Patent EA-003513-B1 (EA)
Title: Heterocyclic compounds as inhibitors of rotamase enzymes
Inventor: KEMP MARK IAN
IPC: C07D235/24
Filed: 1999-06-28
Abstract: 1. A compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is unbranched C3-C5 alkylene optionally substituted by C1-C6 alkyl; X is O, S, NH or N (C1-C6alkyl); Y is O, S, NH or N (C1-C6alkyl); R is a C-linked, 4- to 6-membered ring, non-aromatic, heterocyclic group containing one nitrogen heteroatom, said group being optionally substituted by 1,2 or 3 substituents each independently selected from C1-C6alkyl, C2-C6alkenyl, C3-C7cycloalkyl, aryl, het, -CO2(C1-C6alkyl), -CO(het), -CONR<5>R<6> and -CO(aryl), said alkyl and alkenyl being optionally substituted by 1 or 2 substituent (s) each independently selected from C3-C7cycloalkyl, aryl, het, -O(aryl), -O(C1-C2alkylene)aryl, -CO(het), -CONR<5>R<6> and -CO(aryl); R<1>, R<2>, R<3> and R<4> are each independently selected from H, halo, C1-C6alkyl, C3-C7cycloalkyl, halo(C1-C6)alkyl, C1-C6alkoxy, CONR<5>R<6>, C3-C7cycloalkoxy, C3-C7cycloalkyl-(C2-C4)alkylene, C3-C7cycloalkyl(C2-C4)alkoxy and -CO2(C1-C6alkyl); R<5> and R<6> are either each independently selected from H and C1-C6alkyl or, when taken together, represent unbranched C3-C5alkylene; "aryl" means phenyl, optionally substituted by 1,2 or 3 substituent (s) each independently selected from C1-C6alkyl, C1-C6alkoxy, halo, CONR<5>R<6>, halo(C1-C6alkyl) and -NR<5>R<6>; and "het" means a 5- or 6-membered monocyclic, or 8-, 9- or 10-membered bicyclic, ring heterocyclic group containing from 1 to 3 heteroatoms each independently selected from N, O and S, said group being optionally substituted by 1,2 or 3 substituent (s) each independently selected from C1-C6alkyl, C1-C6alkoxy, halo, halo(C1-C6alkyl), phenyl and -NR5R6. 2. A compound as claimed in claim 1 having the stereochemical formula (IA): wherein R, R<1>, R<2>, R<3>, R<4>, A, X and Y are as defined for a compound of the formula (I) in claim 1. 3. A compound as claimed in claims 1 or 2 wherein A is 1, 4-butylene. 4. A compound as claimed in any of claims 1 to 3 wherein X is O, S or NH. 5. A compound as claimed in claim 4 wherein X is O or NH. 6. A compound as claimed in any of claims 1 to 5 wherein Y is O or NH. 7. A compound as claimed in claim 6 wherein Y is NH. 8. A compound as claimed in any of claims 1 to 7 wherein R is an azetidinyl, pyrrolidinyl or a piperidinyl group, each optionally substituted by 1,2 or 3 substituent (s) each independently selected from C1-C6alkyl, C1-C6alkenyl, C3-C7cycloalkyl, aryl, het, -CO2(C1-C6alkyl), CO(het), -CONR<5>R<6> and -CO(aryl), said alkyl and alkenyl being optionally substituted by 1 or 2 substituent (s) each independently selected from C3-C7cycloalkyl, aryl, het, -O(aryl), -(C1-C2alkylene)aryl, -CO(het), -CONR<5>R<6>and -CO(aryl). 9. A compound according to any of claims 1 to 8 wherein R is an azetidinyl, pyrrolidinyl or a piperidinyl group, each optionally substituted by 1,2 or 3 substituent (s) each independently selected from C1-C6alkyl, het, -CO2(C1-C6alkyl) and -CO(het), said alkyl being optionally substituted by 1 or 2 substituent (s) each independently selected from C3-C7cycloalkyl, aryl, het, -O(aryl), -O(C1-C2alkylene)aryl and CONR<5>R<6>. 10. A compound according to any of claims 1 to 9 wherein R is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted by 1,2 or 3 substituent (s) each independently selected from ethyl, 2-pyridyl, tert butoxycarbonyl, quinolin-2-ylcarbonyl, 2-phenylquinolin-4-ylcarbonyl, 4-methoxyquinolin-2-ylcarbonyl, 6-methoxy-2-phenylquinolin-4-ylcarbonyl, 2-piperidinoquinolin-4-ylcarbonyl, 2-chloroquinolin-4-ylcarbonyl, 1H-benzpyrazol-6-ylcarbonyl, cyclopropylmethyl, phenylmethyl, diphenylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, (1H-1,2,4-triazol-3-yl)methyl, (2-chloroquinolin-3-yl)methyl, quinolin-4-ylmethyl, quinolin-2-ylmethyl, quinolin-3-ylmethyl, 1-(quinolin-4-yl)ethyl, (2-fluoropyridin-4-yl)methyl, phenoxymethyl, benzyloxymethyl, aminocarbonylmethyl, 2-(aminocarbonyl)ethyl and 3-(aminocarbonyl)phenylmethyl. 11. A compound according to any of claims 1 to 10 wherein R is an optionally substituted 3-azetidinyl, 3-pyrrolidinyl, 3-piperidinyl or 4-piperidinyl group. 12. A compound according to any of claims 1 to 11 wherein the aryl group is a phenyl group, optionally substituted by CONR<5>R<6>. 13. A compound according to any of claims 1 to 12 wherein the "het" group is a pyridyl, imidazolyl, triazolyl, quinolinyl or benzpyrazolyl group, each optionally substituted by 1,2 or 3 substituent (s) each independently selected from methyl, methoxy, fluoro, chloro, phenyl and piperidino. 14. A compound according to any of claims 1 to 13 wherein R<1>, R<2>, R<3> and R<4> are each independently selected from H, halo(C1-C6)alkyl and halo. 15. A compound according to any of claims 1 to 14 wherein R<1>, R<2>, R<3> and R<4> are each independently selected from H, fluoro, chloro, bromo and trifluoromethyl. 16. A compound according to any of claims 1 to 15 wherein the group of the formula: is the compound of the formula (I) according to claim 1 is a 1, 3-benzoxazol-2-yl, 1,3-benzothiazol-2-yl, 1H-benzimidazol-2-yl, 6-bromo 1,3-benzoxazol-2-yl or 6-chloro-1, 3-benzothiazol-2-yl group. 17. A compound according to any of claims 1 to 16 wherein A is 1-4 butylene, X is O or NH, Y is NH, R is 3-azetidinyl, 3-pyrrolidinyl, 3-piperidinyl or 4-piperidinyl each optionally substituted by 1,2 or 3 substituent (s) each independently selected from ethyl, 2-pyridyl, tert-butoxycarbonyl, quinolin-2-ylcarbonyl, 2-phenylquinolin-4-ylcarbonyl, 4- methoxyquinolin-2-ylcarbonyl, 6-methoxy-2-phenylquinolin-4-ylcarbonyl, 2-piperidinoquinolin-4-ylcarbonyl, 2-chloroquinolin-4-ylcarbonyl, 1H-benzpyrazol-6-ylcarbonyl, cyclopropylmethyl, phenylmethyl, diphenylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, (1H-1,2,4-triazol-3-yl)methyl, (2-chloroquinolin-3-yl)methyl, quinolin-4-ylmethyl, quinolin-2-ylmethyl, quinolin-3-ylmethyl, 1-(quinolin-4-yl)ethyl, (2-fluoropyridin-4-yl) methyl, phenoxymethyl, benzyloxymethyl, aminocarbonylmethyl, 2- (aminocarbonyl) ethyl and 3- (aminocarbonyl) phenylmethyl. 18. A compound according to any of the preceding claims selected from the group consisting of: (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-[(3S)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide; (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-[(3S)-1-(2-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide; (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-[(3S)-1-(3-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide; (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-[(3S)-1-(4-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[3-(Aminocarbonyl)phenylmethyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[(2-Chlorooquinolin-3-yl)methyl)]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[(Quinolin-3-yl)methyl)]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[(Quinolin-4-yl)methyl)]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[(Quinolin-2-yl)methyl)]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[1-(Quinolin-4-yl)ethyl)]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[Quinolin-2-ylcarbony,]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[2-Phenylquinolin-4-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[4-Methoxyquinolin-2-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[6-Methoxy-2-phenylquinolin-4-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[2-Piperidinoquinoin-4-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[2-Chloroquinolin-4-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-{(3S)-1-[1H-benzpyrazol-6-ylcarbonyl]pyrrolidin-3-yl}-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-N<2>-[(3S)-1-Benzylpyrrolidin-3-yl]-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide; (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-(1-benzyl-3-piperidinyl)-2-piperidinecarboxamide; (2S)-1-(1,3-Benzoxazol-2-yl)-N<2>-(3R,5S)-5-[(benzyloxy)methyl]pyrrolidin-3-yl-2-piperidinecarboxamide hydrochloride; and 1-(1H-1,3-Benzimidazol-2-yl)-N<2>-[(3S)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide. 19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 18 or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier. 20. The use of a compound as claimed in any one of claims 1 to 18 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of neuronal degeneration. 21. The use of a compound as claimed in any one of claims 1 to 18 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the promotion of neuronal regeneration and outgrowth. 22. The use of a compound as claimed in any one of claims 1 to 18 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a neurological disease or disorder such as a neurodegenerative disease. 23. The use as claimed in claim 22 where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e. g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dy