Patent EA-002146-B1 (EA)
Title: Heteroaryl-hexanoicacid amide derivatives, their preparation and their use as selective inhibitors of mip-1-alfa binding to its ccr1 receptor
Inventor: BROWN MATTHEW FRANK
IPC: C07D307/84
Filed: 1998-02-05
Abstract: 1. A compound of the formula     wherein R<1> is (C2-C9)heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, (C1-C6)alkoxy, phenyl, (C2-C9)heteroaryl. R<2> is phenyl-(CH2)m-, naphthyl-(CH2)m-, (C3-C10)cycloalkyl-(CH2)m-, (C1-C6)alkyl or (C2-C9)heteroaryl-(CH2)m-, wherein m is an integer from zero to two; wherein each of said phenyl or (C3-C10)cycloalkyl moieties of said phenyl-(CH2)m-, (C3-C10)cycloalkyl-(CH2)m- may optionally be substituted with one or more substituents independently selected from hydrogen, halo, hydroxy, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkyl-O-(C=O)-, (C1-C6)alkyl-NH-(C=O)-, CF3SO3-, phenyl, benzyloxy; R<3> is hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)n-, (C2-C9)heterocycloalkyl-(CH2)n-, (C2-C9)heteroaryl-(CH2)n- or aryl-(CH2)n-; wherein n is an interger from zero to three; wherein said R<3> (C1-C10)alkyl group may optionally be substituted with one or more substituents, independently selected from hydrogen, halo, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, (C1-C6)alkoxy, phenyl; wherein the (C3-C10)cycloalkyl moiety of said R<3> (C3-C10)cycloalkyl-(CH2)n- group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, hydroxy; wherein the (C2-C9)heterocycloalkyl moiety of said R<3> (C2-C9)heterocycloalkyl- (CH2)n- group may contain from one to three heteroatoms independently selected from sulfur, oxygen, >SO2 wherein said (C2-C9)heterocycloalkyl moiety of said (C2-C9)heterocycloalkyl-(CH2)n- group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with hydroxy; wherein said aryl moiety of said R<3> aryl-(CH2)n- group is optionally substituted with phenyl, wherein said phenyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms; or R<3> and the carbon to which it is attached form a five-membered carbocyclic ring, wherein one of the carbon-carbon bonds of said five-membered carbocyclic ring is condensed with phenyl ring; R<4> is hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C3-C10)cycloalkyl-(CH2)p-, (C2-C9)-heterocycloalkyl-(CH2)p-, (C2-C9)heteroaryl-(CH2)p-, phenyl-(CH2)p-, wherein p is an integer from zero to two; wherein said (C2-C9)heteroaryl and phenyl groups of said (C2-C9)heteroaryl-(CH2)p-, or phenyl-(CH2)p- may be optionally substituted on any of the ring atoms capable of supporting an additional bond with a substituent selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkyl-SO2-; or R<4> and R<5> together with the nitrogen atom to which they are attached form a (C2-C9)heterocycloalkyl group wherein any of the ring atoms of said (C2-C9)heterocycloalkyl group may optionally be substituted with a substituent selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy-(C1-C6)alkyl; R<5> is hydrogen, (C1-C6)alkyl or amino; with the proviso that when either R<4> or R<5> is hydrogen, and the other of R<4> or R<5> is (C1-C6)alkyl, R<2> is (C3-C10)cycloalkyl or isopropyl and R<3> is (C3-C5)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy(C1-C3)alkyl or amino(C1-C4)alkyl then R<1> must be other than indol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, or optionally substituted indol-2 or 3-yl; and the pharmaceutically acceptable salts of such compounds. 2. A compound according to Claim 1, wherein said compound of formula I has the exact stereochemistry depicted in formula   wherein R<1>, R<2>, R<3>, R<4> and R<5> are as described in Claim 1. 3. A compound according to Claim 1, wherein R<1> is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyridinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalinyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl. 4. A compound according to Claim 2, wherein R<1> is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyridinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalinyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl. 5. A compound according to Claim 1, wherein R<1> is optionally substituted pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl. 6. A compound according to Claim 2, wherein R<1> is optionally substituted pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[l]pyridin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl. 7. A compound according to Claim 1, wherein R<1> is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl. 8. A compound according to Claim 2, wherein R<1> is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl. 9. A compound according to Claim 1, wherein R<2> is optionally substituted benzyl. 10. A compound according to Claim 2, wherein R<2> is optionally substituted benzyl. 11. A compound according to Claim 3, wherein R<2> is optionally substituted benzyl. 12. A compound according to Claim 4, wherein R<2> is optionally substituted benzyl. 13. A compound according to Claim 5, wherein R<2> is optionally substituted benzyl. 14. A compound according to Claim 6, wherein R<2> is optionally substituted benzyl. 15. A compound according to Claim 7, wherein R<2> is optionally substituted benzyl. 16. A compound according to Claim 8, wherein R<2> is optionally substituted benzyl. 17. A compound according to Claim 1, wherein R<3> is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n-. 18. A compound according to Claim 2, wherein R<3> is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n- 19. A compound according to Claim 6, wherein R<3> is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n- 20. A compound according to Claim 8, wherein R<3> is optionally substituted (C1-C10)alkyl or (C3-C10)cycloalkyl-(CH2)n- 21. A compound according to Claim 1, wherein R<3> is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methyl-butyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methyl-cyclohexyl, or cyclohexyl-methyl. 22. A compound according to Claim 2, wherein R<3> is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methyl-butyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methyl-cyclohexyl, or cyclohexyl-methyl. 23. A compound according to Claim 6, wherein R<3> is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methyl-butyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methyl-cyclohexyl, or cyclohexyl-methyl. 24. A compound according to Claim 8, wherein R<3> is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methyl-butyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methyl-cyclohexyl, or cyclohexyl-methyl. 25. A compound according to Claim 1, wherein R<3> is substituted by fluoro or hydroxy. 26. A compound according to Claim 2, wherein R<3> is substituted by fluoro or hydroxy. 27. A compound according to Claim 21 wherein R<3> is substituted by fluoro or hydroxy. 28. A compound according to Claim 22 wherein R<3> is substituted by fluoro or hydroxy. 29. A compound according to Claim 23 wherein R<3> is substituted by fluoro or hydroxy. 30. A compound according to Claim 24 wherein R<3> is substituted by fluoro or hydroxy. 31. A compound according to Claim 1, wherein R<3> is 4,4-difluorocyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or 1-hydroxy-cyclohexyl. 32. A compound according to Claim 2, wherein R<3> is 4,4-difluorocyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methyl-propyl, or 1-hydroxy-cyclohexyl. 33. A compound according to Claim 6, wherein R<3> is 4,4-difluorocyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methyl-propyl, or 1-hydroxy-cyclohexyl. 34. A compound according to Claim 8, wherein R<3> is 4,4-difluorocyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methyl-propyl, or 1-hydroxy-cyclohexyl. 35. A compound according to Claim 16, wherein R<3> is 4,4-difluorocyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methyl-propyl, or 1-hydroxy-cyclohexyl. 36. A compound according to Claim 1 wherein R<4> and R<5> are independently selected from hydrogen, hydroxy, amino, methyl, or ethyl. 37. A compound according to Claim 6 wherein R<4> and R<5> are independently selected from hydrogen, hydroxy, amino, methyl, or ethyl. 38. A compound according to Claim 8 wherein R<4> and R<5> are independently selected from hydrogen, hydroxy, amino, methyl, or ethyl. 39. A compound according to Claim 21 wherein