ES2425578T3

Therapeutic compounds

Abstract

A compound selected from the group consisting of: ** Formulas **

ES2425578T3, drawing sheet 1 — Sheet 1 of 84

Term

0.4 yearsto projected expiry

Projected expiry 27 February 2027, counted from filing; an application has no term until it is granted.

4 claims: 1 independent, 3 dependent

1
ES2425578T3-86.png" style="width:38pt;height:25pt;"/ REIVINDICACIONES 1. Un compuesto seleccionado entre el grupo que consiste en: ES 2 425 578 T3 ES 2 425 578 T3
2
El compuesto de la reivindicación 1, o una sal farmacéuticamente aceptable del mismo, para su uso en un procedimiento para terapia médica en animales incluyendo seres humanos.
3
El compuesto de la reivindicación 1, o una sal farmacéuticamente aceptable del mismo, para su uso en animales 5 incluyendo seres humanos, en un procedimiento para mejorar la función cognitiva, para activar la vía CREB, para tratar la enfermedad de Alzheimer, para tratar la enfermedad de Parkinson o para tratar un trastorno psiquiátrico.
4
El compuesto de la reivindicación 1, o una sal farmacéuticamente aceptable del mismo, para su uso en animales incluyendo seres humanos, en un procedimiento para tratar un trastorno psiquiátrico, en donde el trastorno psiquiátrico es alteración de la memoria asociada con la edad (AAMI), un trastorno afectivo, un trastorno psicótico, 10 un trastorno neurológico o un trastorno neurótico, preferentemente seleccionado entre trastorno de déficit de atención, esquizofrenia, demencia vascular, depresión, traumatismo craneal y traumatismo cerebral.

Independent claims4

841 paragraphs in 83 sections, as filed

ES 2 425 578 T3

DESCRIPTION

Therapeutic compounds.

Background of the invention

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-dependent metabolic enzyme responsible for the oxidative deamination of both endogenous aminergic neurotransmitters and xenobiotic amines. There are two reported isoforms of MAO, MAO-A and MAO-B, arising from two independent genes (Bach, et al., Proc. Natl. Acad. Sci., 1988, 85, 4934-4938). Both forms of MAO are distributed in various tissues in varying amounts throughout the body; in the human brain, MAO-B is present to a greater degree than MAO-A (Saura, et al., Neuroscience, 1996, 70, 755-774).

MAO-A has higher selectivity for serotonin and epinephrine while MAO-B is selective for tyramine and phenethylamine, although both isoforms will metabolize dopamine. Studies have shown that the level of MAO-B activity in the brain increases with age (Fowler, et al., J. Neural Transm., 1980, 49, 1-20). The oxidative deamination process, which produces both peroxide and aldehydes as by-products, has also been associated with increased oxidative damage in the brain, especially to dopaminergic neurons, potentially exacerbating neuronal degeneration associated with diseases such as Alzheimer's disease and disease. Parkinson's. There are also reports that the level of MAO-B activity present is higher in Alzheimer's disease patients which may be linked to increased cognitive impairment in Alzheimer's patients (Dostert, et al., Biochem. Pharmacol., 1989, 38, 555-561; and Emilsson, et al., Neuroscience Letters, 2002, 326, 56-60). This link between oxidative stress and the progression of neuronal damage suggests that MAO-B inhibition will minimize the degenerative effects of these two diseases, presumably by preventing monoamine metabolism in the brain. In addition, the relative increase in dopamine levels, due to the inhibition of its metabolism, can have effects on the downstream regulation of cognitive function associated with plasticity, which can help repair, not simply prevent, the progress of these diseases.

The use of selective MAO-B inhibitors for neurological diseases has been known for some time (Bentue-Ferrer, et al., CNS Drugs, 1996, 6,217-236). The old MAO inhibitors for the treatment of depression were irreversible inhibitors with minimal selectivity for MAO-B over MAO-A. This can be problematic due to the potential side effects associated with both the subsequent inability of the irreversibly inhibited enzyme to efficiently metabolize ingested amines associated with cardiovascular events (the cheese effect) and the potential for drug-drug interactions with other drugs. that are metabolized by MAO-B. Newer drugs, including selegiline and rasagiline, although still irreversible inhibitors, have higher selectivity for MAO-B, and have better side effect profiles (Chen and Swope, J Clin Pharmacol. 2005 45, 878-94). There is currently a need for compounds that are useful for enhancing cognitive function and for treating cognitive impairment in Parkinson's disease and Alzheimer's disease, as well as compounds that can generally improve cognition in normal, sick, and elderly subjects. Preferably, such agents will have greater potency and / or fewer side effects than current therapies.

Summary of the invention

The invention provides MAO-B inhibitor compounds of claim 1 that are useful, for example, for enhancing cognitive function in animals (eg, humans). Accordingly, the invention provides the compounds of claim 1 for use in therapy as set forth in claims 2, 3 and 4.

Listed realizations

The following listed embodiments are disclosed:

1. A method of inhibiting one or more MAO enzymes in an animal comprising administering to the animal an effective MAO inhibiting amount of a compound, or a pharmaceutically acceptable salt thereof, of formula I:

in which:

OR)

ES 2 425 578 T3

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Rc;

one of R2 and R3 is absent and the other is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (Ce-Ce) cycloalkyl, (C2-C6) aminoalkyl, or aryl, each unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl or nitro, Het, cycloalkyl (C3-Ce) -alkyl (C1-C6), arylalkyl (C1-C6), (C1-C6) or Het-alkyl (C1 -C6);

B is aryl or heteroaryl;

X is -C (= O), -C (= S) -C (R4) 2, -C (OH) - or -S (O) z;

each z is independently 0, 1, or 2;

Y is R4, -N (R4) 2, -OR4, -MR4 or -C (R4)3;

or two R groups4 are taken together with the atom to which they are attached to form aryl, Het or a 3-8 membered monocyclic or bicyclic 8-12 membered saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more additional heteroatoms selected from O, S (O) z, and NRc, wherein each ring system is optionally substituted with one or more Rd;

each Ra and Rb is independently hydrogen or (C1-C6) alkyl;

each Rc is independently hydrogen, aryl, S (O) 2, (C1-C6) alkanoyl, (C1-C6) hydroxyalkyl, (C1Οβ) alkoxyalkyl, Het, (C1-C6) alkoxybonyl, or (C1-C6) alkyl, without substituted or substituted with one or more Re substituents;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C6) alkylamido, arylamido, carboxylic acid, (C1-C6) alkyl, hydroxyalkyl (C1-C6), (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, Het, aryl, Het-(C1-C6) alkyl or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Re substituents or two Rd join with the atom to which they are attached to form a carbocyclic or heterocyclic ketone or spirocyclic ring, or two Rd join with the atoms to which they are attached to form a ring carbocyclic or heterocyclic bicyclic, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), halo (C1- C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea, carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

Each Rc is independently selected from halo, hydroxy, cyano, nitro, azido, (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) alkanoyl, alkoxycarbonyl (C1-C6), carboxy and (C1-C6) alkanoyloxy;

R5 is H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) arylalkyl; and each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

provided that when X is -C (= O), Y is not H.

2. The method of embodiment 1, wherein B is 6-12 membered monocyclic or bicyclic heteroaryl.

3. The process of any of the above embodiments wherein B is heteroaryl with more than one heteroatom.

Four. The method of any of the above embodiments, wherein B is aryl.

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

6. The method of any of the above embodiments wherein the animal is a healthy animal.

7. The method of any of the above embodiments wherein the animal is an aged animal.

8. A method of activating the CREB pathway in an animal in need of such treatment comprising administering to the animal an effective CREB pathway activating amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, of any of the above embodiments.

9. A method of treating age-associated memory impairment, cognitive impairment, Alzheimer's disease or Parkinson's disease in an animal in need of said treatment comprising administering to the animal an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, of any of the above embodiments.

10. The method of any of the above embodiments, wherein the animal has a psychiatric disorder.

eleven. The procedure of any of the above embodiments, wherein the animal has a psychotic disorder,

ES 2 425 578 T3 a neurological disorder, or a neurotic disorder.

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

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

14. The method of any of the above embodiments, wherein the animal has attention deficit disorder.

fifteen. The method of any of the above embodiments, wherein the psychotic disorder is schizophrenia.

16. The method of any of the above embodiments, wherein the animal has an affective disorder.

17. The method of any of the above embodiments, wherein the cerebrovascular disease is vascular dementia.

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

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

twenty. The method of any of the above embodiments, wherein the psychiatric disorder is a psychotic disorder, a neurological disorder, or a neurotic disorder.

twenty-one. The method of any of the above embodiments, wherein the psychiatric disorder is a central nervous system disorder.

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

2. 3. 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 of any of the above embodiments, wherein the psychiatric disorder is attention deficit disorder.

25. The method of any of the above embodiments, wherein the psychotic disorder is schizophrenia.

26. The method of any of the above embodiments, wherein the psychiatric disorder is an affective disorder.

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

28. The method of any of the above embodiments, wherein the psychiatric disorder is depression.

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

30. The method of any of the above embodiments wherein the animal is an aged animal.

31. The procedure of any one of the previous embodiments, in which R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or phenyl which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, azido, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy and (C1-C6) alkanoyloxy.

32. The procedure of any one of the previous embodiments, in which R1 it is trifluoromethyl, phenyl, methyl, or isopropyl.

33. The procedure of any one of the previous embodiments, in which R2 he is absent.

3. 4. The procedure of any one of the previous embodiments, in which R3 he is absent.

35. The procedure of any one of the previous embodiments, in which R2 is (C1-C6) alkyl, cycloalkyl (Ce-Ce), aryl, Het or Het-(C1-C6) alkyl.

ES 2 425 578 T3

36. The procedure of any one of the previous embodiments, in which R2 is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, cyclopentyl, 2-pyridyl, 2-morpholinoethyl, 2,2,2-trifluoroethyl or 2-hydroxyethyl.

37. The procedure of any one of the previous embodiments, in which R3 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (Ce-Ce) cycloalkyl, aryl, Het, (C1-C6) arylalkyl or Het-(C1-C6) alkyl .

38. The procedure of any one of the previous embodiments, in which R3 is hydrogen, 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 , 2-morpholinoethyl or cyclohexyl.

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

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

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

42. The procedure of any one of the previous embodiments, in which each R4 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C3-cycloalkyl) Ce), (C3-C8) cycloalkyl (C1-C6) alkyl, (Ci-C6) alkoxy (C2-C6) alkyl, (C2-C6) hydroxyalkyl, (C1-C6) cyanoalkyl, (C1-C6) alkylthio )-(C2-C6) alkyl, aryl, arylalkyl (C1-C6), aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1 <C6) -alkyl (C1-C6), NRbRc, Het or Het-(C1-C6) alkyl.

43. The procedure of any one of the previous embodiments, in which each R4 is independently 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-fur-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, 3,5-difluorobenzyl, 2- (2-furyl) ethyl, 3-imidazol-1-ylpropyl, 2-cyanoethyl, 2-ethylbutyl, 2-pyrid-

3- ylethyl, Sa-hydroxy-3-methylphenethyl, Sa-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, Rtetrahydrofuran-2-ylmethyl, S-tetrahydrofuran-2- ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine or Npiperidinyl.

44. The procedure of any one of the previous embodiments, in which each R4 it is independently hydrogen or (C1-C6) alkyl.

Four. Five. The procedure of any one of the previous embodiments, in which both R4 are taken together with the atom to which they are attached to form a 3-8 membered monocyclic or 8-12 membered bicyclic or spirocyclic saturated or partially unsaturated ring system comprising carbon atoms and optionally comprising one or more selected additional heteroatoms between O, S (O) z and NRc, said ring system being optionally substituted with one or more Rd;

z is 0, 1 or 2;

Each Rc is independently hydrogen, aryl, amide, S (O) 2, (C1-C6) alkanoyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxyalkyl, Het, (C1-C6) alkoxybonyl, or (C1- C6), unsubstituted or substituted with one or more Re substituents;

Each Rd is independently selected from halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, alkoxycarbonyl (C1-C6), carboxy, NRfRg and (C1-C6) alkanoyloxy; and each Rf and Rg is independently hydrogen or (C1-C6) alkyl; or

Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring.

46. The procedure of any one of the previous embodiments, in which both R4 are taken together with the atom to which they are attached to form aziridine, morpholine, piperidine, 4-methylpiperidine, 2-hydroxymethylpyrrolidine, pyrrolidine, azetidine, 3-pyrroline, 4- (4-fluorophenyl) piperazine, 3,5-dimethylmorpholine, 4 - (2-hydroxyethyl) piperazine, 3,5-dimethylpiperidine, indoline, R-3-hydroxypyrrolidine, 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-phenylpiperidine, 4- (carboxamide) piperidine, 4-hydroxypiperidine, 4-phenylpiperazine, 4-acetylpiperazine, 3-carboxamidepiperidine, 2-carboxypiperidine, 4-trifluoromethylpiperidine, 3-trifluoromethylpiperifthylpiperazine, 3-trifluoromethylpiperifthylpiperidine, 3-trifluoromethylpiperifthylpiperazine, 3-trifluoromethylpiperifthylpiperidine, 3-hydroxypiperidine , 4-aminopiperidine, 4-hydroxy-4-trifluoromethylpiperidine, 4-methylhomopiperizine, 1,1-thiomorpholine dioxide, 4- (2'-pyridyl) piperazine, 4- (2'-methoxy) ethylpiperazine, 4-t-butoxycarbonylaminopiperidine , 1,1 perhydro-1,2-thiazine dioxide, 3-aminopiperidine, 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-benzylpiperidine.

ES 2 425 578 T3

47. The procedure of any one of the previous embodiments, in which both R4 are taken together with the atom to which they are attached to form a piperidine ring, which is optionally substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, haloalkyl (C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl, or phenylalkyl (C1-C6), wherein any phenyl phenyl is optionally substituted with one or more Rd; each Rd is independently selected from halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, alkoxycarbonyl (C1-C6), carboxy and (C1-C6) alkanoyloxy; and each Rf and Rg is independently hydrogen or (C1-C6) alkyl; or Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring.

48. The process of any one of the above embodiments, wherein the atom to which they are attached to form a piperidine ring.

49. The method of any one of the preceding embodiments, wherein compound of formula II:

both R4 are taken together with the compound of formula

I is a

fifty. The method of any one of the preceding embodiments, wherein the compound compound of formula III:

formula

I is a

51. The procedure of a compound of formula IIIa:

compound of formula

I is a

ES 2 425 578 T3

52. The method of any one of the preceding embodiments, wherein the compound of formula IV:

53. The method of any one of the preceding embodiments, wherein the compound of formula IVa:

54. The method of any one of the preceding embodiments, wherein the compound of formula V:

55. The method of any one of the preceding embodiments, wherein the compound of formula Va:

compound compound compound compound of formula I of formula I of formula I of formula I is is is is a a a a

ES 2 425 578 T3

56. The method of any one of the above embodiments, wherein the compound of formula I is a compound of formula Vb:

57. The method of any one of the preceding embodiments, wherein the compound of formula I is a compound of formula VI:

58. The method of any one of the above embodiments, wherein the compound of formula I is a compound of formula VIa:

59. The method of any one of the above embodiments, wherein the compound of formula I is a compound of formula VIb:

ES 2 425 578 T3

60. The method of any one of the preceding embodiments, wherein the compound compound of formula VII:

of formula I is a

61. The method of any one of the preceding embodiments, wherein the compound of formula I is a compound of formula VIIa:

62. The method of any one of the preceding embodiments, wherein the compound compound of formula VIIIa:

of formula I is a

63. The method of any one of the preceding embodiments, wherein the compound of formula VIIIb:

compound of formula I is a

ES 2 425 578 T3

64. A compound of formula I:

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Re;

one of R2 and R3 is absent and the other is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (Ce-Ce) cycloalkyl, (C2-C6) aminoalkyl, or aryl, each unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl or nitro, Het, cycloalkyl (Ce-Ce) -alkyl (C1-C6), arylalkyl (C1-C6), (C1-C6) or Het-alkyl (C1 -C6);

B is aryl or heteroaryl;

X is -C (= O), -C (= S) -C (R4) 2 or -S (O) z;

each z is independently 0, 1, or 2;

Y is R4, -N (R4) 2, -OR4, -MR4 or -C (R4)and;

each R4 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl C6), cycloalkyl (Ce-Ce), cycloalkyl (Ce-Ce) -alkyl (C1-C6), alkoxy (C1-C6) -alkyl (C2-C6), hydroxyalkyl (C2-C6), cyanoalkyl (C1-C6 ), (C1-C6) alkylthio (C2-C6) alkyl, aryl, arylalkyl (C1-C6), aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1-C6) -alkyl (C1-C6) ), NRaRb, Het or Hetalkyl (C1-C6), wherein each alkyl, aryl or Het is unsubstituted or substituted with one or more Rd; or two R groups4 are taken together with the atom to which they are attached to form aryl, Het or a 3-8 membered monocyclic or bicyclic 8-12 membered saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more additional heteroatoms selected from O, S (O) z, and NRc, wherein each ring system is optionally substituted with one or more Rd;

each Ra and Rb is independently hydrogen or (C1-C6) alkyl;

each Rc is independently hydrogen, aryl, S (O) 2, (C1-C6) alkanoyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxyalkyl, Het, (C1-C6) alkoxybonyl, or (C1-C6) alkyl, without substituted or substituted with one or more Re substituents;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C6) alkylamido, arylamido, carboxylic acid, (C1-C6) alkyl, hydroxyalkyl (C1-C6), (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, Het, aryl, Het-(C1-C6) alkyl or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Rc substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea, carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

each Re is independently selected from halo, hydroxy, cyano, nitro, azido, (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, haloalkyl (¿1C6), alkoxy (C1-C6), haloalkoxy (C1-C6), alkanoyl (C1-C6), (C1-C6) alkoxycarbonyl, carboxy and (C1-C6) alkanoyloxy; R5 is H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl (C1-C6) alkyl; and each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

provided that when Bis thiophene, R1 is trifluoromethyl, R2 is methyl, R3 and R6 are absent, R5 is H, X is C (= O), and Y is N (R4) 2, none of R4 they are methyl.

ES 2 425 578 T3

65. The compound of any one of the above embodiments that is selected from the group consisting of

ES 2 425 578 T3

ES 2 425 578 T3

66. A compound of formula I:

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Re;

one of R2 and R3 is absent and the other is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C8) cycloalkyl, (C2-C6) aminoalkyl, or aryl, each unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl or nitro, Het, cyclo (C3-C8) -alkyl (C1-C6), arylalkyl (C1-C6), (C1-C6) or Hetalkyl (C1-C6) );

B is 6-12 membered monocyclic or bicyclic heteroaryl;

X is -C (= O), -C (= S) -C (R4) 2 or -S (O) z;

each z is independently 0, 1, or 2;

Y is R4, -N (R4) 2, -OR4, -MR4 or -C (R4)3;

each R4 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl C6), cycloalkyl (C3-C8), cycloalkyl (Cs-Csj-alkyl (C1-C6), alkoxy (C1-C6) -alkyl (C2-C6), hydroxyalkyl (C2-C6), cyanoalkyl (C1-C6) , (C1-C6) alkylthio (C2-C6) alkyl, aryl, arylalkyl (C1-C6), aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1-C6) -alkyl (C1-C6) , NRaRb, Het or Het-(C1-C6) alkyl, unsubstituted or substituted with one or more Rd; or two R groups4 are taken together with the atom to which they are attached to form aryl, Het or a 3-8 membered monocyclic or bicyclic 8-12 membered saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more selected heteroatoms between O, S (O) z, and NRc, wherein each ring system is optionally substituted with one or more Rd;

each Ra and Rb is independently hydrogen or (C1-C6) alkyl;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C6) alkylamido, aryl amido, carboxylic acid, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy , Het, aryl, Het-(C1-C6) alkyl or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Re substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea,

ES 2 425 578 T3 carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

Each Re is independently selected from halo, hydroxy, cyano, nitro, azido, (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) alkanoyl, alkoxycarbonyl (C1-C6), carboxy and (C1-C6) alkanoyloxy; R5 is H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) arylalkyl;

each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

or a pharmaceutically acceptable salt thereof.

67. The compound of any one of the above embodiments that is selected from the group consisting of

ES 2 425 578 T3

68. A compound of formula I:

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Rc;

B is thiophene, furan, or pyrrole;

X is -C (= O), -C (= S) -C (R4) 2 or -S (O) z;

each z is independently 0, 1, or 2;

Y is -N (R4)2;

both R4 are taken together with the N to which they are attached to form a 3-8 membered monocyclic or 8-12 membered bicyclic saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more additional heteroatoms selected from O, S (O) z and NRc, unsubstituted or substituted with one or more Rd, provided that none of the R groups4 combines to form 2Hbenzo [b] [1,4] oxazine, in which if the ring system is a 5-7 membered monocyclic ring, it is substituted with one or more Rd other than halo or alkyl;

each Rc is independently hydrogen, aryl, S (O) 2, (C1-C6) alkanoyl, (C1-C6) hydroxyalkyl, (C1-Ce) alkoxyalkyl, Het, (C1-C6) alkoxybonyl, or (C1-C6) alkyl, without substituted or substituted with one or more Re substituents;

ES 2 425 578 T3 each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C6) alkylamido, aryl amido, carboxylic acid, alkyl ( C1-C6), hydroxyalkyl (C1-C6), haloalkyl (C1-C6), alkoxy (C1-C6), haloalkoxy (C1-C6), alkanoyl (C1-C6), alkoxycarbonyl (C1-C6), carboxy, alkanoyloxy (C1-C6), Het, aryl, Het-(C1-C6) alkyl or (C1-C6) arylalkyl, (C1-C6) alkylaryl, sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Re substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea, carbamate, where Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

or a pharmaceutically acceptable salt thereof.

69. The compound of any one of the above embodiments that is selected from the group consisting of

ES 2 425 578 T3

ES 2 425 578 T3

70. A compound of formula I:

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Re;

B is thiophene, furan, or pyrrole;

X is -C (= O), -C (= S) -C (R4) 2 or -S (O) z;

each z is independently 0, 1, or 2;

Y is R4, N (R4) 2, -OR4, -MR4 or -C (R4)3;

each R4 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, amino, (C1-C6) alkoxy, (C1-C6) alkanoyl, alkoxycarbonyl ( C1-C6), cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkyl (C1-C6), alkoxy (C1-C6) -alkyl (C2-C6), hydroxyalkyl (C2-C6), cyanoalkyl (C1 -C6), (C1-C6) alkylthio (C2-C6) alkyl, aryl, aryl (C1-C6) alkyl, aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1-C6) -alkyl (C1-C6), NRbRc, Het or Het-(C1-C6) alkyl, each unsubstituted or substituted with one or more Rd; provided that at least one R4 be it alkenyl, alkynyl or amino;

ES 2 425 578 T3 each Rb and Rc is independently hydrogen or (C1-C6) alkyl;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido , (C1-C6) alkylamido, aryl amido, carboxylic acid, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy , Het, aryl, Het-(C1-C6) alkyl or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Re substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloxalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl ( C1-C6), sulfonyl, sulfonamido, urea, carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

Each Rc is independently selected from halo, hydroxy, cyano, nitro, azido, (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) alkanoyl, alkoxycarbonyl (C1-C6), carboxy and (C1-C6) alkanoyloxy;

R5 is H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) arylalkyl; and each R6 is H, (C1-C6) alkyl, amino, amido, keto, or (C1-C6) arylalkyl;

or a pharmaceutically acceptable salt thereof.

71. A compound of formula I:

in which:

R1 is (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Re;

one of R2 and R3 is absent and the other is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (Ce-Ce) cycloalkyl, (C2-C6) aminoalkyl, or aryl, each unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl or nitro, Het, cyclo (C3-C8) -alkyl (C1-C6), arylalkyl (C1-C6), (C1-C6) or Het-alkyl (C1 -C6);

B is thiophene, furan, or pyrrole;

X is -C (= S) or -C (R4)2;

Y is R4, -N (R4) 2, -OR4, -MR4 or -C (R4)3;

where when X is -C (R4) 2, Y is -SR4;

each R4 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1- C6), cycloalkyl (Ce-Ce), cycloalkyl (C3-C8) -alkyl (CrCe), alkoxy (C1-C6) -alkyl (C2-C6), hydroxyalkyl (C2-C6), cyanoalkyl (C1-C6), (C1-C6) alkylthio (C2-C6) alkyl, aryl, arylalkyl (C1-C6), aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1-C6) alkyl (C1-C6), NRaRb , Het or Het-(C1-C6) alkyl, unsubstituted or substituted with one or more Rd, or two R groups4 are taken together with the atom to which they are attached to form aryl, Het or a 3-8 membered monocyclic or bicyclic 8-12 membered saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more selected heteroatoms between O, S (O) 2 and NRc, wherein each ring system is optionally substituted with one or more Rd;

each z is independently 0, 1, or 2;

each Ra and Rb is independently hydrogen or (C1-C6) alkyl;

ES 2 425 578 T3 hydroxyalkyl (C1-C6), haloalkyl (C1-C6), alkoxy (C1-C6), haloalkoxy (C1-C6), alkanoyl (C1-C6), alkoxycarbonyl (C1Οβ), carboxy, alkanoyloxy (C1 -C6), NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, where Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino ring or thiomorpholino, unsubstituted or substituted with one or more Re substituents;

each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

or a pharmaceutically acceptable salt thereof.

72. A compound, or a pharmaceutically acceptable salt thereof, of formula II

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Re;

2 3 6 6 1 6 each of Z, Z, and Z is independently C (R) p, N (R) q, O, or S, where Z is N (R) q, O, or S; at least one of Z1 or Z2 must be N (R6) q, 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 (R4) 2 or -S (O) z;

each z is independently 0, 1, or 2;

Y is R4, N (R4) 2, -OR4, -MR4 or -C (R4)3;

each R4 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1- C6), (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C8) alkoxy (C2-C6) alkyl, (C2-C6) hydroxyalkyl, (C1-C6) cyanoalkyl ), alkylthio (C1-C6) alkyl (C2-C6), aryl, aryl (C1-C6) alkyl, aryloxyalkyl (C2-C6), haloalkyl (C2-C6), alkoxycarbonyl (C1-C8) -alkyl (C1- C6), NRaRb, Het or Het-(C1-C6) alkyl, wherein each alkyl, aryl, or Het is unsubstituted or substituted with one or more Rd, or two R groups4 are taken together with the atom to which they are attached to form aryl, Het or a 3-8 membered monocyclic or bicyclic 8-12 membered saturated or unsaturated ring system comprising carbon atoms and optionally comprising one or more additional heteroatoms selected from O, S (O) z, and NRc, wherein each ring system is optionally substituted with one or more Rd;

each Ra and Rb is independently hydrogen or (C1-C6) alkyl;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C8) alkylamido, aryl amido, carboxylic acid, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy , Het, aryl, Hetalkyl (C1-C6) or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Rc substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea, carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Re substituents;

each Re is independently selected from halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, Het, aryl, (C1-C8) alkyl-Het, (C1-C6) alkylaryl, (C1-C8) alkyl - Het-(C1-C6) alkyl, (C1-C8) alkylaryl (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C8) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, alkoxycarbonyl (C1-C6), carboxy and (C1-C6) alkanoyloxy;

ES 2 425 578 T3

R5 is H, (C1-C6) alkyl, (C1-C6) arylalkyl; and each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

provided that when X is -C (= O), Y is N (R4) 2, Z1 let O, Z2 let N and Z3 let CH, none R4 from Y let H.

73. A pharmaceutical composition comprising a compound as described in any one of the preceding embodiments and a pharmaceutically acceptable diluent or carrier.

74. A process for preparing a compound of formula I or a salt thereof as described in any one of the preceding embodiments comprising:

a) deprotecting a corresponding compound comprising one or more protecting groups to provide the compound of formula I;

b) forming a pharmaceutically acceptable salt from a compound of formula I;

c) for a compound of formula I, where X is -C (= O) -, reacting an intermediate acid of formula 100 with an amine of formula i:

to provide the compound of formula I; or

d) for a compound of formula I in which R2 is absent, reacting a diketone intermediate of formula 102 with a hydrazine of formula ii:

to provide the compound of formula I.

75. A compound described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

76. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the preceding embodiments for the manufacture of a medicament useful for improving cognitive function in an animal.

77. The use of any of the above embodiments wherein the animal is a healthy animal.

78. The use of any of the above embodiments wherein the animal is an aged animal.

79. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the preceding embodiments for the manufacture of a medicament useful for inhibiting MAO enzymes in an animal.

80. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the previous embodiments for the manufacture of a medicament useful for activating the CREB pathway in an animal.

81. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the preceding embodiments for the manufacture of a medicament useful for treating a psychiatric disorder in an animal.

82. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the preceding embodiments for the manufacture of a medicament useful for treating

ES 2 425 578 T3 Alzheimer's disease in an animal.

83. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, described in any one of the preceding embodiments for the manufacture of a medicament useful for treating Parkinson's disease in an animal.

84. A compound selected from the group consisting of

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

ES 2 425 578 T3

85. The process of any one of the preceding embodiments wherein the compound, or a pharmaceutically acceptable salt thereof, of formula I is the compound of any of the foregoing embodiments.

86. A compound of formula I

in which:

R1 is (C1-C6) alkyl, (C1-C6) haloalkyl or aryl, unsubstituted or substituted with one or more Rc; one of R2 and R3 is absent and the other is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl,

ES 2 425 578 T3 cycloalkyl (Ce-Ce), aminoalkyl (C2-C6) or aryl, each unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl or nitro, Het, cycloalkyl (C3-C8) - (C1-C6) alkyl, arylalkyl (C1-C6), (C1-C6) or Het-(C1-C6) alkyl;

B is 5- to 12-membered monocyclic or bicyclic Het;

X is -C (= O);

Y is -OR4;

R4 is an 8-12 membered bicyclic ring system comprising carbon atoms and optionally comprising one or more heteroatoms selected from O, S and NRc, wherein each ring system is optionally substituted with one or more Rd;

each Rd is independently halo, hydroxy, cyano, nitro, azido, amino, (C1-C6) alkylamino, (C1-C6) aminoalkyl, amido, (C1-C6) alkylamido, aryl amido, carboxylic acid, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy , Het, aryl, Hetalkyl (C1-C6) or arylalkyl (C1-C6), alkylaryl (C1-C6), sulfonyl, sulfonamido, urea, carbamate, unsubstituted or substituted with one or more Rc substituents, or two Rd join with the atom to which they are attached to form a ketone or a spirocyclic or heterocyclic carbocyclic ring, or two Rd join with the atoms to which they are attached to form a carbocyclic or heterocyclic bicyclic ring, wherein each spirocyclic or bicyclic ring is unsubstituted or substituted with one or more halo, hydroxy, cyano, nitro, azido, (C1-C6) alkyl, hydroxyalkyl (C1-C6), haloalkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, carboxy, (C1-C6) alkanoyloxy, NRfRg, RfRgNC (= O) -, phenyl or phenylalkyl (C1- C6), sulfonyl, sulfonamido, urea, carbamate, in which Rf and Rg together with the nitrogen to which they are attached form a piperidino, pyrrolidino, morpholino or thiomorpholino ring, unsubstituted or substituted with one or more Rc substituents;

R5 is H (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) arylalkyl; and each R6 is H, (C1-C6) alkyl, amino, amido, keto or arylalkyl (C1-C6);

or a pharmaceutically acceptable salt thereof.

87. The compound of any one of the above embodiments that is selected from the group consisting of

88. The compound of any of the above embodiments in which Y = R4.

Brief description of the Figures

FIGURE 1 Figure 1 shows data for two representative compounds of the invention in the contextual memory assay described hereinafter. 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 experiments).

Detailed description

The following definitions are used, unless otherwise indicated: halo is fluorine, chlorine, bromine, or iodine. Alkyl, alkoxy, alkenyl, alkynyl, etc. indicate linear or branched groups; but reference to an individual radical, such as propyl, encompasses only the straight chain radical, specifically referring to a branched chain isomer, such as isopropyl. Aryl represents a phenyl radical or an ortho-fused bicyclic radical having about nine to ten ring atoms in which at least one ring is aromatic; Het encompasses a radical of a monocyclic, bicyclic, or tricyclic ring system containing a total of 3-20 atoms, including carbon atoms and one or more heteroatoms selected from oxygen, sulfur, and N (X), in which X is absent or is H, O, (C1-C4) alkyl, phenyl, or benzyl, in which one or more of the ring carbons of Het may be

ES 2 425 578 T3 optionally substituted with (= O); Heteroaryl encompasses a radical of a monocyclic aromatic ring containing five or six atoms in the ring consisting of carbon and one to four heteroatoms each selected from the group consisting of oxygen other than peroxide, sulfur, and N (X), in where X is absent or is H, O, (C1-C4) alkyl, phenyl or benzyl, as well as a radical of an ortho-condensed bicyclic heterocycle of about eight to ten ring atoms obtained therefrom, particularly a benzo derivative or one obtained by condensing a propylene, trimethylene or tetramethylene diradical thereof. The term Het encompasses Heteroaryl.

The term "animal" as used herein includes birds, reptiles, and mammals (eg, domesticated mammals and humans).

The term "selective inhibition" as used herein means that a compound inhibits MAO-B activity to a greater degree than it inhibits MAO-A activity (in vitro or in vivo). In a disclosed embodiment, the compound of formula I inhibits MAO-B activity twice as much as MAO-A activity. In another embodiment, the compound of formula I inhibits MAO-B activity five times more than MAO-A activity. In another embodiment, the compound of formula I inhibits MAO-B activity ten times more than MAO-A activity. In another embodiment, the compound of formula I inhibits MAO-B activity one hundred times more than MAO-A activity.

The term "psychiatric disorder" as used herein includes psychotic disorders, neurological disorders, and neurotic disorders. The term includes schizophrenia, age-associated memory impairment (AAMI); mild cognitive impairment (MCI), delirium (acute confusional state); depression, dementia (sometimes further classified as Alzheimer's or non-Alzheimer's dementia); Alzheimer disease; Parkinson's disease; Huntington's disease (chorea); Mental retardation; (for example, Rubenstein-Taybi and Down syndrome); cerebrovascular disease (eg, vascular dementia, post-cardiac surgery); affective disorders; psychotic disorders; autism (Kanner syndrome); neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal pressure hydrocephalus; brain tumor; head trauma (post-concussion disorder) or brain trauma.

Those skilled in the art will appreciate that compounds of the invention having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can show polymorphism. It should be appreciated that the present invention encompasses any racemic, optically active, polymorphic, stereoisomeric, or regioisomeric form, or mixtures thereof, of a compound of the invention, having the useful properties described herein, being well known in the art. technique how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine MAO-B inhibitory activity using the standard assays described herein, or using other similar assays that are well known in the art.

Specific and preferred values listed below for radicals, substituents, and ranges are for illustration only; these do not exclude other defined values or other defined values within defined ranges for radicals and substituents.

Specifically, (C1-C6) alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3pentyl, or hexyl; (C2-C6) alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6) alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C3-C8) cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C8) cycloalkyl (C1-C6) alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cycloalkyl (Ce) -alkyl (C1-C6) can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl; (C1-C6) alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; cyano (C2-C6) alkyl can be 2-cyanoethyl, 3-cyanopropyl, 2-quanopropyl or 4-cyanobutyl; (C1-C6) alkanoyl can be acetyl, propanoyl or butanoyl; (C1-C6) haloalkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; hydroxyalkyl (C1-C6) can be hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 2,4-hydroxybutyl; (C1-C6) alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C2-C6) alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; (C1-C6) alkoxy (C2-C6) alkyl can be 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 3-ethoxypropyl, 4,4-dimethoxybutyl; cyano (C1-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 furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, 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).

ES 2 425 578 T3

A specific value for R1 it is trifluoromethyl, phenyl, methyl, isopropyl, difluoromethyl, chloro-difluoromethyl or pentafluoroethyl.

A specific value for R2 is methyl, ethyl, propyl, isopropyl, phenyl, cyclopentyl, 2-pyridyl, 2-morpholinoethyl, or 2-hydroxyethyl.

A specific value for R3 is 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, R3 he is absent.

A specific value for B is 2,5-thiophenediyl, 1,4-benzenediyl, 1,3-benzenediyl, 2,4-pyridinediyl, or 2,6-pyridinediyl.

A specific value for X is -C (= O) Y, -C (= S) Y, -C (R4) 2Y or -S (O) 2Y.

A specific value for Y is R4, -N (R4) 2, -OR4, -MR4 or -C (R4)3.

A specific value for R4 is hydrogen, methyl, ethyl, butyl, propyl, isopropyl, 2-fluorophenethyl, 2-pyrrolidinoethyl, 2furylmethyl, 4-methylbenzyl, cyclopropylmethyl, cyclohexylmethyl, 4-methoxybenzyl, 4-fluorobenzyl, 4-pyridylmethyl, 4-chlorohexyl, benzyl, cyclo -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-fur-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, 3, 5-Difluorobenzyl, 2- (2-furyl) ethyl, 3-imidazol-1-ylpropyl,

2- cyanoethyl, 2-ethylbutyl, 2-pyrid-3-ylethyl, Sa-hydroxy-p-methylphenethyl, Sa-methylphenethyl, 4,4-dimethoxybutyl, 3- (2-oxypyrrolidin-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-2ylmethyl, R- 2-ylmethyl, S-tetrahydrofuran-2-ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine or N-piperdinil.

A specific value for both R4 taken together with Y to which they are attached is morpholine, piperidine, 4-methylpiperidine, 2,6-dimethylmorpholine, 2-hydroxymethylpyrrolidine, pyrrolidine, azetidine, 3-pyrroline, 4- (4-fluorophenyl) piperazine, 3,5-dimethylmorpholine, 4- (2 -hydroxyethyl) piperazine, 3,5-dimethylpiperidine, indoline, R-3-hydroxypyrrolidine, 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-phenylpiperidine, 4- (carboxamide) piperidine, 4-hydroxypiperidine, 4-phenylpiperazine, 4-acetylpiperazine, 4-benzylpiperidine, 4-trifluoromethylpiperidine, 3-trifluoromethyl-piperidine, 4-fluoropiperidine, 3-trifluoromethyl-piperidine, 4-fluoropiperidine, 3-trifluoromethyl-piperidine, 4-fluoropiperidine, 3-trifluoromethyl-piperidine 4 difluoropiperidine, 3,3-difluoropiperidine, 4-isopropylpiperizine, 4-t-butoxycarbonyl-piperizine, 4-methoxypiperidine, pyrrolidine or 3-fluoropyrrolidine.

A specific value for both R4 taken together with Y = carbon to which they are attached is cyclohexyl, phenyl, 4-fluorophenyl or 4-trifluoromethylphenyl.

A specific group of compounds are compounds in which an R4 is hydrogen and 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-fur-2-ylmethyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, 2-methylbutyl, 2-imidazole-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-imidazole -1-ylethyl, 2-cyanoethyl, 2-ethylbutyl, 2-pyrid-3-ylethyl, Sa-hydroxy-p-methylphenethyl, Sa-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, Rtetrahydrofuran-2-ylmethyl, S-tetrahydrofuran-2-ylmethyl, 2-aminoethyl, 5-aminopentyl, 4- (4-chlorophenyl) piperazine or Npiperdinil.

A specific value for R5 it is methyl, ethyl, benzyl, propyl, and allyl.

A specific value for R6 is methyl.

A specific value for Het is a radical of a monocyclic or bicyclic ring system that contains a total of 312 atoms, including one or more carbon atoms, and one or two heteroatoms selected from oxygen, sulfur, and N (X), in the that X is absent or is H, O, (C1-C4) alkyl, phenyl or benzyl. Specific values for Het include piperidine, morpholine, thiomorpholine, pyrrolidine, imidazole, furan, pyridine, 2-oxopyrrolidine, furan, tetrahydrofuran, piperazine, and azetidine.

Methods for preparing compounds of formula I are provided and illustrated by the following procedures in which the meanings of the generic radicals are as given above unless

ES 2 425 578 T3 otherwise qualified.

A compound of formula I can be prepared using the general synthetic schemes illustrated below. Bis aryl or Het. For example, a compound of formula I, where X is -C (= O) - can be prepared by reacting an intermediate acid of formula 100 with an amine of formula 101.

A solution of the acid 100 in a suitable solvent (eg, DMF) is treated with EDC-HCl, HOBT hydrate, and Hunig's base to activate the acid; The necessary amine is added to the activated acid to provide an amide of formula 101. Conventional aqueous work-up, followed by normal phase flash chromatography provides the purified amide. The amine can also be coupled to the acid 100 by activation with oxalyl chloride or thionyl chloride.

A compound of formula 103a / b can be prepared by reacting a diketone intermediate of formula 102 with a hydrazine of formula ii, as illustrated below.

It will be understood that the above reaction, as well as other reactions that are useful for preparing or modifying pyrazole rings, can provide a single regioisomer or a mixture of regioisomers (e.g., a mixture of compounds of formula I, where R2 is absent and compounds of formula I in which R3 he is absent). When a mixture originates, the regioisomers can be separated using various conventional techniques (eg, chromatography) that are well known.

ES 2 425 578 T3

Intermediate acids of formula 100a and 100b can be prepared as illustrated below.

An acid of formula 104 can be converted to the corresponding ester using any of suitable conditions (eg, by treatment with oxalyl chloride in a suitable solvent followed by treatment with an alcohol). Conversion of ester 105 to diketone 106, followed by treatment with the necessary hydrazine provides pyrazoles 107a / b. Subsequent hydrolysis of the ester under conventional conditions provides the acids of formula 100a / b. A diketone intermediate of formula 102 can be prepared from a keto acid of formula 108 as illustrated below.

The acid functionality of 108 can be converted to the group -XN (R4) 2 of compound 109 under standard conditions. Ketone 109 can be converted to diketone 102 under conventional conditions, for example, by treatment with an ester of formula R1COOEt.

In cases where the compounds are sufficiently basic or acidic to form stable non-toxic acidic or basic salts, administration of the compounds in the form of salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α- glycerophosphate. Suitable inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid to produce a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.

The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in various forms adapted for the chosen route of administration, i.e., oral or parenteral, intravenous, intramuscular, topical or subcutaneous.

Thus, the present compounds can be administered systemically, for example orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, they can be compressed into tablets, or they can be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and

ES 2 425 578 T3 similar. Said compositions and preparations must contain at least 0.1% of active compound. The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 2 to about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

Tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, cornstarch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose, or aspartame or a flavoring agent such as peppermint, wintergreen oil, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present in the form of coatings or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules can be coated with gelatin, wax, shellac, or sugar and the like. A syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a coloring and flavoring such as cherry or orange flavoring. Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained-release preparations and devices.

The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the improvised preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid medium or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (eg, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be achieved by the use in the compositions of absorption retarding agents, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients listed above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients present in the previously filtered solutions at sterility.

For topical administration, the present compounds can be applied neat, that is, when they are liquid. However, it will generally be desirable to administer them to the skin in the form of compositions or formulations, in combination with a dermatologically acceptable carrier, which can be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol mixtures, in which the present compounds can be dissolved or dispersed to effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use. The resulting liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using aerosol or pump type sprays.

Thickeners such as synthetic polymers, fatty acids, salts of fatty acids and esters, fatty alcohols, modified celluloses or mineral materials modified with liquid carriers can also be employed to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the user's skin.

ES 2 425 578 T3

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and their in vivo activity in animal models. Procedures for extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example see United States patent

States No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in the treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition to be treated, and the age and condition of the patient and finally it will be at the discretion of the doctor or clinician in charge.

In general, however, a suitable dose will be in the range of about 0.15 to about 100 mg / kg, for example, about 1 to about 75 mg / kg of body weight per day, such as 0.75 to about 50 mg per kilogram of recipient body weight per day, preferably in the range of 1 to 90 mg / kg / day, more preferably in the range of 1 to 60 mg / kg / day.

The compound is conveniently administered in unit dosage form; for example, containing 1 to 1000 mg, conveniently 10 to 750 mg, more conveniently 5 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 µΜ, preferably from about 1 to 50 µΜ, more preferably from about 2 to about 30 µΜ. This can be achieved, for example, by intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or oral administration as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion to provide about 0.01-5.0 mg / kg / h or by intermittent infusions containing about 0.4-15 mg / kg of the active ingredient (s).

The desired dose may conveniently be presented in a single dose or in the form of divided doses administered at appropriate intervals, for example, in the form of two, three, four or more sub-doses per day. The sub-dose itself can be further divided, for example, into several different, freely spaced administrations.

The compounds of the invention may also optionally be administered in combination with one or more other therapeutic agents that are effective in improving cognition and / or one or more therapeutic agents that are effective in treating schizophrenia, age-associated memory impairment ( TO AMI); mild cognitive impairment (MCI), delirium (acute confusional state); depression, dementia (sometimes further classified as Alzheimer's or non-Alzheimer's dementia); Alzheimer disease; Parkinson's disease; Huntington's disease (chorea); Mental retardation; (for example, Rubenstein-Taybi and Down syndrome); cerebrovascular disease (eg, vascular dementia, post-cardiac surgery); affective disorders; psychotic disorders; autism (Kanner syndrome); neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal pressure hydrocephalus; brain tumor; head trauma (post-concussion disorder) or brain trauma (see DSM-IV, APA 1994).

The ability of a compound of the invention to act as an MAO-B inhibitor can be determined using pharmacological models that are well known in the art, or using the following assay.

MAO inhibition assay

The MAO enzyme assay was performed according to the fluorometric procedure described by Matsumoto et al. (Matsumoto, et al., Clin. Biochem., 1985 18, 126-129) with the following modifications. Human recombinant MAO-A and MAO-B expressed in insect cells were used. For both assays, the test compound and / or vehicle was pre-incubated with the purified enzyme in phosphate buffer pH 7.4 for 15 minutes at 37 ° C. The reaction was started by adding 50 µM quinuramine. After an incubation period of 60 minutes, the reaction was terminated by the addition of 6N NaOH. The amount of 4-hydroxyquinoline formed was determined spectrofluorimetrically at 325 nm / 465 nm. Results were converted to percent inhibition and IC50s were determined using the IDBS XLfit program (ID Business Solutions Ltd., 2 Occam Court, Surrey Research Park, Guildford, Surrey, GU2 7QB UK). Representative compounds of the invention were evaluated in this assay. Typically the compounds of the invention exhibited MAO-B inhibitory properties at 0.1-10 µM, typically 5-100%. Preferred compounds also demonstrated selectivity for MAO-B over MAO-A.

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

CREB activation assay

The CRE-Luci assay below is a well-founded high-throughput procedure for identifying compounds that enhance cognition by increasing the function of the CREB pathway. The trial enables the identification of cognitive enhancers that do not affect the function of the CREB pathway only, but act by increasing

ES 2 425 578 T3 (enhancing) the function of the CREB pathway in combination with an agent stimulating CREB function.

The assay is performed (a) by contacting host cells (particularly cells of neural origin (eg, human neuroblastoma SK-N-MC cells) that have a luciferase gene operably linked to a CRE promoter with a compound of assay and a suboptimal dose of a CREB function stimulating agent (eg, forskolin); (b) determining luciferase activity in host cells that have been contacted with the test compound and the CREB function stimulating agent; and (c) comparing the luciferase activity determined in step (b) with the luciferase activity in control cells that have been contacted with the agent stimulating CREB function and that have not been contacted with the test compound. (ie, control cells that have been contacted with the CREB function stimulating agent only).

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

SK-N-MC cells stably transfected with the CRE-luc construct are seeded in 96-well white assay plates (PerkinElmer) at a concentration of 20,000 cells / well in 100 µl of MEM complete medium. These cells are incubated in a CO2 incubator under standard cell culture conditions. After 18 to 24 hours of incubation, cells are treated with a vehicle control (DMSO, Sigma), test compounds (5 gM final concentration), or a positive control (HT-0712, 5 gM final concentration) ( 16 wells for each treatment) for 2 hours. Forskolin (final concentration 5 µΜ, Sigma) is then added to 8 wells of each treatment group and an equivalent amount of DMSO is added to the other 8 wells. Six hours after the addition of forskolin, luciferase activity is measured by adding 25 µl of assay reagent (BriteLite kit, PerkinElmer) to each well. After incubation at room temperature for 3 minutes, luminescence is detected using a Wallac Victor5 plate reader (PerkinElmer). The rate of transcription induction is obtained by normalizing the luciferase activity of the compound or positive control in the presence of forskolin over treatment with forskolin alone. Compound treatment only serves as a control to determine if the compound can activate the CRE promoter on its own.

Representative compounds of the invention were found to enhance CREB pathway function using this assay.

The ability of a compound to modulate cognitive behavior can be assessed using the following test to measure memory after contextual fear conditioning.

Contextual memory test: fear conditioning

Contextual memory is a form of Paulovian fear conditioning in which a virgin mouse is placed in a new chamber (context) that contains different visual, olfactory and tactile signals. After a couple of minutes of acclimatization, the mouse receives a brief mild electrical shock to its paws. From this negative experience, the mouse will remember for months that this camera is dangerous. When placed back in the same context some time after training, the mouse's natural response to danger is to freeze, to stand still for many seconds. This is similar to what happens to human beings when they experience fear. The percentage of time during an observation period that the mouse spends frozen represents a quantitative measure (memory value) of its memory of context.

Contextual conditioning has been used extensively to investigate the neural substrates that mediate fear-motivated learning (Phillips, RG, LeDoux, JE, Behav Neurosci, 1992, 106, 274-285; Kim, JJ, et al., Behav Neurosci, 1993, 107, 1093-1098; Bourtchouladze, R., et al., Learn Mem, 1998, 5, 365-374; and Bourtchouladze, R et al., Cell, 1994, 79, 59-68). Contextual conditioning has also been used to study the impact of various mutations on hippocampal dependent memory (Bourtchouladze, R., et al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, 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) . As a robust memory can be activated with a training session of a few minutes, contextual conditioning has been especially useful in studying the biology of temporally different processes of memory in the short and long term (Kim, JJ, et al., Behav Neurosci, 1993, 107, 1093-1098; Bourtchouladze, R., et al., Learn Mem. 1998, 5, 365-374; Bourtchouladze, R., et al., Cell, 1994, 79, 59-68; and Abel, T., et al., Cell, 1997, 88, 615-626). Therefore, contextual conditioning is an excellent model for evaluating the role of various new drug compounds in hippocampal-dependent memory.

ES 2 425 578 T3

Young adult male C57BL / 6 mice (10-12 weeks old) and 250-300 g male Sprague Dawley rats (Taconic, NY) were used. Mice were housed in groups (5 mice) in standard laboratory cages while rats were housed in pairs and maintained on a 12:12 light-dark cycle. The experiments were always carried out during the light phase of the cycle. With the exception of the test moments, the mice had ad lib access to food and water. The experiments were conducted in accordance with the Animal Welfare Guarantee No. A3280-01 and the animals were kept in accordance with the guidelines of the Animal Welfare Act and the Department of Health and Human Services.

To assess contextual memory, a modified contextual fear conditioning task originally developed for the assessment of memory in CREB knock-out mice was used (Bourtchouladze, R., et al., Cell, 1994, 79, 59-68) . On the training day, the mouse was placed in the conditioning chamber (Med Associates, Inc., VA) for 2 minutes before the start of the unconditioned stimulus (US), 0.5 mA, of 2 seconds of foot shock. . US was repeated twice with a 1 min intersessional interval. between crashes. The training was carried out using the automated software package (Med Associates, Inc., VA). After the last training trial, the mice were left in the conditioning chamber for another 30 seconds and then placed back in their housing cages. At 24 hours after training, the mouse was placed in the same training chamber and contextual memory was assessed by assessing freezing behavior ('freezing' serves as memory value). Frostbite was defined as the complete absence of movement in 5-second intervals (Kim, JJ, et al., Behav Neurosci, 1993, 107, 10931098; Phillips, RG, LeDoux, J. E., Behav Neurosci, 1992, 106, 274-285; Bourtchouladze, R., et al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et al., Cell, 1994, 79, 59-68; and Abel, T., et al., Cell, 1997, 88, 615-626). The total test time lasted 3 minutes. After each experimental subject, the experimental apparatus was thoroughly cleaned with 75% ethanol, water, dried, and ventilated for a few minutes.

All experiments were designed and performed in a balanced way, meaning that (i) for each experimental condition (eg, a specific dose effect) an equal number of experimental and control mice were used; and (ii) each experimental condition was repeated 2-3 independent times, and repeat days were added to generate a final number of subjects. The procedure of each experiment was recorded. In each experiment, the experimenter was unaware (blind) of the subjects' treatment during training and testing. Data were analyzed by Student's t test for independent samples using a software package (Statview 5.0.1; SAS Institute, Inc). All values in the text and figures are expressed as the mean ± SEM.

Compounds were dissolved in 1% DMSO / PBS and administered intraperitoneally (IP) in a volume of 8 ml / kg 20 min. before training. Control animals received vehicle only (1% DMSO / PBS). For oral administration, the compounds were dissolved in 30% DMSO / 70% CMC. Consequently, control animals received 30% DMSO / 70% CMC. For each drug injection and training procedure, an experimentally virgin group of animals was used.

To evaluate the effects of compound 162 and compound 177 on contextual memory, mice were injected with a compound or vehicle 20 minutes before training and trained with 2 training trials (US). The mice were then tested in the same context 24 hours after training (Figure 1). The IP administration of 0.01 mg / kg of each compound significantly facilitated freezing to the context 24 h after training. Representative compounds of the invention were also tested and found to produce behavioral effects when administered orally.

The ability of a compound to modulate cognitive behavior was also evaluated using the following object recognition test.

Object recognition test

Object recognition is an ethologically relevant task for rodents, which does not result from negative reinforcement (foot strike). This task is based on the natural curiosity of rodents to explore new objects in their environments beyond the familiar ones. Obviously, for an object to be familiar, the animal must have previously witnessed it and remember that experience. Therefore, animals with better memory will pay attention and explore a new object rather than an object familiar to them. During the test, the animal is presented with the training object and a second new object. The memory of the training object makes it familiar to the animal, and then spends more time exploring the new recent object rather than the familiar one (Bourtchouladze, R., et al., Proc Natl Acad Sci USA, 2003, 100, 10518- 10522). Recent neuroimaging studies in humans demonstrated that object recognition memory is dependent on the prefrontal cortex (PFC) (Deibert, et al., Neurology, 1999, 52, 1413-1417). Consistent with these findings, rats with PFC lesions show poor working memory when required to discriminate between familiar and new objects (Mitchell, JB Laiacona, J., Behav Brain Res, 1998, 97, 107-113). Other studies on 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). Thus, object recognition provides an excellent behavioral model for evaluating the effects of drug compounds on the cognitive task associated with hippocampal and cortex function.

ES 2 425 578 T3

Before the start of training, the animals were handled for 3-5 minutes for 5 days. Training and testing were carried out identically for mice and rats with an exception of the dimensions of the training apparatus (for mice: a Plexiglas box of Length = 48 cm; Width = 38 cm and Height = 20 cm; for rats: a Plexiglas box of Length = 70 cm; Width = 60 cm and Height = 35 cm). The day before training, an individual animal was placed on a training apparatus located in a poorly lit room and allowed to habituate to the environment for 15 minutes (see also Pittenger, C., et al., Neuron, 2002, 34 , 447-462; and Bourtchouladze, R., et al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Training started 24 hours after habituation. An animal was placed back in the training box, which contained two identical objects (eg a small cone-shaped object), and was allowed to explore these objects. The objects were placed in the central area of the box and the spatial position of the objects (left-right sides) was compensated between subjects. The animals were trained for 15 minutes. To test memory retention, the animals were observed for 10 minutes 24 hours after training. A rodent was presented with two objects, one of which was used during training, and therefore 'familiar' and the other of which was new (eg a small pyramid-shaped object). To ensure that the discrimination targets do not differ in odor, after each experimental subject, the apparatus and objects were thoroughly cleaned with 90% ethanol, dried, and ventilated for a few minutes.

The experiments were videotaped using a suspended video camera system. The tapes were then reviewed by an independent observer and the following behavioral parameters were determined: exploration time of each object; total exploration time of objects; number of approaches to objects; and time (latency) until the first approach to an object. The discrimination index - memory value - was determined as previously described (Ennaceur, A., Aggleton, JP, Behav Brain Res, 1997, 88, 181-193; and Bourtchouladze, R., et al., Proc Natl. Acad Sci USA, 2003, 100, 10518-10522). These data were analyzed by Student's t test for independent samples using a software package (Statview 5.0.1; SAS Institute, Inc). All values in the text and figures are expressed as mean ± SEM.

The following Examples illustrate procedures that are generally useful in preparing compounds of the invention.

Examples

Compounds that do not fall within the scope of claim 1 are comparative compounds.

Example 1 Preparation of a compound in which R1 is CF3, X is -C (= O) - and B is a Thiophene Ring.

A commercially available solution of the acid was mixed in DMF. EDC-HCl, HOBT hydrate and Hunig's base were added to the solution to activate the acid; To the activated acid, the desired amine was added to produce the final product. The reactions underwent standard aqueous work-up and the crude products were subsequently purified by normal phase flash chromatography. The purity and identity of the final products were confirmed by LC / MS.

ES 2 425 578 T3

Example 2 Preparation of a Compound in which R1 is CF3, X is -C (= O) - and B is a Phenyl ring

Oxalyl chloride was added to 3-acetyl-benzoic acid (112) in dichloromethane below 20 ° C. After the reaction was complete, the mixture was concentrated to remove excess reagent . The residue was dissolved in fresh dichloromethane, cooled below 20 ° C, then followed by the addition of secondary amine and triethylamine. The reaction was stirred for 1 hour, quenched with water, then washed with 5% HCl to remove excess triethylamine. Subsequently, the organic phase was washed with 5% sodium bicarbonate to remove unreacted starting material, then it was washed with water, dried and concentrated to give 3-acetyl-N, N-dialkylbenzamide (113) in a yield of 75-80%.

Treatment of 3-acetyl-benzamide 113 with a preformed solution of sodium ethyl methyl-ortho-trifluoroacetate, prepared by mixing NaOMe and ethyl trifluoroacetate in benzene, effectively converted the material into a dikete compound. Subsequent acidification of the crude reaction followed by extraction into an organic solvent gave compound 114 in 85-90% yields.

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

Example 3 Preparation of a Compound in which R1 is CF3, X is -C (= O) - and B is a Phenyl Ring

Oxalyl chloride was added to 4-acetyl-benzoic acid in dichloromethane and DMF below 20 ° C, and the reaction mass was concentrated to remove excess reagent. The residue was dissolved in fresh dichloromethane and then the secondary amine was added. Still below 20 ° C, triethylamine was added and stirred for one hour. The reaction was quenched with water, washed with 5% HCl to remove excess triethylamine, and then washed with 5% sodium bicarbonate to remove unreacted starting material. The organic phase was washed with water, dried and concentrated to give 4-acetyldialkyl benzamide 116 in 85-90% yields.

ES 2 425 578 T3

Treatment of the benzamide with preformed sodium ethyl-ortho-trifluoroacetate from NaOMe and ethyl trifluoroacetate in benzene and the reaction of the preformed ortho-alkoxide with 4-acetyl-N, N-dialkyl benzamide and subsequent acidification, followed by Extraction gave compounds 117 in 50-55% yields.

The final pyrazole compounds 118a / b were synthesized by adding the appropriately substituted hydrazine to compound 117 in ethanol, acidified ethanol, or acetic acid, depending on the specific hydrazine used.

Example 4 Preparation of a Compound in which R1 is CF3, X is -C (= O) - and B is a Pyridine Ring

Two procedures (A and B) were used for the synthesis of 2,4-disubstituted pyridine compounds.

Procedure A: (R3 = 2,2,2-Trifluoroethyl, phenyl, 2-hydroxyethyl, benzyl, 2-pyridyl)

Aqueous hydrogen peroxide (30%, 130 ml, 1.2 mmol) was added dropwise to ethyl pyruvate (216 g, 1.9 mol) at -5 ° C to 5 ° C with stirring. The resulting solution was added dropwise to a mixture of 4-acetylpyridine (15.0 g, 0.12 mmol) to a mixture of concentrated sulfuric acid (12.4 g, 0.12 mmol) and ferrous sulfate heptahydrate (345 g, 0.12 mmol) in dichloromethane (1.5 L) and water (100 ml) for a period of 2 hours at room temperature. After stirring the mixture for a further 30 min, the organic phase was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined and washed with 5% aqueous sodium sulfite, followed by water, dried and purified to give 119 (5.79 g, 24%).

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

To 1 equivalent of dikete compound 120, 1.2 equiv. of the monosubstituted hydrazine in an acetic acid medium. The reaction was monitored by TLC. Treatment was carried out by adding a saturated solution of NaHCO3 to pH = 8-9, followed by extraction 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 dissolved in 1.5 equiv. NaOH in water and stirred at room temperature for 2 h. A 20% citric acid solution was added to the mixture at about pH 2. The product was extracted into ethyl acetate and concentrated. To the acid intermediate in DMF was added 1.5 equiv. of EDCI, 1.3 equiv. of HOBT, 1.3 equiv. of dialkylamine and 4 equiv. diisopropylethylamine and stirred at room temperature overnight. The completion of the reaction was monitored by TLC. Water and ethyl were added to the mixture, the ethyl acetate phase was concentrated to give the crude product, which was purified by column chromatography to yield compounds of the general structure 122a / b.

ES 2 425 578 T3

Procedure B: (R2 or R3 = alkyl)

F

126 127

128

E Compound 119 dissolved in 1.5 equiv. NaOH in water and stirred at room temperature for 2 hours. The solution was acidified with a 20% citric acid solution to pH = 2 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. 1.1 equiv. of pentafluorophenol, followed by 1.1 equiv. by DCC. The reaction was stirred at room temperature for 2 h. The mixture was then filtered through a Celite pad and washed with THF and dichloromethane. The filtrate was concentrated in vacuo to obtain a brown solid, which was recrystallized from ethyl acetate / Hexane to give pentafluorophenyl ester 125.

To a solution of the pentafluorophenyl ester 125 in dichloromethane was added 1.2 equiv. dialkylamine and 1.5 equiv. N-methyl morpholine; This solution was stirred at room temperature overnight. After confirming the completion of the reaction by TLC, it was added to the reaction and the phases were separated. The aqueous phase was extracted once more with dichloromethane. The organic phases were combined and washed with a brine solution, then concentrated to give compound 126 in 45-50% yield.

Sodium methyl-ortho-trifluoroacetate, formed by the mixture of NaOMe and ethyl trifluoroacetate in benzene, was reacted with compound 126 in benzene at reflux overnight. The resulting mixture was acidified and extracted into an organic solvent to give compound 127 in good yields (65-70%).

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

To a sample of 200 mg of compound 128 in 2-3 ml of THF was added alkyl iodide and 1 ml of 6N KOH, followed by tetrabutylammonium bromide (25 mg). The reaction was stirred at room temperature for 2-3 h. After completion of the reaction as determined by TLC, the phases were separated. The THF phase was concentrated and placed on a TLC Prep plate. Elusion was performed with 30% ethyl acetate in hexane. After 10-15 elusions, the two geometric isomers (one in which R2 was absent and one in which R3 was absent) were able to separate. The silica gel was discarded and extracted with ethyl acetate and dichloromethane, then concentrated to give the pure regioisomers of compound 129 (where R2 or R3 = Methyl or Ethyl).

ES 2 425 578 T3

Example 5 Preparation of a Compound in which R1 is CF3, X is -C (= O) - and B is a Pyridine Ring

To 8 g of compound 130 in 30 ml of methanol, 11.8 ml of thionyl chloride was slowly added at 5 ° C. The mixture was allowed to stir for 30 min at room temperature and refluxed overnight. The reaction mixture was concentrated under high vacuum, then dissolved in sodium bicarbonate solution. The compound was then extracted into dichloromethane, then dried and concentrated to give a 70% yield of compound 131.

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

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

Compound 133, added at 0 ° C, was added to a 1 liter round bottom flask with 150 ml of DMF. Hydrogen peroxide and ferrous sulfate heptahydrate were added simultaneously to the reaction mixture at 0 ° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured into water, then extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated to provide 2% of the desired compound 134.

To 1 g of compound 134 in 10 ml benzene was added 0.8 g of sodium methoxide. The reaction mixture was carefully heated to reflux and allowed to stir for two hours. The reaction mixture was neutralized with citric acid and then extracted with ethyl acetate. The organic phase was dried and concentrated to give an 80% yield of compound 135.

To 200 mg of ethanol compound 135 was added methylhydrazine. The mixture was left stirring for six hours at room temperature. The reaction mixture was then neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic phase was then dried and concentrated to provide a 50% yield of final compound 136.

Example 6 Preparation of a Compound in which R1 is Phenyl, X is -C (= O) - Y = N, and B is a Thiophene Ring

To the stirring solution of diisopropylethylamine (3.69 g, 36.51 mmol) in THF (60 mL) cooled to -70 ° C was added n-BuLi (2.33 g, 36.51 mmol) over 40 minutes . The mixture was stirred at -70 ° C for 2 hours. Amide 137 is

ES 2 425 578 T3 was dissolved in a minimal amount of THF, slowly added to the reaction mixture and stirring continued for 2 hours at -70 ° C. The reaction was warmed to -30 ° C and stirred for an additional 30 min. The mixture was cooled back to -70 ° C, followed by the addition of benzoyl chloride (5.13 g, 36.51 mmol), added slowly over 20 min. 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, then concentrated to provide the crude product, which was purified by column chromatography on silica gel to give the desired product 138 in 20-25% yield.

Diketone 138 was converted to a compound of Formula I using the procedures described in Example 9 below.

Example 7 Preparation of a Compound in which R1 is Methyl, X is -C (= O) - Y = N and B is a Thiophene ring

Stanic chloride (1.32 g, 5.07 mmol) was added dropwise over a period of 50 min to a stirred mixture of amide 137 (0.5 g, 2.53 mmol) and acetic anhydride (1.03 g, 10.14 mmol), which was pre-cooled to 20 ° C. During the addition, the temperature did not exceed 100 ° C. After standing overnight at room temperature, the reaction mixture was cooled back to 0-20 ° C and hydrolyzed with stirring for 7 hours with 30% HCl (1 ml). Water (20 ml) was added to the mixture and it was stirred for a further 30 min at room temperature. The solid was filtered off and the crude brownish yellow solid was purified by column chromatography using chloroform and methanol. Product 139 was isolated in 40-45% yield.

Diketone 139 was converted to a compound of Formula I using the procedures described in Example 9 below.

Example 8 Preparation of a Compound in which R1 is Isopropyl, X is -C (= O) -, Y = N and B is a Thiophene Ring

Stannic chloride (19.8 g, 76.06 mmol) was added dropwise over a period of 1 hour, to a stirred mixture of amide 139 (5 g, 25.35 mmol) and isobutyric anhydride (24.06 g 152.12 mmol) which was cooled below 20 ° C. During this addition, the temperature never exceeded 100 ° C. After standing overnight at room temperature, the reaction mixture was cooled back to 0-20 ° C and hydrolyzed with stirring for 7 h with 30% HCl (25 ml). Water (100 ml) was added and the mixture was stirred for 30 min at room temperature. The solids were filtered off and a brownish yellow solid was purified by column chromatography on silica gel using chloroform and methanol to give a 45-50% yield of product 140.

Diketone 140 was converted to a compound of Formula I using the procedures described in Example 10 below.

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

ES 2 425 578 T3

Example 9 Preparation of a Compound in which R1 is Phenyl, Methyl, Trifluoromethyl, Chloro-difluoromethyl,

Pentafluoroethyl or Isopropyl; X is -C (= O) -; Y = N; and B is a Thiophene Ring

The following procedures (1-4) were used for the construction of the pyrazole moiety when ring B was a thiophene

Cyclization with substituted hydrazines

R1 = Phenyl, methyl, trifluoromethyl or isopropyl

142

143

<td></td><td>R4 / —N</td><td>EtOH / AcOH</td><td>I heard</td>

Cycling Procedures:

An equimolar mixture of scaffold 141 and mono substituted hydrazine were mixed together in ethanol containing a few drops of acetic acid. The reaction mass was stirred for more than 12 h at room temperature and monitored by TLC.

Equimolar amounts of scaffold 141 and monosustiuid hydrazine hydrochloride (for benzyl, cyclopentyl, and 4-chlorophenyl hydrazines which were present as HCl salts) were mixed together in ethanol and the reaction mass was stirred at room temperature and monitored by TLC. .

Equimolar amounts of scaffold 141 and 2-hydrazino pyridine were mixed together in acetic acid. The reaction was stirred at reflux temperature and the progress of the reaction was monitored by TLC.

The equimolar mixture of scaffold 141 and mono alkyl hydrazines were mixed together in acetic acid. The reaction mass was stirred at room temperature and monitored by TLC.

N-alkylation of 1-H Pyrazoles Using Microwaves

The syntheses were performed by mixing compound 144 with excess alkyl iodide and a catalytic amount of tetrabutylammonium bromide (TBAB). The mixtures were adsorbed on potassium carbonate and irradiated in an open glass flask (15 ml) in a household microwave oven for 2-3 min to provide 145a / b compounds.

ES 2 425 578 T3

Phase Transfer Procedure for N-alkylation of 1-H-Pyrazoles

In certain cases, the utility of microwave assisted alkylation was limited due to the volatility of certain alkyl iodides, such as methyl and ethyl iodides, which prevented complete conversion to the desired product. The following procedure was used in such cases.

To a solution of 1 ml of THF and 1 ml of a 6 N KOH solution were added 200 mg of N-1-H pyrazole 144 and a catalytic amount of tetrabutylammonium bromide (TBAB). The mixture was stirred for 15 min at room temperature. To this mixture was added 2 equivalents of the necessary alkyl halide, which was subsequently stirred at room temperature until the reaction was complete as determined by TLC.

Dialkyl Sulfate Procedure for N-alkylation of 1-H-Pyrazoles

Pyrazoles can be alkylated with regiospecifically favoring product 111 under non-basic conditions using dialkyl sulfates. Generally, ratios> 9: 1 (111: 111a) were obtained.

A suspension of pyrazole 146 in toluene (~ 10 ml / g) was treated with dimethyl sulfate (1.5 equiv.) And heated at 90-100 ° C for 24 h, at which time 0.125 equiv. more dimethyl sulfate, followed by 10 hrs of heating. The reaction mixture was then cooled and diluted with EtOAc, washed with water, a saturated NaHCO3 solution, and brine. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to provide a crude solid. The two regioisomeric products, 111 and 111a could be purified and separated by silica gel chromatography using EtOAc / hexanes as eluent or recrystallized from EtOAc / hexanes.

ES 2 425 578 T3

Example 10 Preparation of a Compound in which R1 is Trifluoromethyl; X is -CH2-; Y = N; and B is a Ring

Thiophene

A solution of aldehyde 147 in dichloromethane (~ 20 ml / g) was treated with amine (1.1 equiv.) Followed by triacetoxyborohydride and stirred for 16 h. The reaction mixture was then treated with a saturated NaHCO3 solution and allowed to stir for 15 min, after which time the reaction mixture was partitioned between EtOAc and water. The organic phase was further washed with a brine solution and dried over MgSO4, filtered and evaporated in vacuo. The crude product could be purified by silica gel chromatography using EtOAc / hexanes as eluent.

Example 11 Preparation of a Compound in which R1 is Trifluoromethyl; X is -C (O) -; Y = C; and B is a Thiophene or Phenyl Ring;

Acylation Procedures: Formylation of scaffold 152 and subsequent treatment of product 153 with 2-4 equiv. of Grignard's reagent at 010 ° C, followed by oxidation of the resulting alcohol 154 to ketone 155.

Weinreb's amide scaffold treatment 158 and 2-4 equiv. Grignard's reagent at 0-10 ° C.

Friedel-Crafts acylation of scaffold 160 with excess acyl halide.

General Procedure for Frame Alkylation 149

A solution of NaH (1.1 equiv.) In DMF (5 ml / g NaH) was treated in portions with diketone 149 and stirred until gas evolution was controlled. The reaction was then treated with alkyl halide (2.0 equiv.) And heated at 50-60 ° C for 16 h with additional amounts of alkyl halide and heating if the reaction was not complete. When complete, the reaction mixture was partitioned between EtOAc (50 ml / g NaH) and a 5% sulfuric acid solution (50 ml / g NaH). The organic phase was further washed with water and brine, then dried over MgSO4, filtered and evaporated in vacuo to provide product 150. The crude product was generally of sufficient purity for use, but can be purified by gel chromatography. silica using EtOAc / hexanes as eluent.

ES 2 425 578 T3

General Procedure for Carbonylation of the Framework 152

A solution of DMF (10 ml / g of 152) at 5-10 ° C was treated with phosphorous oxychloride (10 equiv.) And allowed to warm to room temperature, after which time thiophene 152 was added. The resulting solution heated at 80-100 ° C for 16-24 hrs until the reaction reached completion. The reaction was then cooled to 0-5 ° C and treated carefully with a saturated aqueous solution of K2CO3 and EtOAc. The organic phase was further washed with water and brine, then dried over MgSO4, filtered and evaporated in vacuo to provide product 153. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent.

General Procedure for Adding Grignard to Frame 153

A solution of aldehyde 153 in THF (20 ml / g) was treated with a 1 M solution in THF of Grignard's reagent (1.5 equiv.) And stirred for 1 hr. The reaction was then treated with a saturated aqueous ammonium chloride solution and EtOAc. The organic phase was further washed with brine, dried over MgSO4, filtered and evaporated in vacuo to provide product 154. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent.

General Procedure for Frame oxidation 154

A solution of carbinol 154 in dichloromethane (20 ml / g) was treated with pyridinium dichlorochromate (1.5 equiv.) And stirred for 3 h. The reaction was then evaporated to% volume, diluted with EtOAc, and filtered through a plug of Celite. The organic phase was then evaporated in vacuo to provide crude product 155. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent.

General Procedure for Coupling 157 with N, O-Dimethylhydroxylamine Hydrochloride to Provide the 158 Framework

A mixture of acid 157, N, O-dimethylhydroxylamine hydrochloride (1.2 equiv.), Triethylamine (1.2 equiv.) And DMAP (cat.), In dichloromethane (1 ml / g) and DMF (0.1 ml / g) at 0-5 ° C, treated with DCC (1.2 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 16 h, after which time the reaction was filtered through Celite with the aid of EtOAc and evaporated in vacuo to provide crude product 158. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent.

General Procedure for Adding Grignard to 158 to Provide Frame 159

A solution of Weinreb's amide 158 in THF (20 ml / g) was treated with a 1 M THF solution of Grignard's reagent (4.0 equiv.) And stirred for 2 h. The reaction was then treated with a saturated aqueous ammonium chloride solution and EtOAc. The organic phase was further washed with brine, dried over MgSO4, filtered and evaporated in vacuo to provide crude product 159. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent.

ES 2 425 578 T3

A solution of 160 in dichloromethane (100 ml / g) was treated with FeCL (1.6 equiv.) Followed by carboxylic acid chloride (1.6 equiv.). The reaction was refluxed for 16 hours, followed by partitioning with water. The dichloromethane portion was then dried over Na2SO4, filtered and concentrated in vacuo to provide crude product 161. The crude product can be purified by silica gel chromatography using EtOAc / hexanes as eluent:

Example 12 Preparation of Compounds of the Invention

Using the general procedures identified above, the following compounds of the invention were prepared.

<td>Comp. No.</td><td>Structure</td><td>Compound Name</td><td>P.M</td><td>LC / MS (ES +)</td>

<td> 162</td><td>X — N o7 'ch,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 303,30</td><td> 304,5</td>

<td> 163</td><td>O '—And</td><td>5- (1-Methyl-5-trifluoromethyl- acid hexylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 359,41</td><td> 360,5</td>

<td> 164</td><td>P f</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid hexyl-methyl-amide</td><td> 373,44</td><td> 374,5</td>

<td> 165</td><td></td><td>5- (1methyl-5-triftuoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid [2- (2-Fluoro-phenyl) -ethyl] -amide</td><td> 397,39</td><td> 398,5</td>

<td> 166</td><td>F f '> => Ó he</td><td>(2-Pyrrolidin-1-yl-ethyl) -amide 5- (1-methyl- 5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 372,41</td><td> 373,1</td>

ES 2 425 578 T3

<td> 167</td><td>F ^ f</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (tetrahydro-furan-2-ylmethyl) -amide</td><td> 359,37</td><td> 360,5</td>

<td> 168</td><td> * M 's J</td><td>5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 4-methyl-benzylamide</td><td> 379,40</td><td> 380,5</td>

<td> 169</td><td>Ev ^</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyclopropylmethyl-amide</td><td> 329,34</td><td> 330,5</td>

<td> 170</td><td>F f Kc'Nfr ^ f ^ _</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyclohexylmethyl-amide</td><td> 371,42</td><td> 372,5</td>

<td> 171</td><td></td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 4-Methoxy-benzylamide</td><td> 395,40</td><td> 396,5</td>

<td> 172</td><td>Ή-, r ^ O '</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 4-Fluoro-benzylamide</td><td> 383,36</td><td> 384,5</td>

<td> 173</td><td>F\ sKo</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (Pyridin-4-ylmethyl) -amide</td><td> 366,36</td><td> 367,4</td>

<td> 174</td><td>^ a ^>c ^ · Ι <τ ^ \ r-Cr</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (Pyridin-4-ylmethyl) -amide</td><td> 399,82</td><td> 400,5</td>

<td> 175</td><td>> vAAf></td><td>5- (1-Methyl-5-trifluoromethyl- acid propylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 317,33</td><td> 318,5</td>

ES 2 425 578 T3

<td> 176</td><td>STO rv</td><td>[5- (1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophene- 2-yl] -morpholin-4-yl-methanone</td><td> 345,34</td><td> 346,5</td>

<td> 177</td><td>to '-'</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 343,37</td><td> 344,6</td>

<td> 178</td><td>X, I CM,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid butyl-methyl-amide</td><td> 345,38</td><td> 346,5</td>

<td> 179</td><td>.oA ^ QQ > V „,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyclohexyl-ethyl-amide</td><td> 385,45</td><td> 386,6</td>

<td> 180</td><td>3 \ h,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl-methyl-amide</td><td> 379,40</td><td> 380,5</td>

<td> 181</td><td> \7 F <> —T>ci1* ZA M w Γ CM,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid methyl-p-tolyl-amide</td><td> 379,40</td><td> 380,5</td>

<td> 182</td><td>F f F ^ \ / h, s-¿fJ oH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid methyl-propyl-amide</td><td> 331,36</td><td> 332,5</td>

<td> 183</td><td>'S-,. ZOO-</td><td>[4- (4-Chloro-phenyl) -piperazin-1-yl] - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 454,90</td><td> 455,6</td>

ES 2 425 578 T3

<td> 184</td><td>F Τ OR</td><td>(4-Hydroxy-piperidin-1-yl) - [5- (1 -methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 359,37</td><td> 360,5</td>

<td> 185</td><td>0 s CH></td><td>5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyclopropylmethyl-propyl-amide</td><td> 371,42</td><td> 372,5</td>

<td> 186</td><td>x 'fX</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-phenyl-piperazin-1-yl) -methanone</td><td> 420,45</td><td> 421,5</td>

<td> 187</td><td>ί · \ / = ^ ~ \ - H & Γ ^ CH,</td><td>5- (1-methyl- 5-trifluomethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 394,42</td><td> 395,5</td>

<td> 188</td><td>M. 0 V and CH,</td><td>1 - {4- [5- (1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) thiophene-2-carbonyl] -piperazin-1 -yl} -ethanone</td><td> 386,39</td><td> 387,5</td>

<td> 189</td><td>κο ^ Χγ% 6- <CH, yE O '- ( CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid isobutyl-methyl-amide</td><td> 345,38</td><td> 346,5</td>

<td> 190</td><td>Xs \ TVV_ p X) F</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 5-Fluoro-2-methyl-benzylamide</td><td> 397,39</td><td> 398,5</td>

<td> 191</td><td>S — V > "Yes?</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (Pyridin-3-ylmethyl) -amide</td><td> 366,36</td><td> 367,4</td>

ES 2 425 578 T3

<td> 192</td><td>FF F-\, CM).</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid isobutyl amide</td><td> 331,36</td><td> 332</td>

<td> 193</td><td>or F</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid [2- (4-Fluoro-phenyl) -ethyl] -amide</td><td> 397,39</td><td> 398</td>

<td> 194</td><td>TO r</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Phenoxy-ethyl) -amide</td><td> 395,40</td><td> 396</td>

<td> 195</td><td>> XK.</td><td>(Methyl-furan-2-ylmethyl) -amide 5- (1-methyl- 3-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 369,36</td><td> 370,5</td>

<td> 196</td><td>FF F- ^ X ^ Qv)5 \ orr \ _ ^F V</td><td>5- (1-Methyl5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2,2,2-Trifluoro-ethyl) -amide</td><td> 357,28</td><td> 358,1</td>

<td> 197</td><td>X • v / sA'f ^ 's-4 ¿'' "Λ O-CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Methoxy-ethyl) -amide</td><td> 333,33</td><td> 334</td>

<td> 198</td><td>^ 'γ — Γϊ' = MJ</td><td>5- (1-Methyl-5-trifluoromethyl- acid benzylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 365,37</td><td> 366,1</td>

<td> 199</td><td>Fjε-Λ Kf</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Methyl-butyl) -amide</td><td> 345,38</td><td> 346,1</td>

ES 2 425 578 T3

<td> 200</td><td>F f</td><td>5- (1 methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid [2- (1 H-Imidazol-4-yl) -ethyl] -amide</td><td> 369,37</td><td> 370,1</td>

<td> 201</td><td>FJ rA H, C OR. Μχ~~ \ J ^ - “0</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Morpholin-4-yl-ethyl) -amide</td><td> 388,41</td><td> 389,5</td>

<td> 202</td><td>^ '' 'SrTQ r K_\ _ > - ti, C</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Methyl-butyl) -amide</td><td> 345,38</td><td> 346,5</td>

<td> 203</td><td>h.C'A. / L- ^ íí ^ X or > T “N Cl X~^!</td><td>(2-Piperidin-1-yl-ethyl) -amide 5- (1-methyl- 5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 386,44</td><td> 387</td>

<td> 204</td><td>:: SR Rrf) ίϊ - \ Oj</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Methoxy-propyl) -amide</td><td> 347,36</td><td> 348</td>

<td> 205</td><td></td><td>(4-Methyl-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl- 1H-pyrazol-3- yl) -thiophen-2-yl] -methanone</td><td> 357,39</td><td> 358,1</td>

<td> 206</td><td>F,FΗ ^^ λγΧ Chi> 'or</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid allyl-cyclobecilamide</td><td> 397,46</td><td> 398</td>

ES 2 425 578 T3

<td> 207</td><td>° CR.</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid ethyl-propyl-amide</td><td> 345,38</td><td> 346,5</td>

<td> 208</td><td>X r * x</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid phenyl-propyl-amide</td><td> 393,43</td><td> 394,5</td>

<td> 209</td><td>FSa r <J CH,</td><td>(2,6-Dimethyl-morpholin-4-yl) - [5- (1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 373,39</td><td> 374,6</td>

<td> 210</td><td>X 1 \ Λ Oh«| C 'N'Y'vY / s—) For</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyclohexyl- (2-hydroxy-ethyl) -amide</td><td> 401,45</td><td> 402,3</td>

<td> 211</td><td>and· hc-'QQ V = / rv</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid methyl-phenethyl-amide</td><td> 393,43</td><td> 394,1</td>

<td> 212</td><td>F F X Oh</td><td>(2-Hydroxymethyl-pyrrolidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 359,37</td><td> 360,4</td>

<td> 213</td><td>F ~~ \ it</td><td>Azetidin-1-yl [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 315,32</td><td> 316,5</td>

ES 2 425 578 T3

<td> 214</td><td>F f rO</td><td>(2,5-Dihydro-pyrrol-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 327,33</td><td> 328,6</td>

<td> 215</td><td>WV)0 Yr-s</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Ethylsulfanyl-ethyl) -amide</td><td> 363,42</td><td> 364,3</td>

<td> 216</td><td>to \ / * = > -d <*,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 3,5-dimethyl-benzylamide</td><td> 393,43</td><td> 394,5</td>

<td> 217</td><td>7 Ιψ-Κ ^ Ι ^ / \ W</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Pyrrolidin-1-yl-propyl) -amide</td><td> 386,44</td><td> 387</td>

<td> 218</td><td>\ ¿ F'*\ ° Nx^ Q α</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 3-Chloro-benzylamide</td><td> 399,82</td><td> 400,5</td>

<td> 219</td><td>h*cnWA W</td><td>5- (1-Methyl-3-trifluomethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (Furan-2-ylmethyl) -amide</td><td> 355,54</td><td> 356,5</td>

<td> 220</td><td>;S- < h, - V '-' f> SA P > '- 0 'F</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 3,5-Difluoro-benzylamide</td><td> 401,35</td><td> 402</td>

<td> 221</td><td>F ^ X * -W> V w</td><td>5- (1-Methyl-3-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Thiophen-2-yl-ethyl) -amide</td><td> 385,43</td><td> 386,3</td>

ES 2 425 578 T3

<td> 222</td><td>S-4</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Imidazol-1-yl-propyl) -amide</td><td> 383,39</td><td> 384,5</td>

<td> 223</td><td>XM>C N (β rt F</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophenyl-2-carboxylic acid (2-Cyano-ethyl) -amide</td><td> 328,31</td><td> 329</td>

<td> 224</td><td>S-3 rCK M »,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Ethyl-butyl) -amide</td><td> 359,41</td><td> 360,3</td>

<td> 225</td><td>X ”Κθ</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (thiophen-2-ylmethyl) -amide</td><td> 371,40</td><td> 372</td>

<td> 226</td><td>X</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Pyridin-3-yl-ethyl) -amide</td><td> 380,39</td><td> 381,5</td>

<td> 227</td><td>F- f Chiral % «-VO s-4 «s 0</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid ((S) -2-Hydroxy-1-methyl-2-phenylethyl) -methyl-amide</td><td> 423,45</td><td> 424,5</td>

<td> 228</td><td>0 'X_CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid ethyl-phenyl-amide</td><td> 379,40</td><td> 380,5</td>

<td> 229</td><td>p. Γ Chiral Aa > r</td><td>((R) -3-Hydroxy-pyrrolidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 345,34</td><td> 346,6</td>

ES 2 425 578 T3

<td> 230</td><td>X 0 '* -> - OH</td><td>[4- (2-Hydroxy-ethyl) -piperazin-1-yl] - [5- (1-methyl-5- trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2 -] - methanone</td><td> 388,41</td><td> 389,6</td>

<td> 231</td><td>fXCHj > 'ú ΠΜ</td><td>(3,5-Dimethyl-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 371,42</td><td> 372,6</td>

<td> 232</td><td></td><td>(2,3-Dihydro-indol-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-yl] methanone</td><td> 377,38</td><td> 378,6</td>

<td> 233</td><td>X. x/ = \ H »C</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl-isopropylamide</td><td> 407,45</td><td> 408</td>

<td> 234</td><td>F\==. *)</td><td>5- (1-Methyl-5-triftuoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl-ethyl-amide</td><td> 393,43</td><td> 394</td>

<td> 235</td><td>F f ν-νγ) (Λ s-40 1 Oh</td><td>5- (1-Methyl- 5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 395,40</td><td> 396</td>

<td> 236</td><td>c- f f ^ \. ΧΟΧ} - ·</td><td>[4- (4-Fluoro-phenyl) -piperazin-1-yl] - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 438,44</td><td> 439,6</td>

ES 2 425 578 T3

<td> 237</td><td>X ”Λ</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl- (2-cyano-ethyl) -amide</td><td> 418,44</td><td> 419</td>

<td> 238</td><td> ^-N'ZV> '> <) 0</td><td>(1,4-Dioxa-8-aza-spiro [4.5] dec-8-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 401,40</td><td> 402,6</td>

<td> 239</td><td>F' / = \ r <~ P</td><td>(3,4-Dihydro-1H-isoquinolin-2-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 391,41</td><td> 392,6</td>

<td> 240</td><td>F f Chiral fAΗ, Ο '^ ,,' Χ ^ Χ 'sH, Tn TO</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid ((S) -2-Phenyl-propyl) -amide</td><td> 393,43</td><td> 394,4</td>

<td> 241</td><td>í,. ..</td><td>(4,4-Dimethoxy-butyl) -amide 5- (1-methyl- 5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 391,41</td><td> 392,4</td>

<td> 242</td><td>Y</td><td>Acid [3- (2-Oxo-pyrrolidin-1-yl) -propyl] -amide 5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene2-carboxylic</td><td> 400,42</td><td> 401,6</td>

<td> 243</td><td>X .-vy sJ (y · », üV M, C \ * Or H, C</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2,2-Dimethoxy-ethyl) -amide</td><td> 363,36</td><td> 364,3</td>

ES 2 425 578 T3

<td> 244</td><td>F R 'Ύ, "z1CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-p-Tolyl-ethyl) -amide</td><td> 393,43</td><td> 394</td>

<td> 245</td><td>V nT 'and * V W ^ N Y</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid cyanomethyl-amide</td><td> 314,29</td><td> 315,1</td>

<td> 246</td><td>5 Λ 7</td><td>5- (1-Methyl-5-trifluoromethyl- acid butylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 331,36</td><td> 332,5</td>

<td> 247</td><td>TO s- / jS * 7 9 > V</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Ethoxy-propyl) -amide</td><td> 361,38</td><td> 362,1</td>

<td> 248</td><td>V 'Ag Π CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Dimethylaminopropyl) -amide</td><td> 360,40</td><td> 361</td>

<td> 249</td><td>•TO -Γ kj</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (3-Morpholin-4-yl-propyl) -amide</td><td> 402,44</td><td> 403</td>

ES 2 425 578 T3

<td> 250</td><td>V> F s- ( ? CH</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Hydroxy-ethyl) -amide</td><td> 319,30</td><td> 320,3</td>

<td> 251</td><td>> w?</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dicyclohexylamide</td><td> 439,54</td><td> 440,6</td>

<td> 252</td><td>Fv / θξFTKi Xc>N-N</td><td>5- (1-Methyl- acid bis- (2-hydroxy-propyl) -amide 5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 391,41</td><td> 392,5</td>

<td> 253</td><td>fV / i SH) Czm vs TH,</td><td>5- (1-Methyl-5-trifluoromethyl) -1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dipropylamide</td><td> 359,41</td><td> 360,5</td>

<td> 254</td><td>XrXXl rX ν ' s r'S Xcn.</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid diisobutylamide</td><td> 387,46</td><td> 388</td>

<td> 255</td><td>e F 0. W - <* Ύ \ OR*,</td><td>5- (1-Methyl-5-trifluomethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid bis- (2-Methoxy-ethyl) -amide</td><td> 391,41</td><td> 392,5</td>

<td> 256</td><td>> LX \; y> € Q</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dibenzylamide</td><td> 455,50</td><td> 456,5</td>

<td> 257</td><td>F -= HE HAS) Wi h,C'n-h s Y</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid butyl-phenyl-amide</td><td> 407,45</td><td> 408,6</td>

ES 2 425 578 T3

<td> 258</td><td>.... F H'S W- \ AA H, C S X ^ OH</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid butyl- (2-hydroxy-ethyl) -amide</td><td> 375,41</td><td> 376</td>

<td> 259</td><td>Fy · iX? ot</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl-butyl-amide</td><td> 421,48</td><td> 422,6</td>

<td> 260</td><td>F cXl ° oX. X</td><td>{Benzyl- [5- (1-Methyl-3-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] amino} -acetic acid ethyl ester</td><td> 451,46</td><td> 452,6</td>

<td> 261</td><td>ίΧι rr · " 0 -J</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrozol-3-yl) -thiophene-2-carboxylic acid (2-Cyano-ethyl) -methyl-amide</td><td> 342,34</td><td> 343,5</td>

<td> 262</td><td>ΠFSzF Γ 0</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid benzyl-phenethyl-amide</td><td> 469,52</td><td> 470,6</td>

<td> 263</td><td>FxK η, Χ'Χ ^ Χ'Ό or:</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -perhydroazepin-1-yl-methanone</td><td> 357,39</td><td> 358,4</td>

<td> 264</td><td>'^ -αχτ » up N 5</td><td>(4-Hydroxymethyl-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 373,39</td><td> 374,5</td>

<td> 265</td><td>F k-what 8 i) ·· HJ HG</td><td>5- (1-Methyl-5-trifluoromethyl- acid phenylamide 1 H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 351,35</td><td> 352,5</td>

<td> 266</td><td>XYT ^ s'ií 'Ύ7 nn α _AJ η / Η, οΆ ^</td><td>5- (1-Methyl-5-trifluoromethyl- acid o-Tolylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 365,37</td><td> 366</td>

<td> 267</td><td></td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Chloro-phenyl) -amide</td><td> 385,79</td><td> 386</td>

ES 2 425 578 T3

<td> 268</td><td>5 Λ Η, Ο</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-sulfonic acid amide</td><td> 311,31</td><td> 312,5</td>

<td> 269</td><td>Ν — Μ 0 ° ll, C</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-sulfonic acid dimethylamide</td><td> 339,36</td><td> 340,5</td>

<td> 270</td><td>F\ ο f-Λ> ΐχ U V. χ < F> ~ <and \> and 'CK Η-Η 0 υ'ck</td><td>5- (1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-sulfonic acid dimethylamide</td><td> 339,36</td><td> 340,5</td>

<td> 271</td><td>. Γ ^ ° hH-H 0 Ρ HC</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-sulfonic acid (tetrahydro-furan-2-ylmethyl) -amide</td><td> 395,42</td><td> 396,5</td>

<td> 272</td><td>Χ'ϋ > 4-Ν; 0 ° «,</td><td>5- (1methyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-sulfonic acid (tetrahydro-furan-2-ylmethyl) -amide</td><td> 395,42</td><td> 396,5</td>

<td> 273</td><td>^ χχ4^-^ What'ralη /</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophene-2-carboxylic acid [(R) -1- (Tetrahydrofuran-2-yl) methyl] -amide</td><td> 359,37</td><td> 360,6</td>

<td> 274</td><td>Chiral . · / “Ν 6. κ ^</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophene-2-carboxylic acid [(S) -1 - (Tetrahydrofuran-2-yl) methyl] -amide</td><td> 359,37</td><td> 360,4</td>

<td> 275</td><td>5 Μ s Λ CH,</td><td>5- (1-Methyl-3- trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-sulfonic</td><td> 365,40</td><td> 366,5</td>

<td> 276</td><td>14 — Η Ο Ο V</td><td>5- (1-Methyl-5- trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-sulfonic</td><td> 365,40</td><td> 366,5</td>

<td> 277</td><td>ρ ——, CHj Ñ — Ν «/</td><td>Dimethyl- [5- (1-methyl-5-trifluoromethyl-1H-pyrazole-3- yl) -thiophen-2-ylmethyl] -amine</td><td> 289,32</td><td> 290,5</td>

<td> 278</td><td>'A-fV ^ X -' ^ Ν — Ν /</td><td>Cyclopropylmethyl- [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-ylmethyl] -amine</td><td> 315,36</td><td> 316,6</td>

ES 2 425 578 T3

<td> 279</td><td> - ?Wrv</td><td>5- (1-Phenyl-3-trifluoromethyl- acid dimethylamide 1H-pyrazol-5-yl) -thiophene-2-carboxylic</td><td> 365,37</td><td> 366</td>

<td> 280</td><td>.Η ^ Ο ' OR WLZr1H, C</td><td>5- [1- (4-Nitro-phenyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 410,37</td><td> 411</td>

<td> 281</td><td>rJ j — rf ZA - W — N o FV ^ '^ jr^ r ''CH’ F «, C</td><td>5- [3-Trifluoromethyl-1- (4-trifluoromethyl-phenyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 433,37</td><td> 434</td>

<td> 282</td><td>í;M;F H, C</td><td>5- [3-Trifluoromethyl-1- (3-trifluoromethyl-phenyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 433,37</td><td> 434</td>

<td> 283</td><td>4 p or^ 77 ^ 7 ΤΑ1'1F HjC</td><td>5- [3-Trifluoromethyl-1- (2-trifluoromethyl-phenyl) -2H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 433,37</td><td> 434,5</td>

<td> 284</td><td>FM M, <( F N — N 0 TO</td><td>5- [1- (2,2,2-Trifluoro-ethyl) 5-trifluoromethyl-1H-pyrazol-3-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 371,30</td><td> 372</td>

<td> 285</td><td>rr¿\ F '</td><td>5- [2- (2-Hydroxy-ethyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 333,33</td><td> 334,5</td>

<td> 286</td><td>F NH 0</td><td>5- [1- (4-Chloro-phenyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 399,82</td><td> 400,5</td>

ES 2 425 578 T3

<td> 287</td><td>f Htc</td><td>5- (1-Benzyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 379,40</td><td> 380</td>

<td> 288</td><td>r 0 XH,</td><td>5- (1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 317,33</td><td> 318,5</td>

<td> 289</td><td>, H £ > ívCA “·· ' Ί '</td><td>5- (1-Ethyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 317,33</td><td> 318,5</td>

<td> 290</td><td>HjC ^ , ' N P «, C</td><td>5- (1-Propyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 331,36</td><td> 332,5</td>

<td> 291</td><td>F Γ-Λ ¿\\ / s V r W— fi 0 ^ CH,</td><td>5- (1-Propyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 331,36</td><td> 332,1</td>

<td> 292</td><td>F H, <t AF s ft 0</td><td>5- (1-Cyclopentyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 357,39</td><td> 358,6</td>

<td> 293</td><td>ÁyCH, / . HjC '</td><td>N, N-Dimethyl-4- (1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl) -benzamide</td><td> 297,28</td><td> 298,9</td>

<td> 294</td><td>ΆνΟΛ r NN You,</td><td>N, N-Dimethyl-4- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) -benzamide</td><td> 297,28</td><td> 298,5</td>

<td> 295</td><td>n ^ CH. '-T ^ O ^ oF NN (CH,</td><td>4- (1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) -N, N-dimethyl-benzamide</td><td> 311,30</td><td> 312,9</td>

ES 2 425 578 T3

<td> 296</td><td>h‘C', ^ ch, N — N</td><td>4- (1-Ethyl-3-trifluoromethyl-1H-pyrazol-5-yl) -N, N-dimethyl-benzamide</td><td> 311,30</td><td> 312,5</td>

<td> 297</td><td>F "-4 HC</td><td>N, N-Dimethyl-4- (1-propyl-5-trifluoromethyl-1H-pyrazol-3-yl) -benzamide</td><td> 325,33</td><td> 326,6</td>

<td> 298</td><td>X <y0 ^O <ÍF N — N C,</td><td>N, N-Dimethyl-4- (1-propyl-3-trifluoromethyl-1H- pyrazol-5-yl) -benzamide</td><td> 325,33</td><td> 326,9</td>

<td> 299</td><td>t (P V η / Λ ^</td><td>4- (1-Cyclopentyl-3-trifluoromethyl-1H-pyrazol-5-yl) - N, N-dimethyl-benzamide</td><td> 351,37</td><td> 352,5</td>

<td> 300</td><td>Oh $ Η, Ο '^</td><td>4- [1 - (2-Hydroxy-ethyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -N, N-dimethyl-benzamide</td><td> 327,30</td><td> 328,1</td>

<td> 301</td><td>TO FT *-\</td><td>N, N-Dimethyl-4- [1 - (2,2,2-trifluoro-ethyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -benzamide</td><td> 365,27</td><td> 366,4</td>

<td> 302</td><td>t H "N «/“ V</td><td>4- (1-Benzyl-3-trifluoromethyl-1H-pyrazol-5-yl) -N, N-dimethyl-benzamide</td><td> 373,37</td><td> 374,5</td>

ES 2 425 578 T3

<td> 303</td><td></td><td>N, N-Dimethyl-4- (1-phenyl-3-trifluoromethyl-1H-pyrazole- 5-yl) -benzamide</td><td> 359,35</td><td> 360,6</td>

<td> 304</td><td></td><td>N, N-Dimethyl-4- [5-trifluoromethyl-2- (4-trifluoromethyl- phenyl) -2H-pyrazol-3-yl] -benzamide</td><td> 427,34</td><td> 428,4</td>

<td> 305</td><td>5th Xs ^ H, c</td><td>5- (2-Ethyl-5-phenyl-2H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 325,43</td><td> 326,6</td>

<td> 306</td><td>Γ ΓΥ ^^^ Ι / 'γ01'HC</td><td>5- (1-Ethyl-5-phenyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 325,43</td><td> 326,6</td>

<td> 307</td><td> Γ N— N O ' Ο ^ ί>ΛΓ "· MjC</td><td>5- (3-Phenyl-1-propyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 339,46</td><td> 340,5</td>

<td> 308</td><td>pN 9 .ry-Oyyc ». HC</td><td>5- (5-Phenyl-1-propyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 339,46</td><td> 340</td>

<td> 309</td><td>p, HjC</td><td>5- (1-Cyclopentyl-3-phenyl1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 365,49</td><td> 366,5</td>

<td> 310</td><td>-XF or (Y ^ vA * kc</td><td>5- [3-Phenyl-1- (2,2,2- trifluoro-ethyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic</td><td> 379,40</td><td> 380,5</td>

<td> 311</td><td>Yor- 0. Xs> HjC</td><td>5- [1- (4-Nitro-phenyl) -3-phenyl- acid dimethylamide 1H-pyrazol-5-yl] -thiophene-2-carboxylic</td><td> 418,47</td><td> 419</td>

ES 2 425 578 T3

<td> 312</td><td>+ Ρ Η-Η 0 h, c</td><td>5- [3-Phenyl-1- (2-trifluoromethyl-phenyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 441,47</td><td> 442,5</td>

<td> 313</td><td>Η — N 0 · O ^ XyTOrCM' H, C</td><td>5- [3-Phenyl-1- (4-trifluoromethyl-phenyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 441,47</td><td> 442,5</td>

<td> 314</td><td>FJ jX) CH, WW »/ °</td><td>N, N-Dimethyl-3- (1-methyl-5-trifluoromethyl-1H-pyrazol-3- yl) -benzamide</td><td> 297,28</td><td> 298,5</td>

<td> 315</td><td>T N - f CH, 0</td><td>N, N-Dimethyl-3- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) -benzamide</td><td> 297,28</td><td> 298,4</td>

<td> 316</td><td>Ρ4· * «-N fl 'CS <° YOU</td><td>3- (1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) -N, N-dimethyl-benzamide</td><td> 311,30</td><td> 312,5</td>

<td> 317</td><td>P Vtí T os \ __ CH, or</td><td>3- (1-Ethyl-3-trifluoromethyl-1H-pyrazol-5-yl) -N, N-dimethyl-benzamide</td><td> 311,30</td><td> 312,5</td>

<td> 318</td><td>Mn> c- <q ¥ W <</td><td>3- (1-Isopropyl-5-trifluoromethyl-1 H-pyrazol-3-yl) N, N-dimethyl-benzamide</td><td> 325,33</td><td> 326,5</td>

<td> 319</td><td>pt APVp</td><td>3- (1-Cyclopentyl-3-trifluoromethyl-1H-pyrazol-5-yl) - N, N-dimethyl-benzamide</td><td> 351,37</td><td> 352,6</td>

<td> 320</td><td>F J <FP 0F'v ^ yy</td><td>N, N-Dimethyl-3- [1- (2,2,2-trifluoro-ethyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -benzamide</td><td> 365,27</td><td> 366</td>

<td> 321</td><td> 0.</td><td>N, N-Dimethyl-3- (1-phenyl-3-trifluoromethyl-1 Hpyrazol-5-yl) -benzamide</td><td> 359,35</td><td> 360,1</td>

ES 2 425 578 T3

<td> 322</td><td>ι_7 * ~μ °</td><td>3- (1-Benzyl-3-trifluoromethyl-1H-pyrazol-5-yl-N, N-dimethyl-benzamide</td><td> 373,37</td><td> 374,2</td>

<td> 323</td><td>, -CH. M /? H, c</td><td>5- (1,3-Dimethyl-1H-pyrazole- 5- yl) -thiophene-2-carboxylic</td><td> 249,33</td><td> 250,5</td>

<td> 324</td><td>H, q. N- NO KC'TvS \\ Ji-Oli H, C</td><td>5- (1-Ethyl-3-methyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 263,36</td><td> 264,6</td>

<td> 325</td><td>r orxc</td><td>5- (1-Ethyl-5-methyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 263,36</td><td> 264,5</td>

<td> 326</td><td>X, / MP "ΧΤ ^ ζ δΧ-Ά Λ / f hTO</td><td>5- (1-Isopropyl-3-methyl-1H- acid dimethylamide pyrazol-5-yl) -thiophene-2-carboxylic</td><td> 277,39</td><td> 278,6</td>

<td> 327</td><td>FORN 9 ^ cÁPSfVA CH. XC</td><td>5- (1-Isopropyl-5-methyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 277,39</td><td> 278,1</td>

<td> 328</td><td>P "-NO xc-AíXfSPC CH \ Vj,N ' H> ¿</td><td>5- (1-Cyclopentyl-3-methyl- acid dimethylamide 1H-pyrazol-5-yl) -thiophene-2-carboxylic</td><td> 303,42</td><td> 304,6</td>

<td> 329</td><td>P H, cÁKf syA ^ CH \\. ! N ^ H,</td><td>5- (1-Cyclopentyl-5-methyl- 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 303,42</td><td> 304,2</td>

<td> 330</td><td> /77^ s $ tCf01· H, C</td><td>5- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 311,40</td><td> 312</td>

ES 2 425 578 T3

<td> 331</td><td>F V p hh P H, C</td><td>5- [3-Methyl-1- (2,2,2- trifluoro-ethyl) -1H-pyrazol-5-yl] -thiophene-2-carboxylic</td><td> 317,33</td><td> 318,1</td>

<td> 332</td><td>P NN or "cXXH * - <”H, ¿</td><td>5- (3-methyl-1-pyridin-2-yl- acid dimethylantide 1H-pyrazol-5-yl) -thiophene-2-carboxylic</td><td> 312,39</td><td> 313,9</td>

<td> 333</td><td>F NN ° b</td><td>5- (1-Cyclopentyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 357,39</td><td> 358,5</td>

<td> 334</td><td>HC F N-Ñ 0</td><td>5- (1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 366,36</td><td> 367,5</td>

<td> 335</td><td>K <? ΧγΤΡ- '· fi * -4 0OR</td><td>5- (1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 366,36</td><td> 367,5</td>

<td> 336</td><td>/ ΥνΓνΠ z^n'-nV = / \) M</td><td>N, N-Dimethyl-4- (1-pyridin-2-yl-5-trifluoromethyl-1H- pyrazol-3-yl) -benzamide</td><td> 360,33</td><td> 361,6</td>

<td> 337</td><td>c ¢ --1 Chiral 'Ubb n λ-η X _x \ H> C <*</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-ylmethyl] - [(S) -1- (tetrahydro-furan-2-yl) methyl] amine</td><td> 345,38</td><td> 346,6</td>

<td> 338</td><td>F / Πι QulralΗ, Ο P</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-ylmethyl] - [(R) -1- (tetrahydro-furan-2-yl) methyl] amine</td><td> 345,38</td><td> 346,6</td>

<td> 339</td><td>. N — H 0 \ Γ1 A Jl</td><td>5- (5-Trifluoromethyl-2H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 289,28</td><td> 290,5</td>

ES 2 425 578 T3

<td> 340</td><td>Ρ K, C</td><td>5- [1- (2-Morpholin-4-yl-ethyl) 3-trifluoromethyl-1H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 402,44</td><td> 403,5</td>

<td> 341</td><td></td><td>N, N-Dimethyl-4- (5-trifluoromethyl-2H-pyrazol-3-yl) benzamide</td><td> 283,25</td><td> 284,5</td>

<td> 342</td><td>RR / *CH'/ • W \ = / * ό η ν-ϋ</td><td>N, N-Dimethyl-4- [1- (2-morpholin-4-yl-ethyl) -5-trifluoromethyl-1H-pyrazol-3-yl] -benzamide</td><td> 396,41</td><td> 397,6</td>

<td> 343</td><td>Qj ^ h</td><td>N, N-Dimethyl-4- [1- (2-morpholin-4-yl-ethyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -benzamide</td><td> 396,41</td><td> 397,2</td>

<td> 344</td><td>4-CEpAc FAA</td><td>N, N-Dimethyl-3- (5-trifluoromethyl-1H-pyrazol-3-yl) benzamide</td><td> 283,25</td><td> 284,9</td>

<td> 345</td><td>f</td><td>3- [1- (2-Hydroxy-ethyl) -3-trifluoromethyl-1H-pyrazole-5- yl] -N, N-dimethyl-benzamide</td><td> 327,30</td><td> 328,9</td>

<td> 346</td><td>JJ-yest P ^ • AA- ^ y-ycH, HC</td><td>5- (5-Methyl-2H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 235,31</td><td> 236,6</td>

<td> 347</td><td>C ~ ^ ^ c-Xy ^ yXN^ c ^ H, ¿</td><td>5- (1-Benzyl-3-methyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 325,43</td><td> 326,5</td>

<td> 348</td><td>, Ά H,</td><td>5- (3-Isopropyl-1-methyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 277,39</td><td> 278,5</td>

<td> 349</td><td>HTO ' Jt — NO ^ -oA- K, c</td><td>5- (5-Isopropyl-1-methyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 277,39</td><td> 278,6</td>

ES 2 425 578 T3

<td> 350</td><td>HC) ΧΧΛ ··</td><td>5- (1-Ethyl-3-isopropyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 291,41</td><td> 292,5</td>

<td> 351</td><td>ηρ V_J</td><td>5- (1-Ethyl-5-isopropyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 291,41</td><td> 292,5</td>

<td> 352</td><td>Β rp ;rCH* MjC H, C</td><td>5- (1-Cyclopentyl-3-isopropyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 331,48</td><td> 332,5</td>

<td> 353</td><td>Y * MP</td><td>5- [3-Isopropyl-1- (2,2,2-trifluoro-ethyl) -1 H-pyrazol-5-yl] -thiophene-2-carboxylic acid dimethylamide</td><td> 345,38</td><td> 346,9</td>

<td> 354</td><td>Oh 1 G Χ_ / Κ λ , γ-ητγ</td><td>5- [1- (2-Hydroxy-ethyl) -3- acid dimethylamide isopropyl-1H-pyrazol-5-yl] -thiophene-2-carboxylic</td><td> 307,41</td><td> 308,6</td>

<td> 355</td><td>s>, the I</td><td>5- (3-Isopropyl-5-phenyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 339,46</td><td> 340,5</td>

<td> 356</td><td>PHp ..</td><td>5- (5-Isopropyl-2H-pyrazole-acid dimethylamide 3-yl) -thiophene-2-carboxylic</td><td> 263,36</td><td> 264,6</td>

<td> 357</td><td>f '"Λ> ε, Ζγ».</td><td>5- (3-Isopropyl-1-propyl- acid dimethylamide 1H-pyrazol-5-yl) -thiophene-2-carboxylic</td><td> 305,44</td><td> 306,2</td>

<td> 358</td><td>7 HC</td><td>5- (5-Isopropyl-1-propyl- 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 305,44</td><td> 306</td>

ES 2 425 578 T3

<td> 359</td><td>/ -δ '/ Í-CH, pl 1 CH,</td><td>5- (1,5-Dimethyl-1H-pyrazole- 3-yl) -thiophene-2-carboxylic</td><td> 249,33</td><td> 250,2</td>

<td> 360</td><td>F </ HC / * \ FPl?N lf ** ' n</td><td>4- (1-methyl-5- trifluoromethyl-1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 298,26</td><td> 299,2</td>

<td> 361</td><td>vyFor pf **, · 0</td><td>4- (1-propyl-5- acid dimethylamide trifluoromethyl-1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 326,32</td><td> 327,5</td>

<td> 362</td><td>O%; ] P r- Vp OR</td><td>4- (1-Pyridin-2-yl-5- acid dimethylamide trifluoromethyl-1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 361,32</td><td> 362,1</td>

<td> 363</td><td>p F F h = PF(OR N and CHj σ '</td><td>4- [1- (2,2,2-Trifluoroethyl) - acid dimethylamide 3-trifluoromethyl-1H-pyrozol-5-yl] -pyridine-2-carboxylic</td><td> 366,26</td><td> 367,2</td>

<td> 364</td><td>Yes! 0</td><td>4- [1- (2-Hydroxy-ethyl) -5- acid dimethylamide trifluoromethyl-1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 328,29</td><td> 329,2</td>

<td> 365</td><td>X \ H, C, CH, VSpP ° r H0</td><td>4- [1- (2-hydroxy-ethyl) -3- acid dimethylamide trifluoromethyl-1H-pyrazol-5-yl] -pyridine-2-carboxylic</td><td> 328,29</td><td> 329,3</td>

ES 2 425 578 T3

<td> 366</td><td>Ρ Qp Ρι γ '^ αί, 0</td><td>4- (1-Benzyl-3- acid dimethylamide trifluoromethyl-1H-pyrazol-5-yl) -pyridine-2-carboxylic</td><td> 374,36</td><td> 375</td>

<td> 367</td><td>μ X Υ Π</td><td>4- (1-Phenyl-5-trifluoromethyl- acid dimethylamide 1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 360,33</td><td> 361,1</td>

<td> 368</td><td>FF Ύ ^?'° ·· ν ύ <χ- ^ χ (¿ΐ</td><td>4- (1-Phenyl-3-trifluoromethyl- acid dimethylamide 1H-pyrazol-5-yl) -pyridine-2-carboxylic</td><td> 360,33</td><td> 361</td>

<td> 369</td><td>Q ΓΧ / γΑ> 1 CH,</td><td>5- (1-Methyl-3-phenyl-1H-pyrazol-5-yl) -thiophene-2-carboxylic acid dimethylamide</td><td> 311,40</td><td> 312,1</td>

<td> 370</td><td>F Pf Μ λ JÍ, n ^ VíV ^ YV „,</td><td>4- (1-Ethyl-3-trifluoromethyl-1H-pyrazol-5-yl) -pyridine-2-carboxylic acid dimethylamide</td><td> 312,29</td><td> 313,5</td>

<td> 371</td><td>F Pl</td><td>6- (1-Phenyl-5-trifluoromethyl- acid dimethylamide 1H-pyrazol-3-yl) -pyridine-2-carboxylic</td><td> 360,33</td><td> 361,6</td>

<td> 372</td><td>Ff. OR <And ncm, F ^ Yp</td><td>6- [1- (2,2,2-Trifluoroethyl) -3-trifluoromethyl-1H-pyrazol-5-yl] -pyridine-2-carboxylic acid dimethylamide</td><td> 366,26</td><td> 367,5</td>

ES 2 425 578 T3

<td> 373</td><td>f? Cl? 0 Oh</td><td>6- [2- (2-hydroxy-ethyl) -3- acid dimethylamide trifluoromethyl-1H-pyrazol-5-yl] -pyridine-2-carboxylic</td><td> 328,29</td><td> 329,5</td>

<td> 374</td><td>and > A f *ΝΛΟ</td><td>6- (1-Benzyl-3- acid dimethylamide trifluoromethyl-1H-pyrazol-5-yl) -pyridine-2-carboxylic</td><td> 374,36</td><td> 375,6</td>

<td> 375</td><td>pp ' t___ / M NH, US FTY CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (2-Amino-ethyl) -amide</td><td> 318,32</td><td> 319,3</td>

<td> 376</td><td>ft s-θ '' '' '«.</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid (5-Amino-pentyl) -amide</td><td> 360,40</td><td> 361,4</td>

<td> 377</td><td>F ¡.C s Tf H, C, 0</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid ethyl-methyl-amide</td><td> 317,33</td><td> 318,4</td>

<td> 378</td><td>F- p M<Ί FXsX/ ., - N Λ HjC 0</td><td>5- (1-Methyl-5-trifluoromethyl- acid methylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 289,28</td><td> 290,3</td>

<td> 379</td><td>F/ r — v , N-4t S 1' H, C 0</td><td>5- (1-Methyl-5-trifluoromethyl- acid diethylamide 1H-pyrazol-3-yl) -thiophene-2-carboxylic</td><td> 331,36</td><td> 332,3</td>

<td> 380</td><td>And CH,</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid N ', N'-dimethyl-hydrazide</td><td> 318,32</td><td> 319,5</td>

<td> 381</td><td>Xyy ^ y ^ «>c s></td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid piperidin-1-ylamide</td><td> 358,38</td><td> 359,6</td>

<td> 382</td><td>fJL X and Η, εΤ ^ όΗ,</td><td>(4-Dimethylamino-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 386,44</td><td> 387,6</td>

ES 2 425 578 T3

<td> 383</td><td>\ a Q 7A, 0</td><td>[5 (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone</td><td> 412,47</td><td> 413,7</td>

<td> 384</td><td>/ A / °F J 1 'ΉF CH, A = /</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-phenyl-piperidin-1-yl) -methanone</td><td> 419,46</td><td> 420,6</td>

<td> 385</td><td>OR XO what A k 0</td><td>(4-Hydroxy-4-phenyl-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 435,46</td><td> 436,6</td>

<td> 386</td><td><ytF OR</td><td>1- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] -piperidine-4-carboxylic acid amide</td><td> 386,39</td><td> 387,5</td>

<td> 387</td><td>RF CH,</td><td>(4-Benzyl-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 433,49</td><td> 434,7</td>

<td> 388</td><td><R, AF CM.</td><td>1- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] -piperidine-3-carboxylic acid amide</td><td> 386,39</td><td> 387,7</td>

<td> 389</td><td>zvyO.? ur '[<> * 0</td><td>1- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) - thiophene-2-sulfonyl] -piperidine</td><td> 379,42</td><td> 380,5</td>

<td> 391</td><td><w R9 OR F</td><td>[5- (1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 343,37</td><td> 344,6</td>

<td> 392</td><td>Ά ^ ο</td><td>[4- (1-Methyl-3-trifluoromethyl-1H-pyrazol-3-yl) -phenyl] piperidin-1-yl-methanone</td><td> 337,34</td><td> 338,6</td>

ES 2 425 578 T3

<td> 393</td><td>FJ. ΓΛ / ΤΥΑ / -χ</td><td>[3- (1-Methyl-3-trifluoromethyl-1H-pyrazol-3-yl) -phenyl] - piperidin-1-yl-methanone</td><td> 337,34</td><td> 338,6</td>

<td> 394</td><td>F f 70</td><td>[3-Methyl-5- (1-methyl-5-trifluoromethyl-1H-pyrazole-3- yl) -thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 357,39</td><td> 358,6</td>

<td> 395</td><td>AO χ-ΎF or</td><td>1 - [5- (1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophene-2-carbonyl] -piperidine-2-carboxylic acid</td><td> 387,38</td><td> 388,6</td>

<td> 396</td><td>7j > OR</td><td>[4-Methyl-5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 357,39</td><td> 358,5</td>

<td> 397</td><td>F -) - <f7o 's'Tf'N' '·' ^ F NN o H</td><td>Piperidin-1-yl- [5- (5-trifluoromethyl-1H-pyrazal-3-yl) thiophen-2-yl] -methanone</td><td> 329,34</td><td> 330,4</td>

<td> 398</td><td>h -) - ^ 7XsXfNXF NK or H</td><td>[5- (5-Difluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] piperidin-1-yl-methenone</td><td> 311,36</td><td> 312,4</td>

<td> 399</td><td>aWrOyO. F and N &</td><td>{5- [5- (Chloro-difluoro-methyl) -1H-pyrazol-3-yl] -thiophene- 2-yl} -piperidin-1-yl-methanone</td><td> 345,80</td><td> 346,3</td>

<td> 400</td><td>-AO FF fJ-N £</td><td>[5- (5-Pentafluoroethyl-1H-pyrazol-3-yl) -thiophen-2-yl] - piperidin-1-yl-methanone</td><td> 379,35</td><td> 380,3</td>

<td> 401</td><td>f-TAaX'sXí ' NX F NN .ft H</td><td>[5- (4-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 343,37</td><td> 344,4</td>

<td> 402</td><td>κλΧυ7 F NN or H</td><td>[5- (4-Allyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 369,41</td><td> 370,3</td>

ES 2 425 578 T3

<td> 403</td><td>^ ΧΑγΟ F</td><td>[5- (4-Benzyl-5-trifluoromethyl-1H-pyrazol-3-yl) - thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 419,47</td><td> 420,3</td>

<td> 404</td><td></td><td>Piperidin-1-yl- [3- (5-trifluoromethyl-1H-pyrazol-3-yl) phenyl] -methanone</td><td> 323,32</td><td> 324,4</td>

<td> 405</td><td>f, fN υψΟ 0</td><td>Piperidin-1-yl- [4- (5-trifluoromethyl-1H-pyrazol-3-yl) - phenyl] -methanone</td><td> 323,32</td><td> 324,4</td>

<td> 406</td><td>F χΝ-Ν £</td><td>[5- (5-Difluoromethyl-1-methyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 325,38</td><td> 326,4</td>

<td> 407</td><td>α-ΥγνΟγΌ f nn a t</td><td>{5- [5- (Chloro-difluoro-methyl) -1-methyl-1 H-pyrazol-3-yl] -thiophen-2-yl} -piperidin-1-yl-methanone</td><td> 359,82</td><td> 360,4</td>

<td> 408</td><td>Λ ') / ΥΖΧΟ ff j <-N ¿</td><td>[5- (1-Methyl-5-pentafluoroethyl-1H-pyrazol-3-yl) - thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 393,78</td><td> 394,3</td>

<td> 409</td><td>F -) - <V ^ S ^ V Nkx^ F ZNN OR</td><td>[5- (1,4-Dimethyl-5-trifluoromethyl-1 H-pyrazol-3-yl) - thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 357,39</td><td> 358,4</td>

<td> 410</td><td>4A-V 0 F 0</td><td>[5- (4-Allyl-1 -methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) thiophen-2-yl] -piperidin-1 -yl-methanone</td><td> 383,43</td><td> 384,4</td>

<td> 411</td><td>F ZNN ü</td><td>[5- (4-Benzyl-1 -methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 433,49</td><td> 434,4</td>

<td> 412</td><td>Κ: 0> Λ \ Ο F 'NN £</td><td>[5- (1-Methyl-4-propyl-5-trifluoromethyl-1H-pyrazole-3- yl) -thiophen-2-yl] -piperidin-1-yl-methanone</td><td> 385,45</td><td> 386,4</td>

ES 2 425 578 T3

<td> 413</td><td>F 0</td><td>[5- (1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperidin-1-yl-methanone</td><td> 357,39</td><td> 358,5</td>

<td> 414</td><td>F ^ nn or;</td><td>Piperidin-1-yl- [5- (1-propyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 371,42</td><td> 372,4</td>

<td> 415</td><td>Fy_ ^ yXsA ^ 'N'^ / F NN or w F F</td><td>Piperidin-1 -yl- {5- [1 - (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-1H-pyrazol-3-yl] -thiophen-2-yl} methanone</td><td> 411,37</td><td> 412,4</td>

<td> 416</td><td>'l-A'V'P F NN. g</td><td>Cyclohexyl- [5- (1-methyl-5-trifluoromethyl-1H-pyrazole- 3-yl) -thiophen-2-yl] -methanone</td><td> 342,38</td><td> 343,5</td>

<td> 417</td><td></td><td>2,2-Dimethyl-1- [5- (1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -propan-1-one</td><td> 316,34</td><td> 317,5</td>

<td> 418</td><td></td><td>Cyclohexyl- [5- (1,4-dimethyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 356,41</td><td> 357,6</td>

<td> 419</td><td></td><td>Cyclohexyl- [5- (1,4-dimethyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -methanol</td><td> 358,43</td><td> 359,6</td>

<td> 420</td><td>F and N ^S</td><td>4-Fluoro-1 - [5- (1-methyl-5-t rifluoromethyl-1 H-pyrazole- 3-yl) -thiophen-2-ylmethyl] -piperidine</td><td> 347,38</td><td> 348,6</td>

<td> 421</td><td> /</td><td>4,4-Difluoro-1 - [5- (1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophen-2-ylmethyl] -piperidine</td><td> 365,37</td><td> 366,6</td>

<td> 422</td><td></td><td>[3- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -phenyl] piperidin-1-yl-methanone</td><td> 337,34</td><td> 338,4</td>

ES 2 425 578 T3

<td> 423</td><td>F / F-\N po 0</td><td>[4- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -phenyl] piperidin-1-yl-methanone</td><td> 337,34</td><td> 338,4</td>

<td> 424</td><td>F FÑopo rP or</td><td>Cyclohexyl- [4- (1-methyl-5-trifluoromethyl-1H-pyrazole- 3-yl) -phenyl] -methanone</td><td> 336,35</td><td> 337,6</td>

<td> 425</td><td>a <\ °</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -phenyl-methanone</td><td> 336,34</td><td> 337,6</td>

<td> 426</td><td></td><td>(4-Fluoro-phenyl) - [5- (1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 354,33</td><td> 355,6</td>

<td> 427</td><td>h / 7 '</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-trifluoromethyl-piperidin-1-yl) -methanone</td><td> 411,37</td><td> 412,6</td>

<td> 428</td><td>: ba-ZY</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (3-trifluoromethyl-piperidin-1-yl) -methanone</td><td> 411,37</td><td> 412,6</td>

<td> 429</td><td></td><td>(3-Fluoro-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 361,36</td><td> 362,6</td>

<td> 430</td><td>MA</td><td>(4-Fluoro-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 361,36</td><td> 362,6</td>

<td> 431</td><td></td><td>(4,4-Difluoro-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 379,35</td><td> 380,5</td>

<td> 432</td><td>M1?</td><td>(3,3-Difluoro-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 379,35</td><td> 380,7</td>

ES 2 425 578 T3

<td> 433</td><td>, JpQ</td><td>(4-Isopropyl-piperazin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 386,44</td><td> 387,6</td>

<td> 434</td><td>jan</td><td>4- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] -piperazine-1-carboxylic acid ferc-Butyl ester</td><td> 444,48</td><td> 445,6</td>

<td> 435</td><td></td><td>(4-Methoxy-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 373,39</td><td> 374,5</td>

<td> 436</td><td>TO to?</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -pyrrolidin-1-yl-methanone</td><td> 329,34</td><td> 330,5</td>

<td> 437</td><td>'-Ul AV'</td><td>((S) -3-Fluoro-pyrrolidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 347,33</td><td> 348,6</td>

<td> 438</td><td>n- \ J-s O ~F</td><td>((R) -3-Fluoro-pyrrolidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 347,33</td><td> 348,6</td>

<td> 439</td><td></td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-trifluoromethylphenyl) -methanone</td><td> 404,34</td><td> 405,5</td>

<td> 440</td><td><V JWQsPZNN 0</td><td>(4-Methyl-piperazin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 358,38</td><td> 359,6</td>

<td> 441</td><td>Af / ma ^ NN O</td><td>(4-Ethyl-piperazin-1-yl) - [5- (1-methyl-5-trifluoromethyl- 1 H-pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 372,41</td><td> 373,6</td>

ES 2 425 578 T3

<td> 442</td><td>. TO? -4 No. Ffi</td><td>(3-Hydroxy-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 359,37</td><td> 360,5</td>

<td> 443</td><td>w '</td><td>(3-Fluoro-phenyl) - [5- (1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 354,32</td><td> 355,5</td>

<td> 444</td><td>χΝ-Ν 0 N</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid thiazol-2-ylamide</td><td> 358,36</td><td> 359,5</td>

<td> 445</td><td>- (Ή : wa ° ^ NN 'O</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -piperazin-1-yl-methanone</td><td> 344,36</td><td> 345,5</td>

<td> 446</td><td>^ NN O F</td><td>(2-Fluoro-phenyl) - [5- (1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 354,32</td><td> 355,5</td>

<td> 447</td><td>.0 ΧΉ N RR?NN 0</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (4-pyridin-2-yl-piperazin-1-yl) -methanone</td><td> 421,44</td><td> 422,6</td>

<td> 448</td><td>NN 0 /</td><td>[4- (2-Methoxy-ethyl) -piperazin-1-yl] - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 402,44</td><td> 403,5</td>

<td> 449</td><td>A. <FvA ~ La ./F_)—7 x- F, Ν-Ν 0</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -perhydroazocin-1-yl-methanone</td><td> 371,42</td><td> 372,5</td>

<td> 450</td><td>AQ? -0ZNN 0</td><td>5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 2-Hydroxy-ethyl ester</td><td> 320,29</td><td> 321,5</td>

<td> 451</td><td>TO AA ° / l'N O</td><td>5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophene-2-carboxylic acid 8-methyl-8-aza-bicyclo [3,2,1] oct-3-yl ester</td><td> 399,43</td><td> 400,5</td>

<td> 452</td><td>A <AAr ° A)ZNN QN</td><td>5- (1methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid 1-Aza-bicyclo [2,2,2] oct-3-yl ester</td><td> 385,41</td><td> 386,5</td>

ES 2 425 578 T3

<td> 453</td><td>zNN O</td><td>Aziridin-1-yl- [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 301,29</td><td> 302,4</td>

<td> 454</td><td>NN 0 /</td><td>5 - {[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] -amino} -pentanoic acid</td><td> 375,37</td><td> 376,5</td>

<td> 455</td><td>r?NN .0</td><td>5 - {[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] amino} -pentanoic acid methyl ester</td><td> 389,39</td><td> 390,5</td>

<td> 456</td><td> \ FzNN S 0</td><td>(4-Dimethylamino-phenyl) - [5- (1 -methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 379,40</td><td> 380,5</td>

<td> 457</td><td>FYNN S 0</td><td>(4-Methoxy-phenyl) - [5- (1-methyl-5-trifluoromethyl-1 H- pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 366,36</td><td> 367,5</td>

<td> 458</td><td>zNN 0</td><td>(4-Amino-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 358,39</td><td> 359,5</td>

<td> 459</td><td>F F and N S OR</td><td>(4-Difluoromethylene-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 391,36</td><td> 392,5</td>

<td> 460</td><td>. y — S. [what will 11] f P / v Όύ Άί * F NN 0 H</td><td>((S) -3-Amino-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone, hydrochloride</td><td> 358,38</td><td> 359,5</td>

<td> 461</td><td>, fi ry Í2^ F N: v>* n hF N'N QH</td><td>((R) -3-Amino-piperidin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone, hydrochloride</td><td> 358,38</td><td> 359,5</td>

<td> 462</td><td>AnhF N'N 0</td><td>Cis-3,5-dimethyl-piperazin-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 372,41</td><td> 373,6</td>

<td> 463</td><td>/ -ΛΑ °zNN O</td><td>{1- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carbonyl] piperidin-4-yl) -carbamic acid tert-Butyl ester</td><td> 458,51</td><td> 459,6</td>

<td> 464</td><td>H.orF and N o</td><td>(4-Hydroxy-4-trifluoromethyl-piperidin-1-yl) - [5- (1 methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 427,37</td><td> 428,4</td>

ES 2 425 578 T3

<td> 465</td><td>/ ΑΧ0</td><td>(4-Methyl- [1,4] diazepan-1-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 372,41</td><td> 373,5</td>

<td> 466</td><td></td><td>5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2-carboxylic acid adamantan-1-ylamide</td><td> 409,47</td><td> 410,6</td>

<td> 467</td><td>ΤτΤΤτ Ν-Ν Ο /</td><td>(1,1-Dioxo-1 -lambda * 6 * -thiomorpholin -4-yl) - [5- (1 methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophen-2-yl] methanone</td><td> 393,41</td><td> 394,4</td>

<td> 468</td><td>F ^ »'Ν Ο Ο</td><td>(1,1-Dioxo-1 lambda * 6 * - [1,2] thiazine n-2-yl) - [5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene-2- il] methanone</td><td> 393,41</td><td> 394,4</td>

<td> 469</td><td>fXc ^ vXX'Q) F / 4 'Ν Ο Η</td><td>[5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] - (tetrahydropyridazin-1-yl) -methanone</td><td> 344,36</td><td> 345,4</td>

<td> 470</td><td></td><td>Cyclohexyl- [5- (1-methyl-5-trifluoromethyl-1H-pyrazole- 3-yl) -thiophen-2-yl] -methanol</td><td> 344,40</td><td> 345,4</td>

<td> 471</td><td>F ^ ΝΝ Q</td><td>1- [5- (1-Methyl-5-trifluoromethyl-1H-pyrazol-5-yl) - thiophene-2-carbonyl] -piperidine-4-nitrile</td><td> 368,38</td><td> 369,4</td>

<td> 472</td><td>γηΧΧ ^ F / -Ν Ο</td><td>(4-Fluoro-phenyl) - [5- (1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) -thiophen-2-yl] -methanone</td><td> 354,32</td><td> 355,5</td>

<td> 473</td><td>Λ F?-? ιΓ ST F f'N O</td><td>1 - [5- (1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl) thiophene-2-carbonyl] -piperidin-4-one</td><td> 357,35</td><td> 358,5</td>

<td> 474</td><td>Αλ. /?ΓZN'Ñ S 0</td><td>[5- (1-Methyl-5-trifluoramethyl-1H-pyrazol-3-yl) -thiophene- 2-yl] -thiophen-2-yl-methanone</td><td> 342,36</td><td> 343,4</td>

<td> 475</td><td>aa- NN /</td><td>1-Methyl-4- [5- (1-methyl-5-trifluoromethyl-1 H-pyrazole- 3- yl) -thiophen-2-ylmethyl] -piperazine</td><td> 344,40</td><td> 345,5</td>

ES 2 425 578 T3

Example 13.

The following illustrates representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

<td>(i) Tablet 1</td><td>mg / tablet</td>

<td colspan="2">Compound X = 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0</td>

<td>(ii) Tablet 2</td><td>mg / tablet</td>

<td>Compound X =</td><td> 20,0</td>

<td colspan="2">Microcrystalline cellulose 410.0</td>

<td>Starch</td><td> 50,0</td>

<td colspan="2">Sodium starch glycolate 15.0</td>

<td>Magnesium stearate</td><td> 50 500,0</td>

<td>(iii) Capsule</td><td>mg / capsule</td>

Compound X = 10.0

Colloidal silicon dioxide 1.5

Lactose465.5

Pregelatinized starch 120.0

Magnesium stearate 3.0

600.0 (iv) Injection 1 (1 mg / ml) mg / ml

Compound X = (free acid form) 1.0

Dibasic sodium phosphate12.0

Monobasic sodium phosphate 0.7

Sodium chloride 4.5

1.0 N sodium hydroxide solution (pH adjustment 7.0-7.5) qs

Water for injection qs up to 1 ml (v) Injection 2 (10 mg / ml) mg / ml

Compound X = (free acid form) 10.0

Monobasic sodium phosphate 0.3

Dibasic sodium phosphate1,1

Polyethylene glycol 400 200.0

1.0 N sodium hydroxide solution (pH adjustment 7.0-7.5) qs

Water for injection qs up to 1 ml

ES 2 425 578 T3 (vi) Aerosol mg / can

Compound X = 20.0

Oleic acid 10.0

T ricloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0

Dichlorotetrafluoroethane 5,000.0

The above formulations can be obtained by conventional procedures well known in the pharmaceutical art.

Contents83

35 members in 15 offices

This recordMember, by publication datePriority claim5 more offices are in the list below

Priority claims12

Priority claims
Document	Office	Kind	Date
77733206	United States of America	P	2006-02-28
77733206	United States of America	P	2006-02-28
89045507	United States of America	P	2007-02-16
89045507	United States of America	P	2007-02-16
2007005157	United States of America	W	2007-02-27
2007005157	United States of America	W	2007-02-27
777332P	–	–	–
890455P	–	–	–
PCTUS2007005157	–	–	–
US20060777332P	–	–	–
US20070890455P	–	–	–
WO2007US05157	–	–	–

Members35

Family members, oldest first
Document	Office	Kind
US2007203154A1	United States of America	A1	2007-08-30
AU2007221020A1	Australia	A1	2007-09-07
CA2644068A1	Canada	A1	2007-09-07
WO2007100851A1	World Intellectual Property Organization (WIPO)	A1	2007-09-07
TW200744586A	Taiwan Province of China	A	2007-12-16
AR059687A1	Argentina	A1	2008-04-23
EP1989185A1	European Patent Office (EPO)	A1	2008-11-12
IL193678A0	Israel	A0	2009-05-04
HK1123545A1	Hong Kong, China	A1	2009-06-19
CN101484424A	China	A	2009-07-15
JP2009528362A	Japan	A	2009-08-06
US2010317648A1	United States of America	A1	2010-12-16
US7919626B2	United States of America	B2	2011-04-05
BRPI0708353A2	Brazil	A2	2011-05-24
SG171617A1	Singapore	A1	2011-06-29
US2011160248A1	United States of America	A1	2011-06-30
NZ570847A	New Zealand	A	2011-10-28
EP2465850A1	European Patent Office (EPO)	A1	2012-06-20
AU2007221020B2	Australia	B2	2013-02-14
AU2013200480A1	Australia	A1	2013-02-14
US8399487B2	United States of America	B2	2013-03-19
AU2007221020B9	Australia	B9	2013-04-04
NZ595571A	New Zealand	A	2013-04-26
EP1989185B1	European Patent Office (EPO)	B1	2013-05-22
EP1989185B8	European Patent Office (EPO)	B8	2013-06-26
TWI403321B	Taiwan Province of China	B	2013-08-01
ES2425578T3This record	Spain	T3	2013-10-16
CN101484424B	China	B	2014-05-14
JP5503874B2	Japan	B2	2014-05-28
US8791137B2	United States of America	B2	2014-07-29
CA2644068C	Canada	C	2015-04-21
IL193678A	Israel	A	2016-04-21
AU2013200480B2	Australia	B2	2016-06-09
EP2465850B1	European Patent Office (EPO)	B1	2016-11-23
BRPI0708353A8	Brazil	A8	2017-08-29