Benzoxazinyl-amidocyclopentyl-heterocyclic modulators of chemokine receptors

A compound represented by formula I:

• or a pharmaceutically acceptable salt thereof, or an individual diastereomer thereof, wherein:
• X is C, N, O or S;
• Y is O, S, SO, SO2, or NR9;
• Z is C or N;
• R1 is hydrogen, —C0-6alkyl-W—(C1-6alkyl)-, —(C0-6alkyl)-W—(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), —(C0-6alkyl)-W-phenyl, or —(C0-6alkyl)-W-heterocycle, wherein the alkyl, phenyl, heterocycle and the cycloalkyl are optionally substituted with 1-7 substituents independently selected from halo, hydroxy, —O—C1-3alkyl, trifluoromethyl, C1-3alkyl, —O—C1-3alkyl, —CO2R10, —CN, —NR10R10, —NR10COR10, —NR10SO2R11, and —CONR10R10;
• W is a single bond, —O—, —S—, —SO—, —SO2—, —CO—, —CO2—, —CONR10— or —NR9—;
• R2 is -halo, —C0-6alkyl, C0-6alkyl-W—C1-6alkyl, C0-6alkyl-W—C3-7cycloalkyl, C0-6alkyl-W-phenyl, or C0-6alkyl-W-heterocycle, wherein the C1-6alkyl, C3-7cycloalkyl, phenyl and heterocycle optionally are independently substituted with 1-6 substituents independently selected from halo, trifluoromethyl, —CN, —C1-6alkyl and hydroxy;
• R3 is hydrogen, —(C0-6alkyl)-phenyl, —(C0-6alkyl)-heterocycle, —(C0-6alkyl)-C3-7cycloalkyl, —(C0-6alkyl)-CO2R10, —(C0-6alkyl)-(alkene)-CO2R10 (C0-6alkyl)-SO3H, —(C0-6alkyl)-W—C0-4alkyl, —(C0-6alkyl)-CONR10-phenyl, or —(C0-6alkyl)-CONR12—V—CO2R10, or R3 is absent when X is O, where C0-6alkyl is optionally substituted with 1-5 substituents independently selected from halo, hydroxy, —C0-6alkyl, —O—C1-3alkyl, trifluoromethyl, and —C0-2alkyl-phenyl, where phenyl, heterocycle, cycloalkyl, and C0-4alkyl are optionally substituted with 1-5 substituents independently selected from halo, trifluoromethyl, hydroxy, C1-3alkyl, —O—C1-3alkyl, —C0-3—CO2R10, —CN, —NR10R10, —CONR10R10, and —C0-3-heterocycle, or where phenyl and heterocycle may be fused to another heterocycle, which itself optionally may be substituted with 1-2 substituents independently selected from hydroxy, halo, —CO2R10, and —C1-3alkyl, and where alkene is optionally substituted with 1-3 substituents independently selected from halo, trifluoromethyl, C1-3alkyl, phenyl, and heterocycle;
• V is C1-6alkyl or phenyl;
• R12 is hydrogen or C1-4alkyl, or R12 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring;
• R4 is nothing when X is O or N or when a double bond joins the carbons to which R3 and R6 are attached, or R4 is hydroxy, C1-6alkyl, C1-6alkyl-hydroxy, —O—C1-3alkyl, —CO2R10, —CONR10R10, or —CN;
• or R3 and R4 join to form a 1H-indenyl, 2,3-dihydro-1H-indenyl, 2,3-dihydro-benzofuranyl, 1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzothiofuranyl, 1,3-dihydro-isobenzothiofuranyl, 6H-cyclopenta[d]isoxazol-3-olyl, cyclopentanyl, or cyclohexanyl ring, wherein the ring optionally is substituted with 1-5 substituents independently selected from halo, trifluoromethyl, hydroxy, C1-3alkyl, —O—C1-3alkyl, —C0-3-CO2R10, —CN, —NR10R10, —CONR10R10, and —CO-3-heterocyclyl;
• R5 and R6 are independently hydrogen, hydroxy, C1-6alkyl, C1-6alkyl-CO2R10, C1-6alkyl-hydroxy, —O—C1-3alkyl, or halo, or R5 or R6 is ═O connected to the ring via a double bond;
• or R3 and R5 or R4 and R6 join to form a phenyl or heterocyclyl ring, wherein the ring is optionally substituted with 1-7 substituents independently selected from halo, trifluoromethyl, hydroxy, C1-3alkyl, —O—C1-3alkyl, —CO2R10, —CN, —NR10R10 and —CONR10R10;
• when Z=C, R7 is hydrogen, hydroxy, halo or C1-6alkyl optionally substituted with 1-6 substituents independently selected from fluro, —O—C1-6alkyl optionally substituted with 1-6 fluro, —NR10R10, —NR10CO2R11, —NR10CONR10R10, —NR10—SO2—NR10R10, —NR10—SO2—R11, heterocycle, —CN, —CONR10R10, —CO2R10, —NO2, —S—R10, —SO—R11, —SO2—R11 and —SO2—NR11R11;
• when Z=N, R7 is nothing or oxide;
• R8 is hydrogen, C1-6alkyl, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, phenyl, alkoxy or cyano;
• R9 is SO2R11, COR10, CONHR10, CO2R11, or SO2NHR10;
• R10 is hydrogen, —C1-6 alkyl, benzyl, phenyl, or —C0-6 alkyl-C3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from halo, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
• R11 is C1-6alkyl, —C0-6alkyl-C3-6cycloalkyl, benzyl or phenyl, optionally substituted with 1-3 substituents independently selected from halo, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
• n1 and n2 are independently 0, 1 or 2, wherein the sum of n1 and n2 is 0, 1, 2, or 3;
• and
• the dashed line represents a single or a double bond.

A compound of Formula II:

• or pharmaceutically acceptable salts and individual diastereomers thereof, wherein:
• Y is O, S, SO, SO2, or NR9;
• R1 is hydrogen, —C0-6alkyl-W—(C1-6alkyl)-, —(C0-6alkyl)-W—(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), —(C0-6alkyl)-W-phenyl, or —(C0-6alkyl)-W-heterocycle, wherein the alkyl, phenyl, heterocycle and the cycloalkyl are optionally substituted with 1-7 substituents independently selected from halo, hydroxy, —O—C1-3alkyl, trifluoromethyl, C1-3alkyl, —O—C1-3alkyl, —CO2R10, —CN, —NR10R10, —NR10COR10, —NR10SO2R11, —CONR10R10;
• W is a single bond, —O—, —S—, —SO—, —SO2—, —CO—, —CO2—, —CONR10— or —NR9—;
• R2 is -halo, —C0-6alkyl, C0-6alkyl-W—C1-6alkyl, C0-6alkyl-W—C3-7cycloalkyl, C0-6alkyl-W-phenyl, or C0-6alkyl-W-heterocycle, wherein C1-6alkyl, C3-7cycloalkyl, phenyl and heterocycle optionally are independently substituted with 1-6 substituents independently selected from halo, trifluoromethyl, —CN, —C1-6alkyl and hydroxy;
• R5 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyl-CO2R10, C1-6alkyl-hydroxy, —O—C1-3alkyl, or halo, or R5 or R6 is ═O connected to the ring via a double bond;
• R7 is hydrogen, hydroxy, halo or C1-6alkyl optionally substituted with 1-6 substituents independently selected from fluro, —O—C1-6alkyl optionally substituted with 1-6 fluro, —NR10R10, —NR10CO2R11, —NR10CONR10R10, —NR10—SO2—NR10R10, —NR10—SO2—R11, heterocycle, —CN, —CONR10R10, —CO2R10, —NO2, —S—R10, —SO—R11, —SO2—R11, and —SO2—NR11R11;
• R8 is hydrogen, C1-6alkyl, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, or phenyl;
• R9 is SO2R11, COR10, CONHR10, CO2R11, or SO2NHR10;
• R10 is hydrogen, —C1-6 alkyl, benzyl, phenyl, or —C0-6 alkyl-C3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from halo, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
• R11 is C1-6alkyl, —C0-6alkyl-C3-6cycloalkyl, benzyl or phenyl, optionally substituted with 1-3 substituents independently selected from halo, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
• R13 and R14 are independently hydrogen, halo, trifluoromethyl, hydroxy, —C1-3alkyl, —O—C1-3alkyl, —C0-3—CO2H, —C0-3—CO2C1-3alkyl, —CN, or —C0-3-heterocycle, or R13 and R14 join to form a heterocycle fused to the phenyl ring, which heterocycle is optionally substituted with 1-2 substituents independently selected from hydroxy, halo, —CO2R10, or —C1-3alkyl;
• n is 0, 1, or 2.