Sulfonamide lactam inhibitors of FXa and method

A compound of formula II

• or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrugs thereof, wherein
• Y and Ya are independently a bond, alkyl, alkenyl or alkynyl;
• X and Xa are independently
• —(CH2)m—
• where m is an integer between 1 and 3 and where each methylene group of X may be optionally substituted with oxo, or mono- or di-substituted with lower alkyl or aryl;
• Q is a group B
• where
• (1) n, p, q and r are each independently 0 to 2, provided that at least one of n, p, q and r is other than zero;
• (2) X1 is CR14R15—, or —NR14—;
• (3) the group B ring system optionally contains one or more double bonds where valence allows;
• and
• (4) optionally fused to the group B ring system is an optionally substituted cycloalkyl ring, an optionally substituted cycloheteroalkyl ring, an optionally substituted heteroaryl ring, or an optionally substituted aryl ring;
• R1 and R1a are independently aryl, heteroaryl, cycloalkyl or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1, Z2 or Z3;
• R2, R2a, R3 and R3a are independently selected from
• (1) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl any of which may be optionally substituted with one or more groups Z1a, Z2aor Z3a;
• or
• (2) —C(O)tH, or C(O)tZ6;
• or
• (3) —Z4—NZ7Z8;
• R4, R4a, R4b, R4c, R5, R5a, R5b and R5c are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy,
• any of which may be optionally substituted with one or more groups Z1b, Z2b or Z3b;
• R6 and R6a are independently selected from hydrogen, alkyl, alkenyl, alkyyl, cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1c, Z2c or Z3c;
• Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.
• R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a bond;
• R10 is H, Z1f, —Y2—R11, —Y2—N(R11)(Z4—Z9a), —Y2—OR11, —Y2—C(O)R11, —Y2—C(O)OR11, —Y2—OC(O)R11, —Y2N(Z4—Z9a)—C(O)R11, —Y2—N(Z4—Z9a)—C(O)OR11, —Y2—S(O)tR11 where t is 0 to 2, or —Y2—R12;
• Y2 is —(CH2)u—, —O—(CH2)u, —C(O)—(CH2)u, —C(O)O—(CH2)u—, —OC(O)—(CH2)u— where u is 0 to 3;
• R11 when present combines with R9 to form a bond;
• R12 is
• R13 is H, Z2f,
• R14 is H, Z3f or a group D
• or R13 and R14 combine to form ═O or ═S;
• Z1, Z1a, Z1b, Z1c, Z1d, Z1e, Z1f, Z2, Z2a, Z2b, Z2c, Z2d, Z2e, Z2f , Z3, Z3a, Z3b, Z3c, Z3d, Z3e, Z3f, Z13 and Z14 are each independently
• (1) hydrogen or Z6, where Z6 is
• (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl;
• (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
• or
• (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z1 through Z3f,
• (2) —OH or OZ6,
• (3) —SH or —SZ6,
• (4) —C(O)tH, —C(O)tZ6, or —O—C(O)—Z6,
• (5) —SO3H, —S(O)tZ6, or S(O)tN(Z9)Z6,
• (6) halo,
• (7) cyano,
• (8) nitro,
• (9) —Z4—NZ7Z8,
• (10) —Z4—N(Z9)—Z5—NZ7Z8,
• (11) —Z4—N(Z10)—Z5—Z6,
• (12) —Z4—N(Z10)—Z5—H,
• (13) oxo,
• Z4 and Z5 are each independently
• (1) a single bond,
• (2) —Z11—S(O)t—Z12—,
• (3) —Z11—C(O)—Z12—,
• (4) —Z11—C(S)—Z12—,
• (5) —Z11—O—Z12—,
• (6) —Z11—S—Z12,
• (7) —Z11—O—C(O)—Z12,
• (8) —Z11—C(O)—O—Z12,
• (9) —Z11—C(═NZ9a)—Z12—, or
• (10) —Z11—C(O)—C(O)—Z12—
• Z7, Z8, Z9, Z9a and Z10
• (1) are each independently hydrogen or a group provided in the definition of Z6,
• (2) Z7 and Z8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defmtion of Z1 through Z3,
• (3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the definition of Z1 through Z3, or
• (4) Z7 and Z8 or Z9 and Z10 together with the nitrogen atom to which they are attached may combine to form a group —N═CZ13Z14;
• Z11 and Z12 are each independently
• (1) a single bond,
• (2) alkylene,
• (3) alkenylene, or
• (4) alkynylene.