⁴)₂If, both R⁴Is not methyl) Compound.

65. <img file="JP2009528362A_D0018.tif" /><img file="JP2009528362A_D0019.tif" /><img file="JP2009528362A_D0020.tif" />The compound according to any of the above aspects, selected from the group consisting of.

66. Equation I:<img file="JP2009528362A_D0021.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is a 6-12 member monocyclic or bicyclic heteroaryl; X is -C (= O), -C (= S), -C (R)⁴)₂, Or -S (O)_zIs; Each z is independently 0, 1, or 2; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_aR_{b b}, Het, or Het (C₁~ C₆) One or more Rs selected from the group consisting of alkyl_dUnsubstituted or substituted with; or two Rs with an attached atom⁴The groups are aryl, Het, or carbon atoms and optionally O, S (O)._z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more heteroatoms selected from, each ring system optionally having one or more. R_dReplaced by; Each R_aAnd R_{b b}Independently hydrogen or (C₁~ C₆) Alkyl; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic ring or a heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl) Compound or pharmaceutically acceptable salt thereof.

67. <img file="JP2009528362A_D0022.tif" /><img file="JP2009528362A_D0023.tif" />The compound according to any of the above aspects, selected from the group consisting of.

[00073] 68. Equation I:<img file="JP2009528362A_D0024.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is thiophene, furan, or pyrrole; X is -C (= O), -C (= S), -C (R)⁴)₂, Or -S (O)_zIs; Each z is independently 0, 1, or 2; Y is -N (R⁴)₂Is; Both Rs with N binding⁴The group is a carbon atom and optionally O, S (O)_z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more additional heteroatoms selected from, and one or more Rs._dUnreplaced or replaced with, but both R⁴One or more other than halo or alkyl if the ring system is a monocyclic 5- to 7-membered ring system, provided that the group does not bind to form 2H-benzo [b] [1,4] oxazine. R_dReplaced by; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl) Compound or pharmaceutically acceptable salt thereof.

69. <img file="JP2009528362A_D0025.tif" /><img file="JP2009528362A_D0026.tif" /><img file="JP2009528362A_D0027.tif" />The compound according to any of the above aspects, selected from the group consisting of.

70. Equation I:<img file="JP2009528362A_D0028.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is thiophene, furan or pyrrole; X is -C (= O), -C (= S), -C (R)⁴)₂, Or -S (O)_zIs; Each z is independently O, 1, or 2; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, Amino, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_{b b}R_c, Het, or Het (C₁~ C₆) Selected from the group consisting of alkyl, each with one or more Rs^dUnsubstituted or replaced with; at least one R⁴Must be alkenyl, alkynyl, or amino; Each R_{b b}And R_cIndependently hydrogen or (C₁~ C₆) Alkyl; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl) Compound or pharmaceutically acceptable salt thereof.

71. Equation I:<img file="JP2009528362A_D0029.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is thiophene, furan, or pyrrole; X is -C (= S) or -C (R)⁴)₂Is; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Where X is -C (R)⁴)₂If, Y is -SR⁴Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_aR_{b b}, Het, or Het (C₁~ C₆) One or more Rs selected from the group consisting of alkyl_dTwo Rs with atoms that are unsubstituted, substituted, or bonded in⁴Groups are aryl, Het or carbon atoms and optionally O, S (O)_z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more heteroatoms selected from, each ring system optionally having one or more. R_dReplaced by; Each z is independently 0, 1, or 2; Each R_aAnd R_{b b}Independently hydrogen or (C₁~ C₆) Alkyl; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently, halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic ring or a heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl) Compound or pharmaceutically acceptable salt thereof.

72. Equation II:<img file="JP2009528362A_D0030.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One of them is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; Each Z¹, Z², And Z³Independently C (R⁶)_p, N (R)⁶)_q, O, or S, Z¹Is N (R)⁶)_q, O, or S, at least one Z¹Or Z²Is N (R)⁶)_qMust be, O, or S; Each p is independently 0, 1, or 2; Each q is independently 0 or 1; X is -C (= O), -C (= S), -C (R)⁴)₂, Or -S (O)_zIs; Each z is independently 0, 1, or 2; Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴, Or -C (R)⁴)₃Is; Each R⁴Independently, hydrogen, (C₁~ C₆) Alkyl, (C₂~ C₆) Alkenyl, (C₂~ C₆) Alkyne, (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, (C₃~ C₈) Cycloalkyl, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy (C₂~ C₆) Alkyl, hydroxy (C)₂~ C₆) Alkyl, cyano (C)₁~ C₆) Alkyl, (C₁~ C₆) Archicio (C₂~ C₆) Alkyl, aryl, aryl (C)₁~ C₆) Alkyl, aryloxy (C)₂~ C₆) Alkyl, halo (C₂~ C₆) Alkyl, (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl, NR_aR_{b b}, Het, or Het (C₁~ C₆) Selected from the group consisting of alkyl, each alkyl, aryl, or Het is one or more R_dTwo Rs with atoms that are unsubstituted, substituted, or bonded in⁴Groups are aryl, Het, or carbon atoms and optionally O, S (O)_z, And NR_cForm a saturated or unsaturated 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system containing one or more additional heteroatoms selected from, each ring system optionally having one or more. R_dReplaced by; Each R_aAnd R_{b b}Independently hydrogen or (C₁~ C₆) Alkyl; Each R_cIndependently hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl; X is -C (= O) and Y is -N (R)⁴)₂And Z¹Is O and Z²Is N and Z³If is CH, then both Rs of Y⁴Is not H) Compound or pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising the compound according to any of the above embodiments and a pharmaceutically acceptable diluent or carrier.

74. a) The step of deprotecting the corresponding compound containing one or more protecting groups to obtain the compound of formula I; b) The step of forming a pharmaceutically acceptable salt from the compound of formula I; c) For a compound of formula I where X is -C (= O)-, the intermediate acid of formula 100 is reacted with the amine of formula i.<img file="JP2009528362A_D0031.tif" />Step to obtain compound of formula I; or d) R²For the compound of formula I in which is absent, the intermediate diketone of formula 102 is reacted with the hydrazine of formula ii.<img file="JP2009528362A_D0032.tif" />Step to obtain compound of formula I A method for producing a compound of formula I or a salt thereof according to any one of the above embodiments.

75. A compound according to any of the above embodiments or a pharmaceutically acceptable salt thereof for use in medical treatment.

76. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments for the manufacture of a medicament useful for improving cognitive function in an animal.

77. Use according to any of the above embodiments, wherein the animal is a healthy animal.

78. Use according to any of the above embodiments, wherein the animal is an aging animal.

79. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments for the production of a medicament useful for inhibiting a MAO enzyme in an animal.

80. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments for the production of a medicament useful for activating the CREB pathway in animals.

81. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments for the manufacture of a medicament useful for treating a psychiatric disorder in an animal.

82. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of the above embodiments for the manufacture of a medicament useful for treating Alzheimer's disease in animals.

83. Use of a compound of formula I or a pharmaceutically acceptable salt according to any of the above embodiments for the manufacture of a medicament useful for treating Parkinson's disease in an animal.

84.<img file="JP2009528362A_D0033.tif" /><img file="JP2009528362A_D0034.tif" /><img file="JP2009528362A_D0035.tif" /><img file="JP2009528362A_D0036.tif" /><img file="JP2009528362A_D0037.tif" /><img file="JP2009528362A_D0038.tif" /><img file="JP2009528362A_D0039.tif" /><img file="JP2009528362A_D0040.tif" /><img file="JP2009528362A_D0041.tif" /><img file="JP2009528362A_D0042.tif" /><img file="JP2009528362A_D0043.tif" /><img file="JP2009528362A_D0044.tif" /><img file="JP2009528362A_D0045.tif" /><img file="JP2009528362A_D0046.tif" /><img file="JP2009528362A_D0047.tif" /><img file="JP2009528362A_D0048.tif" /><img file="JP2009528362A_D0049.tif" />A compound selected from the group consisting of.

85. The method of any of the above embodiments, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the compound of any of the above embodiments.

86. Equation I:<img file="JP2009528362A_D0050.tif" />(During the ceremony: R¹Is (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, or aryl, with one or more Rs_eUnreplaced or replaced with; R²And R³One is non-existent, the other is hydrogen, (C₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, (C₃~ C₈) Cycloalkyl, amino (C₂~ C₆) Alkyl, or aryl, respectively, alkyl, halo, haloalkyl or nitro, Het, (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl, aryl (C₁~ C₆) Alkyl, (C₁~ C₆) Or Het (C₁~ C₆) Unsubstituted or substituted with one or more groups selected from alkyl; B is a 5- to 12-membered monocyclic or bicyclic Het; X is -C (= O); Y is -OR⁴Is; R⁴Is a carbon atom and optionally O, S, and NR_cAn 8- to 12-membered bicyclic ring system containing one or more heteroatoms selected from, each ring system optionally having one or more Rs._dReplaced by; Each R_cIndependently, hydrogen, aryl, S (O)₂, (C₁~ C₆) Arcanoyl, hydroxy (C₁~ C₆) Alkoxy, Alkoxy (C₁~ C₆) Alkyl, Het, (C₁~ C₆) Alkoxycarbonyl or (C₁~ C₆) Alkyl and one or more substituents R_eUnreplaced or replaced with; Each R_dIndependently halo, hydroxy, cyano, nitro, azide, amino, (C₁~ C₆) Alkylamino, amino (C)₁~ C₆) Alkyl, amide, (C₁~ C₆) Alchiamide, arylamide, carboxylic acid, (C₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, Het, aryl, Het (C₁~ C₆) Alkyl, or aryl (C)₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl, sulfonyl, sulfonamide, urea, carbamate and one or more substituents R_eTwo Rs with atoms that are unsubstituted, substituted, or bonded in_dTwo Rs with atoms forming or bonding ketone or spirocyclic carbocyclic or heterocyclic rings_dForm a bicyclic carbocyclic or heterocyclic ring, where each spirocyclic or bicyclic ring is halo, hydroxy, cyano, nitro, azide, (C.₁~ C₆) Alkyl, hydroxy (C)₁~ C₆) Alkyl, halo (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, halo (C₁~ C₆) Alkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, (C₁~ C₆) Arcanoyloxy, NR_fR_g, R_fR_gNC (= O)-, phenyl, or phenyl (C)₁~ C₆) R with nitrogen that is unsubstituted or substituted with one or more of alkyl, sulfonyl, sulfonamide, urea, carbamate and bound_fAnd R_gForm a piperidino ring, pyrrolidino ring, morpholino ring, or thiomorpholino ring and one or more substituents R_eUnreplaced or replaced with; Each R_eIndependently, halo, hydroxy, cyano, nitro, azide, (C₁~ C₆) Alkyl, Het, Aryl, (C₁~ C₆) Alkyl Het, (C₁~ C₆) Alkylaryl, (C₁~ C₆) Alkyl Het (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylaryl (C₁~ C₆) Alkyl, (C₁~ C₆) Haloalkyl, (C₁~ C₆) Alkoxy, (C₁~ C₆) Haloalkoxy, (C₁~ C₆) Arcanoyl, (C₁~ C₆) Alkoxycarbonyl, carboxy, and (C₁~ C₆) Selected from alkanoyloxy; R⁵Is H, (C₁~ C₆) Alkyl, (C₁~ C₆) Alkenyl, (C₁~ C₆) Alkyne, aryl (C₁~ C₆) Alkyl; Each R⁶Is H, (C₁~ C₆) Alkyl, amino, amide, keto, or aryl (C)₁~ C₆) Alkyl) Compound or pharmaceutically acceptable salt thereof.

87. <img file="JP2009528362A_D0051.tif" />The compound according to any of the above aspects, selected from the group consisting of.

88. Y = R⁴The compound according to any one of the above embodiments.

(Detailed description of the invention) Unless otherwise stated, the following definitions are used: halos are fluorine, chlorine, bromine or iodine. Alkoxy, alkoxy, alkenyl, alkynyl, etc. indicate both straight chain and branched chain groups, but references to individual groups such as propyl are specifically referred to as straight chain groups, branched chains such as isopropyl. Includes only chain isomers. Aaryl represents a phenyl or ortho-fused bicyclic carbocyclic group having about 9-10 ring atoms with at least one aromatic ring; Het is a carbon atom and oxygen, sulfur, and N (X). ) Includes monocyclic, bicyclic or tricyclic ring system groups containing a total of 3 to 20 atoms, such as one or more heteroatoms selected from), where X is absent. Or H, O, (C₁~ C₄) Alkyl, phenyl or benzyl, one or more ring carbons of Het can be optionally substituted with oxo (= O); heteroaryls are carbons and oxygen, sulfur, and each non-peroxide oxygen, sulfur, and A group of monocyclic aromatic rings containing 5 or 6 ring atoms consisting of 1 to 4 heteroatoms selected from the group consisting of N (X), where X is absent or H, O, (C₁~ C₄) Alkyl, phenyl or benzyl, and ortho-fused bicyclic heterocycle radicals of about 8-10 ring atoms derived from ortho-fused bicyclic heterocycle radicals, specifically benz derivatives or Includes derivatives derived by fusing propylene, trimethylene, or tetramethylene bicyclic radicals to it. The term Het includes heteroaryl.

As used herein, the term "animal" includes birds, reptiles and mammals (eg, domestic mammals and humans).

As used herein, the term "selectively inhibits" means that a compound inhibits MAO-B activity to a greater extent than it inhibits MAO-A activity (in vitro or in vivo). means. In one aspect of the invention, the compound of formula I inhibits MAO-B activity more than twice as much as it inhibits MAO-A activity. In another aspect of the invention, the compound of formula I inhibits MAO-B activity more than 5-fold than it inhibits MAO-A activity. In another aspect of the invention, the compound of formula I inhibits MAO-B activity more than 10-fold more than it inhibits MAO-A activity. In another aspect of the invention, the compound of formula I inhibits MAO-B activity more than 100-fold more than it inhibits MAO-A activity.

As used herein, the term "psychiatric disorder" includes psychotic disorders, neurological disorders and neurotic disorders. The terms include schizophrenia, age-related memory impairment (AAMI); mild cognitive impairment (MCI), dementia (acute confusion); depression, dementia (often further classified as Alzheimer's or non-Alzheimer's); Alzheimer's disease; Parkinson's disease; Huntington's disease (butoh disease); mental retardation; (eg Rubinstein-Tevi syndrome and Down syndrome); cerebrovascular disease (eg vascular dementia, after heart surgery); emotional disorder; psychotic disorder Autism (Kanna syndrome); Neurological disorder; Attention defect disorder (ADD); Subdural hematoma; Alzheimer's disease; Brain tumor, head trauma (disorder after brain shaking) or brain trauma.

Those skilled in the art will appreciate that the compounds of the invention having a chiral center are optically active and in racemic form and can be isolated in that state. Some compounds may show polymorphisms. The present invention includes any racemic, optically active, polymorphic, stereoisomer or positional isomer of the compounds of the invention or mixtures thereof and has the useful properties described herein. That, how to prepare the optically active substance (eg, by resolution of racemate by recrystallization technique, synthesis from optically active initiator, chiral synthesis, or chromatographic separation using chiral stationary phase). And how to measure MAO-B inhibitory activity using the standard tests described herein or using other similar tests well known in the art is well known in the art. It will be understood that.

The specific and preferred values listed below for groups, substituents and ranges are for illustrative purposes only; do not exclude other specified values for groups and substituents or other values within the specified range. ..

Specifically, (C₁~ C₆) Alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl or hexyl; (C₂~ C₆) Alkenyl is vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2 -Can be hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; (C₂~ C₆) Alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, Can be 3-hexynyl, 4-hexynyl or 5-hexynyl; (C₃~ C₈) Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (C₃~ C₈) Cycloalkyl (C)₁~ C₆) Alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl; (C)₁~ C₆) Alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy or hexyloxy; cyano (C)₂~ C₆) Alkyl can be 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl or 4-cyanobutyl; (C₁~ C₆) Arcanoyl is acetyl, propanoyl or butanoyl; halo (C)₁~ C₆) Alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl: hydroxy (C)₁~ C₆) Alkyl can be hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 2,4-hydroxybutyl; (C₁~ C₆) Alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl or hexyloxycarbonyl; (C)₂~ C₆) Arcanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy or hexanoyloxy; (C)₁~ C₆) Alkoxy (C₂~ C₆) Alkyl can be 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 3-ethoxypropyl, 4,4-dimethoxybutyl; cyano (C)₁~ C₆) Alkyl can be cyanomethyl or cyanoethyl; (C₁~ C₆) Alkoxycarbonyl (C₁~ C₆) Alkyl can be methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl or ethoxycarbonylethyl; aryl can be phenyl, indenyl or naphthyl; and heteroaryl can be frill, imidazolyl, triazolyl, triazinyl, oxazoyl, isooxazoyl, thiazolyl. , Isothiazyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N oxide), thienyl, pyrimidinyl (or its N oxide), indolyl, isoquinolyl (or its N oxide) or quinolyl (or its N oxide). ..

R¹Specific values for are trifluoromethyl, phenyl, methyl, isopropyl, difluoromethyl, chlorodifluoromethyl or pentafluoroethyl.

R²Specific values for are methyl, ethyl, propyl, isopropyl, phenyl, cyclopentyl, 2-pyridyl, 2-morpholinoethyl or 2-hydroxyethyl.

R³Specific values for are methyl, ethyl, propyl, isopropyl, 2-pyridyl, cyclopentyl, phenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,2,2- Trifluoroethyl, 2-hydroxyethyl, 4-chlorophenyl, benzyl, 4-nitrophenyl, hydrogen, 2-morpholinoethyl or cyclohexyl.

In a preferred embodiment, R³Does not exist.

Specific values for B are 2,5-thiophenediyl, 1,4-benzenediyl, 1,3-benzenediyl, 2,4-pyridinediyl or 2,6-pyridinediyl.

Specific values for X are -C (= O) Y, -C (= S) Y, -C (R)⁴)₂Y or -S (O)₂Y.

The specific value for Y is R⁴, -N (R)⁴)₂, -OR⁴, -SR⁴Or -C (R)⁴)₃Is.

R⁴Specific values for are hydrogen, methyl, ethyl, butyl, propyl, isopropyl, 2-fluorophenethyl, 2-pyrrolidinoethyl, 2-furylmethyl, 4-methylbenzyl, cyclopropylmethyl, cyclohexylmethyl, 4-methoxy. Benzyl, 4-fluorobenzyl, 4-pyridylmethyl, 4-chlorobenzyl, cyclohexyl, benzyl, 4-methylphenyl, 3-pyrrolidin-1-ylpropyl, 3-chlorobenzyl, 3,5-dimethylbenzyl, 2-( Ethylthio) ethyl, isobutyl, allyl, 2-hydroxyethyl, phenyl, 3-fluoro-6-methylbenzyl, 3-pyridylmethyl, 4-fluorophenethyl, 2-phenoxyethyl, 5-methyl-flu-2-ylmethyl, 2 , 2,2-Trifluoroethyl, 2-methoxyethyl, 2-methylbutyl, 2-imidazol-4-ylethyl, phenethyl, 2-morpholinoethyl, 3-methylbutyl, 2-piperidinoethyl, 3-methoxypropyl, 3-chloro Benzyl, 2-furylmethyl, 3,5-difluorobenzyl, 2- (2-furyl) ethyl, 3-imidazol-1-ylpropyl, 2-cyanoethyl, 2-ethylbutyl, 2-pyrid-3-ylethyl, S- α-Hydroxy-β-methylphenethyl, S-α-methylphenethyl, 4,4-dimethoxybutyl, 3- (2-oxopyrrolidin-1-yl) propyl, 2,2-dimethoxyethyl, 4-methylphenethyl, cyanomethyl , 3-ethoxypropyl, 3- (N, N-dimethylamino) propyl, 3-morpholinopropyl, 2-hydroxypropyl, 2-methylpropyl, ethoxycarbonylmethyl, 2-methylphenyl, 2-hydroxyphenyl, tetrahydrofuran- 2-Ilmethyl, R-tetra-2-ylmethyl, S-tetra-2-ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine or N-piperdinyl.

Both Rs with Y binding⁴Specific values for are morpholine, piperidine, 4-methylpiperidine, 2,6-dimethylmorpholine, 2-hydroxymethylpyrrolidin, pyrrolidine, azetidine, 3-pyrrolin, 4- (4-fluorophenyl) piperidine, 3,5-Dimethylmorpholine, 4- (2-hydroxyethyl) piperidine, 3,5-dimethylpiperidine, indolin, R-3-hydroxypyrrolidin, 1,4-dioxa-8-aza-spiro [4.5] decane, 1,2,3,4-tetrahydroisoquinoline, 2,3,4,5,6,7-hexahydroazepine, 4-hydroxymethylpiperidine, 4- (N, N-dimethylamino) piperidine, 4- (1- (1- Pyrrolidinyl) piperidine, 4-phenylpiperidine, 4-hydroxy-4-phenylpiperidine, 4- (carboxamide) piperidine, 4-hydroxypiperidino, 4-phenylpiperazine, 4-acetylpiperazine, 4-benzylpiperidine, 4-tri Fluoromethylpiperidine, 3-trifluoromethylpiperidine, 3-fluoropiperidine, 4-fluoropiperidine, 4,4-difluoropiperidine, 3,3-difluoropiperidine, 4-isopropylpiperidine, 4-t-butoxycarbonyl-piperidine, 4 -Methoxypiperidine, pyrrolidine or 3-fluoropyrrolidin.

Both R with Y = carbon bonded⁴Specific values for are cyclohexyl, phenyl, 4-fluorophenyl or 4-trifluoromethylphenyl.

The specific group of the compound is R⁴One is hydrogen, the other is hydrogen, methyl, ethyl, butyl, propyl, isopropyl, 2-fluorophenethyl, 2-pyrrolidinoethyl, 2-furylmethyl, 4-methylbenzyl, cyclopropylmethyl, cyclohexylmethyl, 4 -Methoxybenzyl, 4-fluorobenzyl, 4-pyridylmethyl, 4-chlorobenzyl, cyclohexyl, benzyl, 4-methylphenyl, 3-pyrrolidin-1-ylpropyl, 3-chlorobenzyl, 2-furylmethyl, 3,5 -Dimethylbenzyl, 2- (ethylthio) ethyl, isobutyl, allyl, 2-hydroxyethyl, phenyl, 3-fluoro-6-methylbenzyl, 3-pyridylmethyl, 4-fluorophenethyl, 2-phenoxyethyl, 5-methyl- Flu-2-ylmethyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, 2-methylbutyl, 2-imidazol-4-ylethyl, phenethyl, 2-morpholinoethyl, 3-methylbutyl, 2-piperidinoethyl, 3 -Methoxypropyl, 3-chlorobenzyl, 2-furylmethyl, 2-ethylthioethyl, 3,5-difluorobenzyl, 2- (2-furyl) ethyl, 3-imidazol-1-ylethyl, 2-cyanoethyl, 2- Ethylbutyl, 2-pyrido-3-ylethyl, S-α-hydroxy-β-methylphenethyl, S-α-methylphenethyl, 4,4-dimethoxybutyl, 3- (2-oxopyrrolidin-1-yl) propyl, 2 , 2-Dimethoxyethyl, 4-methylphenethyl, cyanomethyl, 3-ethoxypropyl, 3- (N, N-dimethyl) propyl, 3-morpholinopropyl, 2-hydroxypropyl, 2-methylpropyl, ethoxycarbonylmethyl, 2 -Methylphenyl, 2-hydroxyphenyl, tetrahydrofuran-2-ylmethyl, R-tetra-2-ylmethyl, S-tetra-2-ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine, Or a compound that is N-piperdinyl.

R⁵Specific values for are methyl, ethyl, benzyl, propyl and allyl.

R⁶The specific value for is methyl.

Specific values for Het are monocyclic atoms containing a total of 3-12 atoms, including one or more carbon atoms and a heteroatom selected from one or two oxygen, sulfur and N (X). Alternatively, it is the group of a bicyclic ring system, where X is absent or H, O, (C1-C4) alkyl, phenyl or benzyl. Specific values for Het include piperidine, morpholine, thiomorpholin, pyrrolidine, imidazole, furan, pyridine, 2-oxopyrrolidine, furan, tetrahydrofuran, piperazine and azetidine.

As a further aspect of the invention, methods for preparing compounds of formula I are provided, exemplified by the following procedure in which common group values are given as described above, unless otherwise specified.

The compounds of formula I can be prepared using the general synthetic schemes exemplified below. Bisaryl or Het. For example, a compound of formula I in which X is -C (= O)-can be prepared by reacting an intermediate acid of formula 100 with an amine of formula 101.<img file="JP2009528362A_D0052.tif" />

A solution of acid 100 in a suitable solvent (eg, DMF) is treated with EDC-HCl, HOBT hydrate, and the base of Hunig to activate the acid; the activated acid is supplemented with the required amine. The amide of formula 101 is provided. A standard underwater work-up is followed by the usual steps to provide the purified amide by flash chromatography. Amines can also bind to acid 100 via activation with oxalyl chloride or thionyl chloride.

Compounds of formula 103a / b can be prepared by reacting the intermediate diketone of formula 102 with the hydrazine of formula ii, as shown below.<img file="JP2009528362A_D0053.tif" />

One positional isomer or a mixture of positional isomers (eg, R) by the above reactions, as well as other reactions useful for the preparation or modification of the pyrazole ring.²Compounds of formula I and R in which is absent³It will be understood that a mixture of compounds of formula I in which is absent) can result. If the result is a mixture, some well-known standard techniques (eg, chromatography) can be used to separate the positional isomers.

The intermediate acids of formulas 100a and 100b can be prepared as illustrated below.<img file="JP2009528362A_D0054.tif" />

The acid of formula 104 can be converted to the corresponding ester by using any suitable conditions (eg, by treatment with oxalyl chloride in a suitable solvent followed by treatment with alcohol). Continued treatment with essential hydrazine after conversion of ester 105 to diketone 106 yields pyrazole 107a / b. Subsequent hydrolysis of the ester under standard conditions yields an acid of formula 100a / b. The intermediate diketone of formula 102 can be prepared from the keto acid of formula 108, as illustrated below.<img file="JP2009528362A_D0055.tif" />

The acid functionality of 108 is the group of compound 109-XN (R) under standard conditions.⁴)₂Can be converted to. Ketone 109 can be used under standard conditions, eg formula R.¹It can be converted to diketone 102 by treatment with an ester of COOEt.

Administration of the compound as a salt may be appropriate if the compound is basic or acidic enough to form a stable, non-toxic acid salt or basic salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed by acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascor. Bate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts such as hydrochlorides, sulfates, nitrates, bicarbonates, and salts of carbonates may be formed.

Pharmaceutically acceptable salts use standard techniques well known in the art to react a well-basic compound, such as an amine, with a suitable acid that imparts a physiologically acceptable anion. Can be obtained. Alkali metals of carboxylic acids (eg, sodium, potassium or lithium) or salts of alkaline earth metals (eg, calcium) can also be made.

The compounds of formula I can be prepared as pharmaceutical compositions in a variety of forms adapted to the route of administration chosen for mammalian hosts such as human patients, i.e. orally or parenterally, intravenously or intramuscularly. , Can be administered by local or subcutaneous route.

Thus, the compounds of the invention may be administered systemically, eg, orally, in combination with a pharmaceutically acceptable vehicle such as an Inactive Diluent or an anabolic edible carrier. The compound may be encapsulated in hard or soft putamen gelatin capsules, compressed into tablets, or mixed directly into the food of the patient's diet. For oral therapeutic administration, the active compound may be used in combination with one or more excipients in the form of edible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. .. Such compositions and formulations should contain at least 0.1% active compound. The proportions of the compositions and formulations may, of course, vary and may be conveniently from about 2 to about 60% by weight in a given unit dosage form. The amount of active compound in a composition useful for such treatment is an amount that provides an effective dosing level.

Tablets, troches, pills, capsules, etc. may also include: Binders such as tragacanto gum, arabic gum, cornstarch or gelatin; Excipients such as dicalcium phosphate; Disintegrants; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame or fragrances such as peppermint, winter green oil, or cherry flavor may be added. When the unit dosage form is a capsule, in addition to the above-mentioned types of materials, a liquid carrier such as vegetable oil or polyethylene glycol may be included. Various other materials may be present as a coating or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, or the like. The syrup or elixir may contain active compounds, sucrose or fructose as sweeteners, methyl and propylparabens as preservatives, pigments and flavors such as cherry or orange flavors. As a matter of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amount used. The active compound may also be incorporated into sustained release formulations and sustained release devices.

The active compound can also be administered intravenously or intraperitoneally by infusion or injection. A solution of the active compound or a salt thereof can be prepared in water, optionally in combination with a non-toxic surfactant. Dispersions can also be prepared in glycerin, liquid polyethylene glycol, triacetin and mixtures thereof and oils. Under normal conditions of storage and use, these formulations contain preservatives to prevent the growth of microorganisms.

Suitable pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions or dispersions or sterilized powders containing the active ingredient and are adapted for the immediate preparation of sterile injectable or infusion solutions or dispersions as needed. It can be encapsulated in liposomes. In all cases, the final dosage form should be sterile, liquid and stable under manufacturing and storage conditions. The liquid carrier or vehicle can be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (eg, glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters and suitable mixtures thereof. Suitable liquids can be maintained, for example, by forming liposomes, maintaining the required particle size in the case of dispersions, or using surfactants. Various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal and the like can prevent the activity of microorganisms. In many cases, it is preferable to include an isotonic agent such as sugar, buffer, or sodium chloride. The use of drug compositions that delay absorption, such as aluminum monostearate and gelatin, can result in long-term absorption of the injectable composition.

Sterilized Injectable solutions are prepared by combining the required amount of active compound in a suitable solvent with the various other ingredients listed above and, if necessary, subsequent filtration sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and lyophilization techniques, which yield powders of the active ingredient and any further desirable ingredients present in the sterile filtered solution. ..

For topical administration, the compound may be applied in pure form, i.e. in liquid form. However, it is usually desirable to administer the compound to the skin in combination with a skin-acceptable carrier as a composition or formulation that can be solid or liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica and alumina. Useful liquid carriers include water, alcohol or glycols or water-alcohol / glycol mixtures in which the compounds of the invention can optionally be dissolved or dispersed at effective levels with the assistance of non-toxic surfactants. Be done. Auxiliary agents such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use. The resulting liquid composition can be applied with an adsorption pad, used to impregnate bandages and other traumatic pharmaceutical materials, or sprayed onto the affected area using a pump or aerosol spray. obtain.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and fatty acid esters, fatty alcohols, modified celluloses, or modified mineral substances are also used with liquid carriers and are stretchable pastes for direct application to the user's skin. , Gels, ointments, soaps, etc. can be formed.

A useful dose of the compound of formula I can be determined by comparing the activity of the compound in vitro and in vivo in an animal model. Methods for extrapolation of effective doses in mice and other animals up to humans are known in the art, see, eg, US Pat. No. 4,938,949.

The amount of compounds required for therapeutic use, or active salts or derivatives thereof, will vary depending not only on the particular salt selected, but also on the route of administration, the nature of the symptoms being treated and the age and symptoms of the patient. Ultimately at the discretion of the attending physician or clinician.

However, in general, suitable doses range from about 0.15 to about 100 mg / kg, eg, about 1 to about 75 mg / kg body weight per day, eg 0.75 to about 0.75 to 1 kg of body weight per day for the recipient. It is in the range of about 50 mg, preferably 1 to 90 mg / kg / day, most preferably 1 to 60 mg / kg / day.

Conveniently, the compound is administered in a unit dosage form and comprises, for example, 1 to 1000 mg, conveniently 10 to 750 mg, and most conveniently 5 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve a peak plasma concentration of active compound of about 0.5 to about 75 μM, preferably about 1 to 50 μM, most preferably about 2 to about 30 μM. This can be achieved, for example, by intravenous injection of a 0.05-5% solution of the active ingredient in saline, if desired, or by oral administration as a bolus containing about 1-100 mg of the active ingredient. The desired blood level may be maintained by continuous infusions providing about 0.01-5.0 mg / kg / hour or intermittent infusions containing about 0.4-15 mg / kg of the active ingredient (one or more). ..

For convenience, the desired dose may be present in a single dose, or in divided doses such as at appropriate intervals, eg, 2 times, 3 times, 4 times or more sub-dose per day. May be administered as. The co-dose itself may be further subdivided into, for example, a plurality of vague discontinuous doses.

The compounds of the present invention may also, if desired, one or more other therapeutic agents effective in improving cognition, and / or Alzheimer's disease, age-related memory impairment (AAMI); mild cognitive impairment (MCI), Dementia (acute confusion); depression, dementia (often further classified as Alzheimer's or non-Alzheimer's); Alzheimer's disease; Parkinson's disease; Huntington's disease (butoh disease); mental retardation; Syndrome and Down Syndrome); Cerebrovascular disease (eg, vascular dementia, after heart surgery); Emotional disorder; Psychotic disorder; Autism (Kanna syndrome); Neurological disorder; Attention defect disorder (ADD); Subdural Hematoma; Alzheimer's disease; Brain tumors; Can be administered in combination with one or more therapeutic agents effective in treating head trauma (post-cerebral injuries) or brain trauma (DSM-IV, APA 1994, see) ).

The ability of the compounds of the invention to act as inhibitors of MAO-B can be measured using pharmacological models well known in the art or using the following assays.

MAO inhibition assay The MAO enzyme assay was performed according to the fluorescence assay described by Matsumoto and co-workers (Matsumoto, et. Al., Clin. Biochem., 1985 18, 126-129) with the following modifications. Human recombinant MAO-A and MAO-B expression in insect cells was used. For both assays, test compounds and / or vehicles were pre-incubated with purified enzyme in phosphate buffer pH 7.4 at 37 ° C for 15 minutes. 50 μM quinuramine was added to initiate the reaction. After 60 minutes of incubation, 6N NaOH was added to terminate the reaction. The amount of 4-hydroxyquinoline formed was measured spectrofluorescently at 325 nm / 465 nm. Convert results to% inhibition and IC using XLfit program from IDBS (ID Business Solutions Ltd., 2 Occam Court, Surrey Research Park, Guildford, Surrey, GU2 7QB UK)₅₀Was measured. Representative compounds of the invention were evaluated in this assay. Typically, the compounds of the present invention exhibited MAO-B inhibitory properties, typically 5-100%, at 0.1-10 μM. Preferred compounds also showed selectivity for MAO-B over MAO-A.

The ability of a compound to activate CREB can be measured using the following assay (see WO 2004/016227).

CREB activation assay The CRE-Luci assay below is a high-power, good method for identifying compounds that enhance cognition by enhancing the function of the CREB pathway. The assay allows the identification of cognitive enhancers that act to increase (enhance) CREB pathway function in combination with CREB function stimulators, rather than acting alone in CREB pathway function.

The assay was performed with (a) host cells having a luciferase gene operably linked to the CRE promoter (particularly cells of neurogenic origin (eg, human neuroblastoma SK-N-MC cells), and test compounds and optimized doses. Steps of contacting CREB functional stimulators (eg, forskolin); (b) Measuring luciferase activity of host cells in contact with test compounds and CREB functional stimulators; and (c) Measured in step (b) The procedure is to compare the luciferase activity with the luciferase activity of control cells that have been contacted with the CREB function stimulator but not with the test compound (ie, control cells that have been contacted with the CREB function stimulator only).

A host cell containing a luciferase gene operably linked to the CRE promoter can be produced by introducing a DNA construct containing the luciferase gene operably linked to the CRE promoter into the cell. DNA constructs can be introduced into cells according to methods known in the art (eg, transformation, direct uptake, calcium phosphate precipitation, electroporation, projectile bombardment, use of liposomes). Such methods include, for example, Sambrooke et al., Molecular cloning: A laboratory Manual, 2nd edition (New York: Cold Spring Harbor University Press) (1989); and Ausubel, et al., Current Protocols in Molecular Biology ( New York: John Wiley &amp; Sons) (1998) for more details.

SK-N-MC cells stably transfected with the CRE-luc construct are seeded into 96-well white assay plates (PerkinElmer) at a concentration of 20,000 cells / well in 100 μL MEM complete medium. These cells were subjected to CO under standard cell culture conditions.₂Incubate in an incubator. After 18-24 hours of incubation, cells were subjected to either vehicle control (DMSO, Sigma), test compound (5 μM final concentration), or positive control (HT-0712, 5 μM final concentration) (16 wells for each treatment). Process for 2 hours. Forskolin (5 μM final concentration, Sigma) is then added to 8 wells of each treatment group and an equal volume of DMSO is added to the remaining 8 wells. Six hours after forskolin addition, 25 μL of assay reagent (BriteLite kit, PerkinElmer) is added to each well and luciferase activity is measured. After incubation for 3 minutes at room temperature, luminescence is detected using a Wallac Victor 5 plate reader (PerkinElmer). Transcription induction is derived by standardizing the activity of the compound or positive control luciferase in the presence of forskolin for forskolin monotherapy. Compound alone treatment can also be used as a control to determine if the compound itself is capable of activating the CRE promoter.

Using this assay, it was found that the representative compounds of the invention enhance CREB pathway function.

The ability of a compound to regulate cognitive behavior can be assessed using the following assay to measure memory after situational fear conditioning.

Situational Memory Assay: Fear Conditioning Situational memory is a form of Pavlov's fear conditioning that places naive mice in new chambers (situations) that contain obvious visual, olfactory, and tactile cues. After a few minutes of acclimation, give the mouse paws a short, light electric shock. From this negative experiment, mice learn in a few months that this chamber is dangerous. When the mouse is returned to the same situation shortly after training, the response to the mouse's instinctive danger is to "freeze" and sit like a stone for a few seconds. This is similar to what happens when humans experience fear. The percentage of time the mouse spends freezing during observation indicates a quantitative measurement of the memory of the situation (memory score).

Situational conditioning has been extensively used to investigate neuromaterial-mediated fear-motivational learning (Phillips, RG, LeDoux, JE, Behav Neurosci, 1992, 106, 274-285; Kim, JJ, et. al., Behav Neurosci, 1993, 107, 1093-1098; Bowlchouladze, R., et .al., Learn Mem, 1998, 5, 365-374; and Bowlchouladze, R et .al., Cell, 1994, 79, 59-68). Situational conditioning also includes various mutations in hippocampal-dependent memory (Bourtchouladze, R., et .al., Learn Mem, 1998, 5, 365-374; Bowlchouladze, R., et. Al., Cell, 1994, 79, 59-68; Silva, AJ, et. Al., Curr Biol, 1996, 6, 1509-1518; Kogan JL et al., Curr Biol, 1997, 7, 1-11; Abel, T., et. Al., Cell, 1997, 88, 615-626; and Giese KP, et al., Science, 1998, 279, 870 -873); and differences in lineage and genetic background in mice (Logue, SF, et. Al., Behav Neurosci, 1997, 111, 104-113; and Nguyen, PV, et. Al., Learn Mem, 2000 , 7, 170-179) It is also used to study the effects. Situational conditioning is particularly useful in studying the biology of temporally apparent short-term and long-term memory processes, as a few-minute training session can elicit strong memory (Kim, JJ, et. . al., Behav Neurosci, 1993, 107, 1093-1098; Bowlchouladze, R., et. al., Learn Mem, 1998, 5, 365-374; Bowlchouladze, R., et. Al., Cell, 1994, 79, 59-68; and Abel, T., et. Al., Cell, 1997, 88 , 615-626). Thus, situational conditioning is an excellent model for assessing the function of various novel drug compounds in hippocampal-dependent memory.

Young adult (10-12 weeks old) C57BL / 6 male mice and 250-300 g Sprague Dawley male rats (Taconic, NY) were used. Mice were group-reared in standard laboratory cages (5 mice) and rats were paired to maintain a 12:12 light-dark cycle. Experiments were always performed in the bright stages of the cycle. Outside of test time, mice were free to eat and water. Experiments were conducted in accordance with Animal Protection Guarantee # A3280-01 and animals were maintained in accordance with Animal Protection Act and Ministry of Health and Welfare guidelines.

To evaluate situational memory, we used a modified situational fear conditioning task developed independently to evaluate memory in CREB knockout mice (Bourtchouladze, R., et. Al., Cell, 1994, 79, 59-68). ). On training day, mice were placed in a conditioning chamber (Med Associates, Inc., VA) for 2 minutes prior to the start of unconditional stimulation (US) of 0.5 mA, 2-second foot shock. US was repeated twice with a 1-minute test interval between shocks. Trained with automated software packages (Med Associates, Inc, VA). After the final training test, the mice were left in the conditioning chamber for an additional 30 seconds and then returned to the rearing cage. Twenty-four hours after training, mice were placed in the same training chamber and situational memory was evaluated by scoring freeze behavior (freeze is used as a memory score). Freeze defined a complete lack of behavior at 5-second intervals (Kim, JJ, et. Al., Behav Neurosci, 1993, 107, 1093-1098; Phillips, R. G., LeDoux, JE, Behav Neurosci, 1992, 106, 274-285; Bowlchouladze, R., et. Al., Learn Mem, 1998, 5, 365-374; , 1994, 79, 59-68; and Abel, T., et. Al., Cell, 1997, 88, 615-626). The test time lasted a total of 3 minutes. After each experiment, the experimental equipment was thoroughly washed with 75% ethanol, water, dried and exposed to air for several minutes.

All experiments were designed and performed in a balanced manner, which (i) used the same number of experimental and control mice for each experimental condition (eg, specific dose effect); and ( ii) It means that each experimental condition was repeated 2-3 times independently and repeated for several days to prepare the final number of subjects. The progress of each experiment was photographed. In each experiment, the experimenter was unaware of the subject's treatment during training and testing (no hypothesis). Data were analyzed by Student's asymmetric t-test using a software package (Statview 5.0.1; SAS Institute, Inc). All values in context and drawings are represented by mean ± SEM.

Compounds were dissolved in 1% DMSO / PBS and administered intraperitoneally (IP) in a volume of 8 ml / kg 20 minutes prior to training. Control animals were fed vehicle only (1% DMSO / PBS). For oral administration, the compound was dissolved in 30% DMSO / 70% CMC. As a result, control animals were given 30% DMSO / 70% CMC. An experimentally naive population of animals was used for each training and drug injection procedure.

To assess the effect of Compound 162 and Compound 177 on contextual memory, mice were injected with compound or vehicle 20 minutes prior to training and subjected to two training tests (US). Then (than), mice were tested in the same situation 24 hours after training (Fig. 1). IP administration of 0.01 mg / kg of each compound significantly promoted freeze in the situation after 24 hours of training. It was also found that representative compounds of the present invention were tested and produced behavioral effects when orally administered.

The ability of a compound to regulate cognitive behavior can also be assessed using the following object recognition assays.

Object recognition assay For rodents, object recognition is a behavioral biologically relevant task that does not occur with negative strengthening (foot shock). This task relies on the instinctive curiosity that rodents seek new objects in their environment rather than familiar ones. Obviously, for an object that was "familiar," the animal would have reminded it of its experience, paying attention to it as being earlier. Therefore, animals with good memory pay attention to and explore new objects rather than objects that are familiar to them. During the test, the animal is present with a training object and a second new object. The memory of the training object makes it familiar to animals, after which animals spend more time exploring new and new objects than familiar ones (Bourtchouladze, R., et. Al., Proc Natl Acad). Sci USA, 2003, 100, 10518-10522). Recent neuroimaging studies in humans have shown that memory of object recognition relies on the anterior frontal cortex (PFC) (Deibert, et. al., Neurology, 1999, 52, 1413-1417). Consistent with these findings, PFC-deficient rats exhibit poor working memory when it is necessary to distinguish between familiar and new objects (Mitchell, JB, Laiacona, J., Behav Brain Res, 1998, 97, 107-113). Other studies in monkeys and rodents suggest that the hippocampus is important for the recognition of new objects (Teng, E., et. Al., J. Neurosci, 2000, 20, 3853-3863). ; And Mumby, DG, Brain Res, 2001, 127, 159-181). As such, object recognition provides an excellent behavioral model for assessing the effects of drug-compounds on cognitive tasks related to hippocampal and cortical function.

Prior to the start of training, the animals were treated for 3-5 minutes for 5 days. Same for mice and rats except for the size of the training device (for mice: L = 48 cm; W = 38 cm and H = 20 cm Plexiglas boxes; for rats: L = 70 cm; W = 60 cm and H = 35 cm Plexiglas boxes) Training and testing were performed. The day before training, individual animals were placed in a training device placed in a dimly lit room and acclimatized to the environment for 15 minutes (Pittenger, C., et. Al., Neuron, 2002, 34, 447-462; and Bourtchouladze, R., et. See also al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Training began 24 hours after acclimatization. The animals were returned to a training box containing two identical objects (eg, small pyramidal objects) and were asked to examine these objects. The objects were placed in the central area of the box, and the spatial arrangement (left and right sides) of the objects was balanced between the objects. The animals were trained for 15 minutes. Animals were observed for 10 minutes after 24 hours of training to test memory retention. The rodents were placed with two objects, one became "familiar" because it was used during training, and the other was new (eg, a small conical object). After each experiment, the device and objects were thoroughly washed with 90% ethanol, dried and exposed to air for a few minutes to ensure that the odors to be identified did not differ.

The experiment was recorded on videotape with an overhead video camera system. The species was then verified by a blind observer, followed by behavioral parameters determined: time of exploration of each object; total time of exploration of both objects; number of contacts with both objects; and first to one object. Contact time (potential). The discriminant index-memory score-was measured as described above (Ennaceur, A., Aggleton, JP, Behav Brain Res, 1997, 88, 181-193; and Courtchouladze, R., et. Al., Proc Natl Acad. Sci USA, 2003, 100, 10518-10522). This data was analyzed by Student's asymmetric t-test using a software package (Statview 5.0.1; SAS Institute, Inc). All values in context and drawings are represented by mean ± SEM.

The following examples illustrate methods that are generally useful for the preparation of compounds of the invention.

Example 1 In the equation, R¹Is CF₃Preparation of compounds in which X is -C (= O)-and B is a thiophene ring.<img file="JP2009528362A_D0056.tif" /> Commercially available acid solutions were mixed in DMF. EDC-HCl, HOBT hydrate and Hunig base were added to this solution to activate the acid. The desired amine was added to the activated acid to give the final product. The reaction underwent standard aqueous preparation, followed by purification of the crude product by normal phase flash chromatography. The final product was confirmed for purity and substance by LC / MS.

Example 2 In Equation 2, R¹Is CF₃Preparation of compounds in which X is -C (= O)-and B is a phenyl ring.<img file="JP2009528362A_D0057.tif" /> Oxalyl chloride was added to 3-acetylbenzoic acid (112) in dichloromethane at less than 20 ° C. After completion of the reaction, the mixture was concentrated to remove excess reagents. The residue was dissolved in fresh dichloromethane, cooled below 20 ° C., and then secondary amines and triethylamine were added. The reaction, stirred for 1 hour, was quenched with water and then washed with 5% HCl to remove excess triethylamine. The organic layer was then washed with 5% sodium bicarbonate to remove unreacted starting material, then washed with water, dried and concentrated to give 3-acetyl-N, N-dialkylbenzamide (113). Obtained in a yield of 75-80%.

Treatment of 3-acetyl-benzamide 113 with a preformed solution of ethylmethyl-ortho-sodium trifluoroacetate prepared by mixing NaOMe and ethyl trifluoroacetate in benzene allows the material to be efficiently converted to diketo compounds. Transformed. Subsequent acidification of the crude reaction was followed by extraction into an organic solvent to give compound 114 in 85-90% yield.

The final pyrazole compound (115a / b) was synthesized by the addition of the appropriate substituted hydrazine to compound 114 in ethanol, acidified ethanol or acetic acid, depending on the specific hydrazine used.

In Example 3, R¹Is CF₃Preparation of compounds in which X is -C (= O)-and B is a phenyl ring.<img file="JP2009528362A_D0058.tif" /> Oxalyl chloride was added to 4-acetyl-benzoic acid in dichloromethane and DMF below 20 ° C. to concentrate the reactants and remove excess reagents. The residue was dissolved in fresh dichloromethane and then a secondary amine was added. Further, at less than 20 ° C, triethylamine was added and the mixture was stirred for 1 hour. The reaction was quenched with water and washed with 5% HCl to remove excess triethylamine and then washed with 5% sodium bicarbonate to remove unreacted starting material. The organic layer was washed with water, dried and concentrated to give 4-acetyl-dialkylbenzamide 116 in 85-90% yield.

Ethylmethyl-ortho-sodium trifluoroacetate is preformed from NaOMe and ethyl trifluoroacetate in benzene, and the preformed ortho-alkoxide is reacted with 4-acetyl-N, N-dialkylbenzamide to treat benzamide. Then, after acidification, extraction gave compound 117 in a yield of 50-55%.

The final pyrazole compound 118a / b was synthesized in ethanol, acidified ethanol or acetic acid by the addition of the appropriate substituted hydrazine to compound 117, depending on the specific hydrazine used.

In Example 4, R¹Is CF₃Preparation of compounds in which X is -C (= O)-and B is a pyridine ring. Two methods (A and B) were used to synthesize the 2,4 disubstituted pyridine compound. Method A: (R³ = 2,2,2 trifluoroethyl, phenyl, 2-hydroxyethyl, benzyl, 2-pyridyl)<img file="JP2009528362A_D0059.tif" /> Aqueous hydrogen peroxide solution (30%, 130 mL, 1.2 mmol) was added dropwise to ethyl pyruvate (216 g, 1.9 mol) with stirring at -5 ° C to 5 ° C. The resulting solution was mixed with a mixture of 4-acetylpyridine (15.0 g, 0.12 mmol), dichloromethane (1.5 L) and water (100 mL) in medium concentrated sulfuric acid (12.4 g, 0.12 mmol) and iron sulfate heptahydrate (345 g, 345 g,). To a mixture of 0.12 mmol) was added dropwise at room temperature for 2 hours. After stirring the mixture for an additional 30 minutes, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with 5% aqueous sodium sulfite solution, followed by water, then dried and purified to give 119 (5.79 g, 24%).

A preformed solution of ethylmethyl-ortho-sodium trifluoroacetate from NaOMe and ethyl trifluoroacetate was reacted with 4-acetylpyridine 2-carboxylic acid ethyl ester in benzene. After an overnight reflux reaction, the mixture was acidified and extracted with an organic solvent to give 120 in 65-70% yield.

To 1 equivalent of diketopiperazine 120, 1.2 equivalents of monosubstituted hydrazine was added in acetic acid medium. The reaction was monitored by TLC. Saturated to pH = 8-9 LVDS₃After the solution was added to prepare the mixture, the mixture was extracted with methylene chloride. The solvent was removed and the crude material was purified by column chromatography to give compound 121a / b in 40-50% yield.

Compound 121a / b was dissolved in 1.5 equivalents of NaOH in water and stirred at room temperature for 2 hours. A 20% citric acid solution was added to the mixture to about pH 2. The product was extracted in ethyl acetate and concentrated. To the acid intermediate in DMF, 1.5 eq of EDCI, 1.3 eq of HOBT, 1.3 eq of dialkylamine and 4 eq of diisopropylethylamine were added and stirred overnight at room temperature. The completion of the reaction was monitored by TLC. Water and ethyl were added to the mixture and the ethyl acetate layer was concentrated to give the crude product, which was purified by column chromatography to give a compound with a general structure of 122a / b.

Method B: (R²Or R³ = Alkyl)<img file="JP2009528362A_D0060.tif" /> Compound 119 was dissolved in 1.5 equivalents of NaOH in water and stirred at room temperature for 2 hours. The solution was acidified to pH = 2 with a 20% citric acid solution and extracted into ethyl acetate. Concentration of the solvent gave product 124 in 45-50% yield.

Compound 124 was dissolved in 5 volumes of THF and 5 volumes of dichloromethane. After adding 1.1 equivalents of pentafluorophenol to this solution, 1.1 equivalents of DCC was added. The reaction was stirred at room temperature for 2 hours. The mixture was then filtered through a Celite bed and washed with THF and dichloromethane. The filtrate was concentrated under vacuum to give a brown solid, which was recrystallized from ethyl acetate / hexane to give pure pentafluorophenyl ester 125.

To a solution of pentafluorophenyl ester 125 in dichloromethane, 1.2 eq of dialkylamine and 1.5 eq of N-methylmorpholine were added and the solution was stirred at room temperature overnight. After confirming the completion of the reaction by TLC, water was added to the reactants to separate the layers. The aqueous layer was extracted once more with dichloromethane. The organic layers were combined, washed with brine solution and then concentrated to give compound 126 in 45-50% yield.

Sodium ethylmethyl orthotrifluoroacetate formed by mixing NaOMe and ethyl trifluoroacetate in benzene was reacted with compound 126 in benzene and refluxed overnight. The resulting mixture was acidified and extracted into an organic solvent to give compound 127 in good yield (65-70%).

To compound 127 in 10 volumes of ethanol, a few drops of acetic acid were added, followed by 6-7 equivalents of hydrazine hydrate (80%). The reaction was monitored by TLC with stirring of the mixture at room temperature for 3-4 hours. After completion of the reaction, ethanol was completely removed under vacuum, water was added and the product was vigorously stirred at room temperature to precipitate the product as a solid. The material was filtered, washed with abundant amounts of water and then dried to give compound 128.

Alkylation iodide and 1 mL of 6N KOH were added to a sample of compound 128 in 200 mg in 2 to 3 mL of THF, followed by tetrabutylammonium bromide (25 mg). The reaction was stirred at room temperature for 2-3 hours. After completion of the reaction measured by TLC, the phases were separated. The THF layer was concentrated and spotted on a Prep TLC plate. Elution was performed using 30% ethyl acetate in hexane. After 10 to 15 elutions, two geometric isomers (R)²Does not exist, and R³Was separable). Silica gel is disassembled, extracted with ethyl acetate and dichloromethane, then concentrated to the pure regioisomer of compound 129 (in formula, R).²Or R³ = Methyl or ethyl) was obtained.

Example 5 In Equation 5, R¹Is CF₃Preparation of compounds in which X is -C (= O)-and B is a pyridine ring.<img file="JP2009528362A_D0061.tif" /> To 8 g of compound 130 in 30 mL of methanol was slowly added 11.8 ml of thionyl chloride at 5 ° C. The mixture was stirred for 30 minutes at room temperature and refluxed overnight. The reaction mixture was concentrated under high vacuum and then dissolved in sodium bicarbonate solution. The compound was then extracted into dichloromethane and then dried and concentrated to give compound 131 in 70% yield.

2.6 g of NaOMe was added to 6 g of compound 131 in 100 mL of benzene. The reactants were heated to 80 ° C., 5 ml of ethyl acetate was added to the reaction and the mixture was further refluxed for 1 hour. The reaction was neutralized with citric acid and extracted with dichloromethane. Removal of the solvent gave compound 132 in a yield of 60%.

40 mL of 20% sulfuric acid was added to 4 g of compound 132, which was then refluxed for 2 hours. The reaction mixture was then neutralized with sodium hydroxide, extracted in dichloromethane and concentrated to give the desired compound 133 in 60% yield.

Compound 133 was added at 0 ° C. to a 1 liter round bottom flask containing 150 mL of DMF. Hydrogen peroxide and iron sulfate heptahydrate were simultaneously added to the reaction mixture at 0 ° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water and then extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to give 2% of the desired compound 134.

To 1 g of compound 134 in 10 mL of benzene was added 0.8 g of sodium methoxide. The reaction mixture was gently heated to reflux and stirred for 2 hours. The reaction mixture was neutralized with citric acid and then extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 135 in 80% yield.

Methylhydrazine was added to 200 mg of compound 135 in ethanol. The mixture was stirred for 6 hours at room temperature. The reaction mixture was then neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was then dried and concentrated to give the final compound 136 in 50% yield.

Example 6 In Equation 6, R¹Preparation of compounds where is phenyl, X is -C (= O)-, Y = N, and B is a thiophene ring<img file="JP2009528362A_D0062.tif" /> N-BuLi (2.33 g, 36.51 mmol) was added to a stirred solution of diisopropylethylamine (3.69 g, 36.51 mmol) in THF (60 mL) cooled to -70 ° C for 40 minutes. The mixture was stirred at -70 ° C for 2 hours. Amide 137 dissolved in a minimum amount of THF was slowly added to the reaction mixture and stirring was continued at -70 ° C for 2 hours. The reaction was warmed to -30 ° C and stirred for an additional 30 minutes. After cooling the mixture back to -70 ° C, the addition of benzoyl chloride (5.13 g, 36.51 mmol) was added slowly over 20 minutes. The reaction was stirred for 3 hours at 70 ° C. and quenched with 23 mL of 1.5N HCl. The product was extracted with dichloromethane (dichoromethane) and then concentrated to give the crude product, which was purified by column chromatography on silica gel to give the desired product 138 in 20-25% yield. ..

The procedure described in Example 9 below was used to convert the diketone 138 to a compound of formula I.

Example 7 In the equation, R¹Preparation of compounds where is methyl, X is -C (= O)-, Y = N, and B is a thiophene ring<img file="JP2009528362A_D0063.tif" /> Stin chloride (1.32 g, 5.07 mmol) in a stirred mixture of amide 137 (0.5 g, 2.53 mmol) and acetic anhydride (1.03 g, 10.14 mmol) pre-cooled to 20 ° C for 50 minutes. Dropped. During the addition, the temperature did not exceed 100 ° C. After allowing to stand overnight at room temperature, the reaction mixture was cooled again to 0-20 ° C and hydrolyzed by stirring with 30% HCl (1 mL) for 7 hours. Water (20 mL) was added to the mixture and stirred for an additional 30 minutes at room temperature. The solid was filtered and separated, and the crude tan solid was purified by column chromatography using chloroform and methanol. Product 139 was isolated in yields of 40-45%.

The procedure described in Example 9 below was used to convert the diketone 139 to a compound of formula I.

In Example 8 equation, R¹Preparation of compounds in which is isopropyl, X is -C (= O)-, Y = N, and B is a thiophene ring.<img file="JP2009528362A_D0064.tif" />

Sttin chloride (19.8 g, 76.06 mmol) was added dropwise to a stirred mixture of amide 139 (5 g, 25.35 mmol) and isobutyric anhydride (24.06 g, 152.12 mmol) cooled to below 20 ° C. for 1 hour. During this addition, the temperature never exceeded 100 ° C. After allowing to stand overnight at room temperature, the reaction mixture was cooled again to 0-20 ° C and hydrolyzed by stirring with 30% HCl (25 mL) for 7 hours. Water (100 mL) was added and the mixture was stirred for 30 minutes at room temperature. The solids were filtered off and the crude yellow-brown solid was purified by column chromatography on silica gel with chloroform and methanol to give product 140 in 45-50% yield.

The diketone 140 was converted to a compound of formula I using the procedure described in Example 10 below.

The acylating agent anhydrous isobutyric acid was prepared as follows. Isobutyric acid (50 g, 562.4 mmol) was added slowly to thionyl chloride (85 g, 703.03 mmol) over 45 minutes. The mixture was refluxed for 30 minutes and the acid chloride was isolated by distillation. Isobutyryl chloride (27 g, 253 mmol) was added to a mixture of pyridine (40 g, 506 mmol) and dry benzene (50 mL). Isobutyric acid (22.32 g, 253 mmol) was then added slowly over 10 minutes and the reaction was stirred for 3 hours at room temperature. The solids were filtered off and washed with dry benzene. The filtrate was concentrated to give a crude product of reddish color.

Example 9 In the equation, R¹Preparation of compounds in which is phenyl, methyl, trifluoromethyl, chlorodifluoromethyl, pentafluoroethyl, or isopropyl, X is -C (= O)-, and Y = N; and B are thiophene rings. The following methods (1-4) were used to construct the pyrazole moiety when the B ring was thiophene. Cyclization with substituted hydrazine<img file="JP2009528362A_D0065.tif" />

Cyclization method An equimolar mixture of backbone 141 and mono-substituted hydrazine was mixed together in ethanol containing a few drops of acetic acid. The reactants were stirred at room temperature for 12 hours or longer and monitored by TLC.

An equimolar amount of skeleton 141 and mono-substituted hydrazine hydrochloride (cyclopentyl and 4-chlorophenylhydrazine present as HCl salts in the case of benzyl) were mixed together in ethanol and the reactants were stirred at room temperature and monitored by TLC. ..

Equal molar amounts of Skeleton 141 and 2-hydrazinopyridine were mixed together in acetic acid. The reaction was stirred under reflux and the progress of the reaction was monitored by TLC.

An equimolar mixture of backbone 141 and monoalkyl hydrazine was mixed together in acetic acid. The reactants were stirred at room temperature and monitored by TLC.

N-alkylation of 1-H pyrazole using microwaves<img file="JP2009528362A_D0066.tif" />

Synthesis was carried out by mixing compound 144 with an excess of alkyl iodide and a catalytic amount of tetrabutylammonium bromide (TBAB). The mixture was adsorbed on potassium carbonate and irradiated in an open glass bottle (15 mL) for 2-3 minutes in a household microwave oven to give compound 145a / b.

Phase transfer method for N-alkylation of 1-H-pyrazole In some cases, the use of microwaves to assist in alkylation has been limited due to the volatility of certain alkyl iodides, such as methyl iodide and ethyl iodide, which prevent the complete conversion of the desired product. In such cases, the following procedure was used.<img file="JP2009528362A_D0067.tif" />

To a solution of 1 mL of THF and 1 mL of 6N KOH solution was added 200 mg of N-1-H pyrazole 144 and a catalytic amount of tetrabutylammonium bromide (TBAB). The mixture was stirred for 15 minutes at room temperature. To this mixture was added 2 equivalents of the required alkyl halide, followed by stirring at room temperature until the reaction was complete as measured by TLC.

Dialkyl sulfate method for N-alkylation of 1-H-pyrazole Pyrazole can be alkylated to a good regioselectively advantageous product 111 using dialkyl sulfate under non-basic conditions. In general, a ratio of&gt; 9: 1 (111: 111a) is obtained.<img file="JP2009528362A_D0068.tif" />

A suspension of pyrazole 146 in toluene (about 10 mL / g) was treated with dimethyl sulphate (1.5 eq) and heated at 90-100 ° C for 24 hours, at which point an additional 0.125 eq of dimethyl sulphate was added. Heated for 10 hours. The reaction mixture is then cooled, diluted with EtOAc, water, saturated LVDS.₃Washed with solution and brine. EDTA the organic layer₄It was dried on top, filtered and evaporated under vacuum to give a crude solid. The two legio isomer products 111 and 111a can be purified and separated by chromatography on silica gel using EtOAc / Hexanes as an eluent or recrystallization from EtOAc / Hexanes.

Example 10 In the formula, R¹Preparation of compounds in which is trifluoromethyl, X is -CH2-, and Y = N; and B is a thiophene ring.<img file="JP2009528362A_D0069.tif" />

A solution of aldehyde 147 in dichloromethane (about 20 mL / g) was treated with amine (1.1 eq), then treated with triacetoxyborohydride and stirred for 16 hours. The reaction mixture is then saturated with LVDS.₃After treatment with solution and stirring for 15 minutes, the reaction mixture was partitioned between EtOAc and water. The organic layer is further washed with brine solution and deli₄It was dried on top, filtered and evaporated under vacuum. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.

Example 11 In the formula, R¹Preparation of compounds in which is trifluoromethyl, X is -C (O)-, and Y = C; and B are thiophene or phenyl rings. Acylation method After formylation of scaffold 152 and subsequent treatment of product 153 with 2-4 equivalents of Grignard reagent at 0-10 ° C, oxidation of the resulting alcohol 154 to ketone 155.

Treatment of Weinreb amide skeleton 158 and 2-4 equivalents of Grignard reagent at 0-10 ° C. Friedel-Crafts acylation of skeleton 160 with excess acyl halide<img file="JP2009528362A_D0070.tif" />

General procedure for alkylation of backbone 149 A solution of NaH (1.1 eq) in DMF (5 mL / g NaH) was treated stepwise with diketone 149 and stirred until gas generation subsided. The reaction was then treated with an alkyl halide (2.0 eq) and heated with an additional amount of alkyl halide at 50-60 ° C for 16 hours, if the reaction was not complete. At the end, the reaction mixture was partitioned between EtOAc (50 mL / g NaH) and 5% sulfuric acid solution (50 mL / g NaH). The organic layer is further washed with water and brine, then DDL₄It was dried on top, filtered and evaporated under vacuum to give product 150. The crude product is generally of sufficient purity for use, but may be purified by chromatography on silica gel using EtOAc / Hexane as an eluent.

General procedure for carbonylation of backbone 152 A solution of DMF (15 ml / g 152) at 5-10 ° C was treated with phosphorus oxychloride (10 eq), warmed to room temperature, and then thiophene 152 was added. The resulting solution was heated at 80-100 ° C. for 16-24 hours until the reaction was complete. The reaction is then cooled to 0-5 ° C and K₂CO₃Carefully treated with saturated aqueous solution and EtOAc. The organic layer is further washed with water and brine, then DDL₄It was dried on top, filtered and evaporated under vacuum to give product 153. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.

General procedure for Grignard addition of Skeleton 153 A solution of aldehyde 153 in THF (20 mL / g) was treated with a 1 M THF solution of Grignard reagent (1.5 eq) and stirred for 1 hour. The reaction was then treated with saturated aqueous ammonium chloride solution and EtOAc. The organic layer is further washed with brine and EDTA₄It was dried on top, filtered and evaporated under vacuum to give product 154. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.

General procedure for oxidation of skeleton 154 A solution of carbinol 154 in dichloromethane (20 mL / g) was treated with pyridinium dichlorochromate (1.5 eq) and stirred for 3 hours. The reaction was then evaporated to 1/4 volume, diluted with EtOAc and filtered through a Celite plug. The organic layer was then evaporated under vacuum to give the crude product 155. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent. 2. <img file="JP2009528362A_D0071.tif" />

General procedure for coupling 157 with N, O-dimethylhydroxylamine hydrochloride to obtain skeleton 158 0-5 ° of acid 157, N, O-dimethylhydroxylamine hydrochloride (1.2 eq), triethylamine (1.2 eq), and DMAP (catalyst) in dichloromethane (1 mL / g) and DMF (0.1 mL / g) The mixture of C was treated with DCC (1.2 eq). After warming the reaction mixture to room temperature and stirring for 16 hours, the reaction was filtered through Celite with the aid of EtOAc and evaporated under vacuum to give crude product 158. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.

General procedure for Grignard addition to 158 to obtain skeleton 159 A solution of Weinreb amide 158 in THF (20 mL / g) was treated with a 1 M THF solution of Grignard reagent (4.0 eq) and stirred for 2 hours. The reaction was then treated with saturated aqueous ammonium chloride solution and EtOAc. The organic layer is further washed with brine and EDTA₄It was dried on top, filtered and evaporated under vacuum to give crude product 159. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.<img file="JP2009528362A_D0072.tif" />

FeCl a solution of 160 in dichloromethane (100 ml / g)₃ After treatment with (1.6 eq), it was treated with a carboxyl chloride (1.6 eq). The reaction was reflux heated for 16 hours and subsequently dispensed into water. Then the dichloromethane portion is Na₂SO₄It was dried on top, filtered and concentrated in vacuo to give crude product 161. The crude product can be purified by chromatography on silica gel using EtOAc / Hexane as the eluent.

Example 12 Preparation of the compound of the present invention The following compounds of the invention were prepared using the general procedures specified above.

<img file="JP2009528362A_D0073.tif" />

<img file="JP2009528362A_D0074.tif" />

<img file="JP2009528362A_D0075.tif" />

<img file="JP2009528362A_D0076.tif" />

<img file="JP2009528362A_D0077.tif" />

<img file="JP2009528362A_D0078.tif" />

<img file="JP2009528362A_D0079.tif" />

<img file="JP2009528362A_D0080.tif" />

<img file="JP2009528362A_D0081.tif" />

<img file="JP2009528362A_D0082.tif" />

<img file="JP2009528362A_D0083.tif" />

<img file="JP2009528362A_D0084.tif" />

<img file="JP2009528362A_D0085.tif" />

<img file="JP2009528362A_D0086.tif" />

<img file="JP2009528362A_D0087.tif" />

<img file="JP2009528362A_D0088.tif" />

<img file="JP2009528362A_D0089.tif" />

<img file="JP2009528362A_D0090.tif" />

<img file="JP2009528362A_D0091.tif" />

<img file="JP2009528362A_D0092.tif" />

<img file="JP2009528362A_D0093.tif" />

<img file="JP2009528362A_D0094.tif" />

<img file="JP2009528362A_D0095.tif" />

<img file="JP2009528362A_D0096.tif" />

<img file="JP2009528362A_D0097.tif" />

<img file="JP2009528362A_D0098.tif" />

<img file="JP2009528362A_D0099.tif" />

<img file="JP2009528362A_D0100.tif" />

<img file="JP2009528362A_D0101.tif" />

<img file="JP2009528362A_D0102.tif" />

<img file="JP2009528362A_D0103.tif" />

<img file="JP2009528362A_D0104.tif" />

<img file="JP2009528362A_D0105.tif" />

<img file="JP2009528362A_D0106.tif" />

<img file="JP2009528362A_D0107.tif" />

<img file="JP2009528362A_D0108.tif" />

<img file="JP2009528362A_D0109.tif" />

<img file="JP2009528362A_D0110.tif" />

<img file="JP2009528362A_D0111.tif" />

<img file="JP2009528362A_D0112.tif" />

<img file="JP2009528362A_D0113.tif" />

<img file="JP2009528362A_D0114.tif" />

<img file="JP2009528362A_D0115.tif" />

<img file="JP2009528362A_D0116.tif" />

<img file="JP2009528362A_D0117.tif" />

<img file="JP2009528362A_D0118.tif" />

<img file="JP2009528362A_D0119.tif" />

<img file="JP2009528362A_D0120.tif" />

<img file="JP2009528362A_D0121.tif" />

<img file="JP2009528362A_D0122.tif" />

<img file="JP2009528362A_D0123.tif" />

<img file="JP2009528362A_D0124.tif" />

<img file="JP2009528362A_D0125.tif" />

Example 13. The following exemplifies typical pharmaceutical dosage forms containing a compound of formula I (Compound X) for therapeutic or prophylactic use in humans.

<img file="JP2009528362A_D0126.tif" /><img file="JP2009528362A_D0127.tif" />The above-mentioned preparation can be obtained by a conventional procedure well known in the pharmaceutical field.

All publications, patents and patent documents are incorporated herein by reference as if they were individually incorporated by reference. The present invention has been described with respect to various specific and preferred embodiments and techniques. However, it should be understood that many modifications and modifications can be made while maintaining the spirit and scope of the invention.

<figref num="1">FIG. 1 shows data for two representative compounds of the invention in the contextual memory assay described herein. Specifically, compounds 162 and 177 injected 20 minutes before training significantly enhanced contextual memory in mice (N indicates the number of subjects used in the experiment).</figref>