Renin inhibitors

A compound of formula I,

• or a pharmaceutically acceptable salt thereof,
• wherein:
• S is
• wherein the nitrogen atom in IIa and IIb above is attached to T;
• T is a bond;
• —(CH2)r;
• —(CH2)r-A-(CH2)s—;
• or —(CH2)r-A-(CH2)r—B—;
• A and B are independently selected from the group consisting of —O—, —S—, —S(O)— and —S(O)2—;
• r is the integer 2, 3, 4, or 5;
• s is the integer 0, 1, or 2;
• U is unsubstituted aryl;
• mono-, di-, tri- or tetra-substituted aryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, cyano and —CF3;
• or mono-, di-, or tri-substituted heteroaryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, cyano and —CF3;
• V is selected from the group consisting of:
• hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, cyano and C1-C5 alkoxy,
• wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and alkoxy are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of:
• halogen, C1-C5 alkyl, C2-C5 alkenyl, cyano and C1-C5 alkoxy, wherein each of the foregoing alkyl, alkenyl and alkoxy substituents is optionally substituted with 1-3 halogens;
• Q and R1 are independently selected from the group consisting of:
• hydrogen, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, C2-C5 alkenyl, C3-C8 cycloalkenyl, C2-C5 alkynyl, cyano and C1-C5 alkoxy, aryl and heteroaryl;
• wherein said aryl and heteroaryl are optionally substituted with 1-4 halogens,
• wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and alkoxy are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of:
• halogen, C1-C5 alkyl, C2-C5 alkenyl, cyano and C1-C5 alkoxy, wherein each of the foregoing alkyl, alkenyl and alkoxy substituents is optionally substituted with 1-3 halogens;
• W is cyclopropyl, unsubstituted or mono-, di-, tri-, tetra- or penta-substituted with halogen;
• X is selected from the group consisting of:
• OR2, R2, —(C1-C5 alkylene)-(O)0-1-aryl and —(C1-C5 alkylene)-(O)0-1-heteroaryl,
• wherein R2 is selected from the group consisting of:
• hydrogen, C1-C5 alkyl, C3-C8 cycloalkyl, C2-C5 alkenyl, C3-C8 cycloalkenyl, C2-C5 alkynyl, C1-C5-cyano, —(C1-C5 alkylene)-O—R3, —(C1-C5 alkylene)-N(—R3)—C(═O)—(C1-C5 alkyl), —(C1-C5 alkylene)-C(═O)—N(—R3)—(C1-C5 alkyl), —(C1-C5 alkylene)-N(—R3)—C(═O)—O—(C1-C5 alkyl), —(C1-C5 alkylene)-O—C(═O)—N(—R3)—(C1-C5 alkyl), —(C1-C5 alkylene)-N(—R3)—(C1-C5 alkyl), —(C1-C5 alkylene)-S—(C1-C5 alkyl), —(C1-C5 alkylene)-S(═O)—(C1-C5 alkyl) and —(C1-C5 alkylene)-S(═O)2—(C1-C5 alkyl),
• wherein R2, except hydrogen, is optionally substituted with 1-3 substituents, independently selected from the group consisting of:
• halogen, C(═O)OH, C1-C5 alkyl, C2-C5 alkenyl, and C1-C5 alkoxy, wherein each of the alkyl, alkenyl, and alkoxy substituents is optionally substituted with 1-3 halogens,
• wherein the heteroaryl of the —(C1-C5 alkylene)-(O)0-1-heteroaryl contains 1-3 heteroatoms, independently selected from the group consisting of:
• N, O and S, wherein each N is optionally in the form of an oxide and each S is optionally in the form of an oxide selected from the group consisting of:
• S(═O) and S(═O)2,
• wherein the aryl and heteroaryl of —(C1-C5 alkylene)-(O)0-1-aryl and —(C1-C5 alkylene)-(O)0-1-heteroaryl, respectively, are optionally substituted with 1-4 halogens, and
• wherein R3 is selected from the group consisting of:
• hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, and C2-C6 alkynyl, wherein each of the foregoing alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally substituted with 1-3 halogens;
• Z is C1-C2 alkylene optionally substituted with 1-2 substituents, independently selected from the group consisting of:
• halogen, C1-C3 alkyl and C3 cycloalkyl, wherein the foregoing alkyl and cycloalkyl substituents are optionally substituted with 1-3 halogens;
• n1 is 0 or 1;
• Y is (i) a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic monocyclic ring (“monocyclic ring”) or (ii) a fused ring system which is a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring which is fused to a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring (“fused ring”),
• wherein the heterocyclic ring(s) of (i) or (ii) contain from 1-3 heteroatoms, independently selected from N, O and S, wherein each N is optionally in the form of an oxide and each S is optionally in the form of an oxide selected from the group consisting of:
• S(═O) and S(═O)2,
• wherein the heterocyclic or carbocyclic ring(s) of (i) or (ii) is optionally mono-, di-, tri-, tetra-, penta- or hexa-substituted, each substituent of which is independently selected from the group consisting of:
• (1) halogen,
• (2) —OH,
• (3) —NH(R4),
• (4) oxo,
• (5) —C(═O)—R4,
• (6) —O—C(═O)—R4,
• (7) C1-C5 alkyl optionally substituted with 1-3 halogens,
• (8) C3-C8 cycloalkyl optionally substituted with 1-3 halogens,
• (9) C2-C5 alkenyl optionally substituted with 1-3 halogens,
• (10) C3-C8 cycloalkenyl optionally substituted with 1-3 halogens,
• (11) C2-C5 alkynyl optionally substituted with 1-3 halogens,
• (12) C1-C5 alkoxy optionally substituted with 1-3 halogens,
• (13) cyano,
• (14) C1-C5-cyano optionally substituted with 1-3 halogens,
• (15) —OCF3,
• (16) —C(R5)3,
• (17) —(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (18) —N(R4)—(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (19) —O—(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (20) —S—(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (21) —S(═O)—(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (22) —S(═O)2—(C1-C5 alkylene)-OR6 optionally substituted with 1-3 halogens,
• (23) —(C1-C5 alkylene)-N(R4)—C(═O)—(C1-C5 alkylene)-R6 optionally substituted with 1-3 halogens,
• (24) —(C1-C5 alkylene)-N(R4)—C(═O)—OR6 optionally substituted with 1-3 halogens,
• (25) —(C1-C5 alkylene)-N(R4)(R6) optionally substituted with 1-3 halogens,
• (26) —O—(C1-C5 alkylene)-C(R4)2—C(═O)OR6 optionally substituted with 1-3 halogens,
• (27) —(C1-C5 alkylene)-C(R4)2—C(═O)—OR6 optionally substituted with 1-3 halogens,
• (28) —O—(C1-C5 alkylene)-morpholine optionally substituted with 1-3 halogens,
• (29) —OC(═O)-morpholine,
• (30) —SR6,
• (31) —S(═O)—R6,
• (32) —S(═O)2—R6
• (33) —N(R4)(R6),
• (34) —(C1-C5 alkylene)-C(R4)2—(R6) optionally substituted with 1-3 halogens,
• (35) —(R7)0-1R8,
• (36) C2-C5 alkenyl-OR6 optionally substituted with 1-3 halogens,
• (37) C2-C5 alkynyl-OR6 optionally substituted with 1-3 halogens,
• (38) —(C1-C5 alkylene)-C(═O)—(C1-C5 alkylene)-R6 optionally substituted with 1-3 halogens,
• (39) —(C1-C5 alkylene)-O—C(═O)—(C1-C5 alkylene)-R6 optionally substituted with 1-3 halogens,
• (40) —(C1-C5 alkylene)-C(═O)—N(R4)(R6) optionally substituted with 1-3 halogens,
• (41) —(C1-C5 alkylene)-O—C(═O)—N(R4)(R6) optionally substituted with 1-3 halogens,
• (42) —(C1-C5 alkylene)-SR6 optionally substituted with 1-3 halogens,
• (43) —(C1-C5 alkylene)-S(═O)—R6 optionally substituted with 1-3 halogens, and
• (44) —(C1-C5 alkylene)-S(═O)2—R6 optionally substituted with 1-3 halogens,
• wherein R4 is selected from the group consisting of:
• hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloakenyl and C2-C6 alkynyl, wherein each of the foregoing alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally substituted with 1-3 halogens,
• wherein R5 is halogen,
• wherein R6 is selected from the group consisting of:
• hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl and C2-C6 alkynyl, wherein each of the foregoing alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynl substituents is optionally substituted with 1-3 halogens,
• wherein R7 is selected from the group consisting of:
• —C(H)(OH)—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—, —OC(═O)O—, C1-C5 alkylene, C2-C5 alkenylene, —N(R4)—, —S—, —S(═O)—, —S(═O)2—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —OC(═O)—N(R4)—, —N(R4)—C(═O)O—, —N(R4)—S(═O)2—, and —S(═O)2—N(R4)—, wherein each of the foregoing alkylene and alkenylene substituents is optionally substituted with 1-3 halogens, and wherein R4 is defined above, and
• wherein R8 is a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring which is optionally mono-, di-, tri-, tetra- or penta-substituted, wherein each substituent is independently selected from the group consisting of:
• halogen, —OH, —SR4, —N(R4)(R6), C1-C5 alkyl, C3-C8 cycloalkyl, C2-C5 alkenyl, C3-C6 cycloalkenyl, C2-C5 alkynyl, C1-C5 alkoxy, cyano and C1-C5-cyano, wherein said heterocyclic ring contains from 1 to 3 heteroatoms, independently selected from N, O and S, wherein each N is optionally in the form of an oxide and each S is optionally is in the form of an oxide selected from the group consisting of:
• S(═O)and S(═O)2, and wherein R4 and R6 are defined above.