Substituted 8-heteroaryl xanthines

A compound of formula I:

• wherein:
• R is H, (C1-C5)alkyl, halo(C1-C8)alkyl, (C3-C5)alkenyl, or (C3-C5)alkynyl;
• R1 and R2 are independently H, (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C4-C10)heterocycle, (C4-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, or (C5-C10)heteroaryl(C1-C8)alkyl-;
• X is selected from:
• imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyrimidinyl, indolyl, isoquinolyl, and quinolyl;
• Z is —OR3, —SR3, halo, —S(O)m—NR4R5, —NR4R5, or (C4-C10)heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —ORa, —SRa, (C1-C8)alkyl, (C6-C10)aryl, —O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, —NRbRc, —C(O)Ra, —COORa, and —C(O)NRbRc;
• each Z1 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, —OR6, —SR6, halo, R6O(C1-C8)alkyl, R7R8N(C1-C8)alkyl, halo(C1-C8)alkyl, —NR7R8, R7R8N(C1-C8)alkyl, —C(O)R6, —COOR6, and —C(O)NR7R8;
• R3 is (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, —C(O)R6, or —C(O)NR7R8;
• R4 and R5 are independently H, (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C6-C18)polycycloalkyl, (C6-C18)polycycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle, (C3-C10)heterocycle(C1-C8)alkyl-, —NR7R8, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, —((CH2)2-4)Y)q—(CH2)2-4—X1, —C(O)R6, —CO2R6, —C(O)NR7R8, or —S(O)2NR7R8;
• or R4 and R5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O)2—) and amine —N(R9)— in the ring, and wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —ORa, —SRa, (C6-C10)aryl, —O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, —NRbRc, —C(O)Ra, —COORa, and —C(O)NRbRc;
• X1 is —OR6, —C(O)R6, —CO2R6, or —NR7R8;
• and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O)2—) and amine —N(R9)—;
• wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocycle or heteroaryl groups of R1, R2, R3, R4 and R5 groups are optionally substituted with one or more substituents independently selected from halo, cyano, nitro, —ORa, —SRa, (C6-C10)aryl, —O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, —NRbRc, —C(O)Ra, —COORa, and —C(O)NRbRc;
• wherein R6 is H, (C1-C8)alkyl, RaO(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C10)heterocycle, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C4-C10)heteroaryl, (C4-C10)heteroaryl(C1-C8)alkyl-;
• wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —ORa, —SRa, (C6-C10)aryl, —O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, —NRbRc, —C(O)Ra, —COORa, and —C(O)NRbRc;
• wherein R7, R8 and R9 are independently H, (C1-C8)alkyl, RaO(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C10)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C4-C10)heteroaryl;
• —COORa, —C(O)Ra, or —C(O)NRbRc wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —ORa, —SRa, (C6-C10)aryl, —O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halo(C1-C8)alkyl, —NRbRc, —C(O)Ra, —COORa, and —C(O)NRbRc;
• or R7 and R8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O)2—) or amine —N(Rb)— in the ring;
• Ra is H, or (C1-C6)alkyl;
• Rb and Rc are each independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C1-C6)alkylthio, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl-, heteroaryl, or heteroaryl(C1-C6)alkyl-;
• or Rb and Rc together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring;
• and
• where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
• m is 1, or 2;
• and q is 1, 2, 3, or 4;
• or
• a pharmaceutically acceptable salt thereof.