Nova Patents
EP0702012A1

Substituted isoxazole sulfonamides and their use as endothelin antagonists

Abstract

Compounds of the formula inhibit the activity of endothelin. The symbols are defined as follows:    R¹, R², R³ and R⁴ are each directly bonded to a ring carbon and are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³;(c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -Z⁴-NR⁶R⁷;(j) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹; or(k) R³ and R⁴ together may also be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; and the remaining symbols are as defined in the specification.

EP0702012A1, drawing sheet 1
Sheet 1 of 80

Term

Term ended

Projected expiry passed 25 August 2015, 11.1 years ago.

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  3. Published
  4. Projected expiry
  5. Today

33 claims: 3 independent, 30 dependent

  1. 1
    A compound of the formula or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof,    wherein:one of X and Y is N and the other is O;R¹, R², R³ and R⁴ are each directly bonded to a ring carbon and are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³ ;(c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -Z⁴-NR⁶R⁷;or (j) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;or (k) R³ and R⁴ together may also be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;R⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently (a) hydrogen;or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;or    R⁶ and R⁷ together may be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;or any two of R⁸, R⁹ and R¹⁰ together are alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;R¹¹, R¹², R¹³ and R¹⁴ are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³, (c) heterocycle, substituted heterocycle or heterocyclooxy;(d) halo;(e) hydroxyl;(f) cyano;(g) nitro;(h) -C(O)H or -C(O)R⁵;(i) -CO₂H or -CO₂R⁵;(j) -SH, -S(O) n R⁵, -S(O) m -OH, -S(O) m -OR⁵, -O-S(O) m -OR⁵, -O-S(O) m OH or -O-S(O) m -OR⁵;(k) -Z⁴-NR⁶R⁷;or (l) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;Z¹, Z² and Z³ are each independently (a) hydrogen;(b) halo;(c) hydroxy;(d) alkyl;(e) alkenyl;(f) aryl;(g) aralkyl;(h) alkoxy;(i) aryloxy;(j) aralkoxy;(k) heterocycle, substituted heterocycle or heterocyclooxy;(l) -SH, -S(O) n Z⁶, -S(O) m -OH, -S(O) m -OZ⁶, -O-S(O) m -Z⁶, -O-S(O) m OH or -O-S(O) m -OZ⁶;(m) oxo;(n) nitro;(o) cyano;(p) -C(O)H or -C(O)Z⁶;(q) -CO₂H or -CO₂Z⁶;(r) -Z⁴-NZ⁷Z⁸;(s) -Z⁴-N(Z¹¹)-Z⁵-H;(t) -Z⁴-N(Z¹¹)-Z⁵-Z⁶;or (u) -Z⁴-N(Z¹¹)-Z⁵-NZ⁷Z⁸;Z⁴ and Z⁵ are each independently (a) a single bond;(b) -Z⁹-S(O) n -Z¹⁰-;(c) -Z⁹-C(O)-Z¹⁰-;(d) -Z⁹-C(S)-Z¹⁰-;(e) -Z⁹-O-Z¹⁰-;(f) -Z⁹-S-Z¹⁰-;(g) -Z⁹-O-C(O)-Z¹⁰-;or (h) -Z⁹-C(O)-O-Z¹⁰-;Z⁶ is alkyl, alkyl substituted with one, two or three halogens, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryl substituted with one, two or three halogens, aryl substituted with trihaloalkyl, or aralkyl;Z⁷ and Z⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z⁷ and Z⁸ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;Z⁹ and Z¹⁰ are each independently a single bond, alkylene, alkenylene or alkynylene;Z¹¹ is (a) hydrogen;or (b) alkyl, alkyl substituted with one, two, or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;or any two of Z⁷, Z⁸ and Z¹¹ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;J is O, S, N or NR¹⁵;K and L are N or C, provided that at least one of K or L is C;R¹⁵ is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;each m is independently 1 or 2;each n is independently 0, 1 or 2;and    p is 0 or an integer from 1 to 2.
  2. 2
    A compound of Claim 1, wherein R¹ and R² are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -CO₂R⁵ or -Z⁴-NR⁶R⁷.
  3. 3
    A compound of Claim 1, wherein R³ and R⁴ are each independently alkyl.
  4. 4
    A compound of Claim 1, wherein R¹¹ and R¹² are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  5. 5
    A compound of Claim 1, wherein R¹ and R² are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -CO₂R⁵ or -Z⁴-NR⁶R⁷;R³ and R⁴ are each independently alkyl;and R¹¹ and R¹² are each independently hydrogen, hydroxy, amino heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  6. 6
    A compound of Claim 1, wherein R¹ and R² are each independently hydrogen or lower alkyl.
  7. 7
    A compound of Claim 1, wherein R³ and R⁴ are each independently alkyl of 1 to 4 carbon atoms.
  8. 8
    A compound of Claim 1, wherein R³ and R⁴ are each methyl.
  9. 9
    A compound of Claim 1, wherein R¹¹ and R¹² are each independently hydrogen, hydroxy, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  10. 10
    A compound of Claim 1, wherein R¹ and R² are each independently hydrogen or lower alkyl;R³ and R⁴ are each independently alkyl of 1 to 4 carbon atoms;and R¹¹ and R¹² are each independently hydrogen, hydroxy, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  11. 11
    A compound of Claim 1, wherein R¹ and R² are each independently hydrogen or lower alkyl;R³ and R⁴ are each methyl;and R¹¹ and R¹² are each independently hydrogen, hydroxy, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  12. 12
    A compound of Claim 1, wherein p is 0.
  13. 13
    A compound of Claim 1, wherein p is 1.
  14. 14
    A compound of Claim 1, wherein p is 0;R¹ and R² are each independently hydrogen or lower alkyl;R³ and R⁴ are each methyl;and R¹¹ and R¹² are each indepenently hydrogen, hydroxy, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  15. 15
    A compound of Claim 1, wherein p is 1;R¹ and R² are each independently hydrogen or lower alkyl;R³ and R⁴ are each methyl;and R¹¹ and R¹² are each independently hydrogen, hydroxy, heterocyclo, alkenyl, carboxamide or substituted lower alkyl.
  16. 16
    A compound of Claim 1, selected from the group consisting of:2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-carboxylic acid methyl ester;N-(3,4-Dimethyl-5-isoxazolyl)-2'-(1-hydroxy-1-methylethyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2-methylpropanamide;N-[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2,2-trifluoroacetamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(methylamino)carbonyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2',4'-bis(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;(Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;(E)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;4-Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]phenylacetamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,2,2-trimethylpropanamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylbenzamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-oxazolyl-5-yl-4'-oxazol-2-yl-[1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylcyclopropanamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2-dimethyl-N-(1-methylethyl)propanamide;N-Cyclopropyl-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2-dimethylpropanamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2-dimethyl-N-(2,2,2-trifluoroethyl)propanamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1-methylethyl)-5-oxazolyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-oxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1-methylethyl)-4-oxazolyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-oxazolylmethyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[5-(1-methylethyl)-2-oxazolyl]methyl][1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[4-(1-methylethyl)-2-oxazolyl]methyl][1,1'-biphenyl]-2-sulfonamide;(E)-N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-methyl-2-pentenyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;(Z)-N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-methyl-2-pentenyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-methylpentyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;trans-N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[2-(1-methylethyl)cyclopropyl]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;cis-N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[2-(1-methylethyl)cyclopropyl]methyl]-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1':2',1''-terphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-3''-(1-methylethyl)-4'-(2-oxazolyl)[1,1':2',1''-terphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4''-(1-methylethyl)-4'-(2-oxazolyl)[1,1':2',1''-terphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(2-methylpropoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1-methylethoxy)ethyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;and    N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-[(1-methylethyl)sulfonyl]ethyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.
  17. 17
    A compound of Claim 1, selected from the group consisting of:N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-thiazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4,5-dimethyl-2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-methyl-4-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4-methyl-2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-methyl-2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1 H -pyrazol1-yl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-[1-[(2-methoxyethoxy)methyl]-1 H -imidazol-2-yl][1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-[1-[(2-hydroxyethoxy)methyl]-1 H -imidazol-2-yl][1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1-methyl-1 H -imidazol-2-yl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1 H -imidazol-2-yl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-methyl-4-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1H-imidazol-1-ylmethyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(3-isoxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolylmethyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-isoxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-hydroxy-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;2-[2'-[[(3,4-Dimethyl-5-isoxazoly)amino]sulfonyl][1,1'-biphenyl]-4-yl]-4-oxazolecarboxamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(formylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(methoxycarbonyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-methylurea;N-(3,4-Dimethyl-5-isoxazolyl)-2'[[(methylsulfonyl)amino]methyl)-4'-(2-oxazolyl)-1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]acetamide;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-phenylurea;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]-sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-propylurea;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylacetamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]benzamide;and    N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2-dimethylpropanamide.
  18. 18
    A compound of Claim 1, selected from the group consisting of:N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-thiazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1 H -pyrazol-1-yl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1-methyl-1 H -imidazol-2-yl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-hydroxy-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;2-[2'-[[(3,4-Dimethyl-5-isoxazoly)amino]sulfonyl][1,1'-biphenyl]-4-yl]-4-oxazolecarboxamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(formylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(methoxycarbonyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-methylurea;N-(3,4-Dimethyl-5-isoxazolyl)-2'[[(methylsulfonyl)amino]methyl]-4'-(2-oxazolyl)-1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]acetamide;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-phenylurea;N-[[2'-[[3,4-Dimethyl-5-isoxazolyl)amino]-sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]N'-propylurea;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylacetamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]benzamide;and    N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2-dimethylpropanamide.
  19. 19
    A compound of Claim 1, selected from the group consisting of;2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-carboxylic acid methyl ester;N-(3,4-Dimethyl-5-isoxazolyl)-2'-(1-hydroxy-1-methylethyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2-methylpropanamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2,2-trifluoroacetamide;N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(methylamino)carbonyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;N-(3,4-Dimethyl-5-isoxazolyl)-2',4'-bis(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;(Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;(E)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;4-Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)a mino]sulfonyl]-4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]phenylacetamide;N-[[2'-[[(3,4-Dimethyl-5-izoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,2,2-trimethylpropanamide;N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylbenzamide;and    N-(3,4-Dimethyl-5-isoxazolyl)-2'-oxazolyl-5-yl-4'-oxazol-2-yl-[1,1'-biphenyl]-2-sulfonamide.
  20. 25
    Use of a compound of Claim 1, for manufacturing a medicament for treating ischemia.
  21. 32
    A compound of the formula or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof,    wherein:one of X and Y is N and the other is O;R¹, R², R³ and R⁴ are each directly bonded to a ring carbon and are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³;(c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -Z⁴-NR⁶R⁷;or (j) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;or (k) R³ and R⁴ together may also be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;R⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently (a) hydrogen;or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;or    R⁶ and R⁷ together may be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;or any two of R⁸, R⁹ and R¹⁰ together are alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;R¹¹, R¹², R¹³ and R¹⁴ are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³, (c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -SH, -S(O) n R⁵, -S(O) m -OH, -S(O) m -OR⁵, -O-S(O) m -OR⁵, -O-S(O) m OH or -O-S(O) m -OR⁵;(j) -Z⁴-NR⁶R⁷;or (k) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;Z¹, Z² and Z³ are each independently (a) hydrogen;(b) halo;(c) hydroxy;(d) alkyl;(e) alkenyl;(f) aralkyl;(g) alkoxy;(h) aryloxy;(i) aralkoxy;(j) -SH, S(O) n Z⁶, -S(O) m -OH, -S(O) m -OZ⁶, -O-S(O) m -Z⁶, -O-S(O) m OH or -O-S(O) m -OZ⁶;(k) oxo;(l) nitro;(m) cyano;(n) -C(O)H or -C(O)Z⁶;(o) -CO₂H or -CO₂Z⁶;(p) -Z⁴-NZ⁷Z⁸;(q) -Z⁴-N(Z¹¹)-Z⁵-H;(r) -Z⁴-N(Z¹¹)-Z⁵-Z⁶;or (s) -Z⁴-N(Z¹¹)-Z⁵-NZ⁷Z⁸;Z⁴ and Z⁵ are each independently (a) a single bond;(b) -Z⁹-S(O) n -Z¹⁰-;(c) -Z⁹-C(O)-Z¹⁰-;(d) -Z⁹-C(S)-Z¹⁰-;(e) -Z⁹-O-Z¹⁰-;(f) -Z⁹-S-Z¹⁰-;(g) -Z⁹-O-C(O)-Z¹⁰-;or (h) -Z⁹-C(O)-O-Z¹⁰-;Z⁶ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;Z⁷ and Z⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z⁷ and Z⁸ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;Z⁹ and Z¹⁰ are each independently a single bond, alkylene, alkenylene or alkynylene;Z¹¹ is (a) hydrogen;or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;or any two of Z⁷, Z⁸ and Z¹¹ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;J is O, S, N or NR¹⁵;K and L are N or C, provided that at least one of K or L is C;R¹⁵ is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;each m is independently 1 or 2;each n is independently 0, 1 or 2;and    p is 0 or an integer from 1 to 2.
  22. 33
    A compound of the formula or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof,    wherein:one of X and Y is N and the other is O;R¹, R², R³ and R⁴ are each directly bonded to a ring carbon and are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³;(c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -Z⁴-NR⁶R⁷;or (j) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;or (k) R³ and R⁴ together may also be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;R⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently (a) hydrogen;or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³;or    R⁶ and R⁷ together may be alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;or any two of R⁸, R⁹ and R¹⁰ together are alkylene or alkenylene, either of which may be substituted with Z¹, Z² and Z³, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;R¹¹, R¹², R¹³ and R¹⁴ are each independently (a) hydrogen;(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z¹, Z² and Z³, (c) halo;(d) hydroxyl;(e) cyano;(f) nitro;(g) -C(O)H or -C(O)R⁵;(h) -CO₂H or -CO₂R⁵;(i) -SH, -S(O) n R⁵, -S(O) m -OH, -S(O) m -OR⁵, -O-S(O) m -OR⁵, -O-S(O) m OH or -O-S(O) m -OR⁵;(j) -Z⁴-NR⁶R⁷;or (k) -Z⁴-N(R¹⁰)-Z⁵-NR⁸R⁹;Z¹, Z² and Z³ are each independently (a) hydrogen;(b) halo;(c) hydroxy;(d) alkyl;(e) alkenyl;(f) aralkyl;(g) alkoxy;(h) aryloxy;(i) aralykoxy;(j) -SH, -S(O) n Z⁶, -S(O) m -OH, -S(O) m -OZ⁶, -O-S(O) m -Z⁶, -O-S(O) m OH or -O-S(O) m -OZ⁶;(k) oxo;(l) nitro;(m) cyano;(n) -C(O)H or -C(O)Z⁶;(o) -CO₂H or -CO₂Z⁶;(p) -Z⁴-NZ⁷Z⁸;(q) -Z⁴-N(Z¹¹)-Z⁵-Z⁶;or (r) -Z⁴-N(Z¹¹)-Z⁵-NZ⁷Z⁸;Z⁴ and Z⁵ are each independently (a) a single bond;(b) -Z⁹-S(O) n -Z¹⁰-;(c) -Z⁹-C(O)-Z¹⁰-;(d) -Z⁹-C(S)-Z¹⁰-;(e) -Z⁹-O-Z¹⁰-;(f) -Z⁹-S-Z¹⁰-;or (g) -Z⁹-O-C(O)-Z¹⁰-;(h) -Z⁹-C(O)-O-Z¹⁰-;Z⁶ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;Z⁷ and Z⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z⁷ and Z⁸ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;Z⁹ and Z¹⁰ are each independently a single bond, alkylene, alkenylene or alkynylene;Z¹¹ is (a) hydrogen;or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;or any two of Z⁷, Z⁸ and Z¹¹ together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;J is O, S, N or NR¹⁵;K and L are N or C, provided that at least one of K or L is C;R¹⁵ is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;each m is independently 1 or 2;each n is independently 0, 1 or 2;and    p is 0 or an integer from 1 to 2.
Independent claims22