Tissue factor antagonists and methods of use thereof

A method for treating a mammal susceptible to or suffering from a cardiovascular disease, a blood coagulation disorder, a cell proliferation disorder, an immune disorder, atheroselerosis, inflammation or cancer comprising administering to the mammal an effective amount of a compound or pharmaceutically acceptable salt thereof of the following Formulae I, II, III, IIIA, IV, IVA, V, VI, VIa, VII, VIII, IX, IXa, IXb, IXc, IXd, X, XI, XII or XIII:

• Ar—(CXY)m—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p I
• Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
• Het is optionally substituted N, O or S;
• each T is independently an amido, thioamido, carboxy, sulfinyl, sulfonyl, sulfonic, or nitro group;
• each X, each Y, each X′, each Y′ and each Z are each independently hydrogen;
• halogen;
• hydroxyl;
• sulfhydryl;
• amino;
• optionally substituted alkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted alkoxy;
• optionally substituted alkylthio;
• optionally substituted alkylsulfinyl;
• optionally substituted alkylsulfonly;
• or optionally substituted alkylamino;
• m is an integer of from 0 to 4, and n is an integer of from 0 to 4;
• p is 1 or 2;
• wherein X, Y, Het, T, X′, Y′, Z, m, and p are the same as defined in Formula I above;
• wherein each R1 is independently halogen;
• amino;
• hydroxy;
• nitro;
• carboxy;
• sulfhydryl;
• optionally substituted;
• optionally substituted;
• optionally substituted alkynyl;
• optionally substituted;
• optionally substituted;
• optionally substituted;
• optionally substituted alkylsulfonyl;
• optionally substituted;
• optionally substituted;
• optionally substituted carbocyclic aryl;
• or optionally substituted aralkyl;
• q is an integer of from 0 to 5, or 3;
• wherein in each of Formula III and IV, T, R1, X, Y, X′, Y′, Z, q, m, n and p are the same as defined in Formulae I and II above;
• and W is hydrogen, optionally substituted alkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted alkoxy;
• optionally substituted alkylthio;
• optionally substituted alkylsulfinyl;
• optionally substituted alkylsulfonyl;
• optionally substituted alkylamino;
• optionally substituted alkanoyl;
• optionally substituted carbocyclic aryl;
• or optionally substituted aralkyl;
• wherein T, R1, X′, Y′, n and q are the same as defined in Formulae I and II above;
• (R2)2N—(CXY)m1—(Het)0 or 1—CX1Y1)n—C(Z)p—(T)3−p V
• wherein each of X, Y, Het, X′, Y′, Z, T, n, g, p are each the same as defined in Formula I above;
• each R2 is independently hydrogen alkyl, carbocyclic aryl;
• m1 is an integer of from 0 to 4;
• Ar1—(CXY)m2—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VI
• wherein each of X, Y, X′, Y′, Z, n and p is defined as in Formula I above and Ar1 represents a polycyclic aromatic group m2 is an integer of from 0 to 4;
• (R1)q1—Ar1—(CXY)m2—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VIa
• wherein R1 is the same as defined above in Formula II;
• and each of X, Y, X′, Y′, Z, g, n and p is defined as in Formula I above;
• m2 is the same as defined above in Formula VI;
• q1 is an integer from 0 to 7;
• B—(CXY)m3—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VII
• wherein B is an optionally substituted alicyclic or heteroalicyclic group;
• each of T, X, Y, X′, Y′, Z, n and p is defined as in Formula I above, m3 is an integer of from 0 to 4;
• (R1)q2—B—(CXY)m3—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VIIa
• wherein R1 is the same as defined above in Formula II, each of X, Y, X′, Y′, Z, g, n and p is defined as in Formula I above, m3 is the same as defined above in Formula VIII, and q2 is an integer from 0 to 10;
• In a more preferred embodiment of the Formula VIIa shown above, R1 is hydroxyl;
• B is cyclohexyl or cyclopentyl;
• m3 and n are each 0;
• g is 1;
• Het is nitrogen;
• Z is hydrogen;
• q2 is 1;
• p is 2;
• (T′)q3—D—(T″)q4 VIII
• wherein T′ and T″ are each the same or different and are the same as defined for T in Formula I above;
• D is an optionally substituted imide, optionally with a C1-6 alkylene linkage between D and either or both T′ or T″ groups;
• (V)—(C═O)—(Het)0 or 1—Ar—(R1)q5 IX
• wherein V is a heteroalicyclic or heteroaromatic group having from 1 to 3 separate or fused rings, 5 to about 8 atoms in each ring, and 1-3 N, O or S atoms in each ring;
• Ar, Het are each the same as defined above in Formula I;
• R1 is the same as defined above in Formula II;
• q5 is an integer from 0 to 5;
• wherein each of R3a, R3b, R3c and R3d is the same as the R1 group defined in Formula II above with the proviso that each of R3a, R3b, R3c and R3d can be the same or different;
• Het1 and Het2 are each independently N, O or S the same or different;
• each of Ar2a, Ar2b, Ar2c, and Ar2d is independently an optionally substituted carbocyclic aryl or optionally substituted heteroaryl group the same or different;
• V is the same as defined in Formula IX above;
• q6 is an integer from 0 to 5;
• q7 is the same as q6 with the proviso that q6+q7 is not greater than 5;
• q8 is an integer from 0 to 5;
• q9 is the same as q8 with the proviso that q7+q8 is not greater than 5;
• wherein R3e is the same as the R1 group defined in Formula II above, with the proviso that each of R3a, R3b, R3c, R3d and R3e is the same or different;
• q10 is an integer from 0 to 5;
• q11 and q12 are each independently the same as q10 defined above with the proviso that q10+q11+q12 is not be greater than 5;
• q13 is an integer from 0 to 5;
• q14 is the same as q13 defined above with the proviso that q13+q14 is not greater than 5;
• wherein R3f is the same as R1 as defined above in Formula II with the proviso that R3f can also be an optionally substituted cycloalkyl group having from about 5 to about 8 carbons, and R3f can be the same or different from each of R3a, R3b, and R3c as defined above;
• q7 is an integer from 0 to 5, with the proviso that q6+q7 in Formula IXc is not greater than 5;
• q15 is an integer from 0 to 2;
• m4 is an integer from 0 to 4;
• wherein each of (V2a) and (V2b) is independently the same as V defined above in Formula IXd with the proviso that each of (V2a) and (V2b) can be the same or different and with the proviso that both V2a and V2b are not both 0;
• m6 is an integer from 0 to 4;
• Ar3—(CXY)m7—(Het)0 or 1—(V) X
• wherein Ar3 is an optionally substituted carbocyclic aryl or heteroaryl group;
• each of X, Y, and Het is the same as defined above in Formula I with the proviso that X and Y can also join together to form a carbonyl group;
• m7 is an integer from 0 to 4;
• V is the same as defined above in Formula IXa;
• wherein R1, R2, R3, X and Y each may be independently the same as defined for R1 of Formula II above;
• or R1 and R2 of this Formula XI may be taken together to form a fused carbocyclic aryl, alicyclic, heteroalicyclic or heteroaromatic group having 1-3 fused or separate rings;
• Het is oxygen, optionally substituted N, S, S(O) or S(O)2;
• and X is an in integer of from 1 to 4;
• wherein each R1 is independently the same as defined for R1 of Formula II above;
• and x is an integer of from 1 to 10.

A compound of the following Formulae I, II, III, IIIA, IV, IVA, V, VI, VIa, VII, VIII, IX, IXa, IXb, IXc, IXd, X, XI, XII or XIII:

• Ar—(CXY)m—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p I
• Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
• Het is optionally substituted N, O or S;
• each T is independently an amido, thioamido, carboxy, sulfinyl, sulfonyl, sulfonic, or nitro group;
• each X, each Y, each X′, each Y′ and each Z are each independently hydrogen;
• halogen;
• hydroxyl;
• sulfhydryl;
• amino;
• optionally substituted alkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted alkoxy;
• optionally substituted alkylthio;
• optionally substituted alkylsulfinyl;
• optionally substituted alkylsulfonly;
• or optionally substituted alkylamino;
• m is an integer of from 0 to 4;
• n is an integer of from 0 to 4;
• p is 1 or 2;
• wherein X, Y, Het, T, X′, Y′, Z, m, and p are the same as defined in Formula I above;
• wherein each R1 is independently halogen;
• amino;
• hydroxy;
• nitro;
• carboxy;
• sulfhydryl;
• optionally substituted;
• optionally substituted;
• optionally substituted alkynyl;
• optionally substituted;
• optionally substituted;
• optionally substituted;
• optionally substituted alkylsulfonyl;
• optionally substituted;
• optionally substituted;
• optionally substituted carbocyclic aryl;
• or optionally substituted aralkyl;
• q is an integer of from 0 to 5, or 3;
• wherein in each of Formula III and IV, T, R1, X, Y, X′, Y′, Z, q, m, n and p are the same as defined in Formulae I and II above;
• and W is hydrogen, optionally substituted alkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted alkoxy;
• optionally substituted alkylthio;
• optionally substituted alkylsulfinyl;
• optionally substituted alkylsulfonyl;
• optionally substituted alkylamino;
• optionally substituted alkanoyl;
• optionally substituted carbocyclic aryl;
• or optionally substituted aralkyl;
• wherein T, R1, X′, Y′, n and q are the same as defined in Formulae I and II above;
• (R2)2N—(CXY)m1—(Het)0 or 1—CX1Y1)n—C(Z)p—(T)3−p V
• wherein each of X, Y, Het, X′, Y′, Z, T, n, g, p are each the same as defined in Formula I above;
• each R2 is independently hydrogen alkyl, carbocyclic aryl;
• m1 is an integer of from 0 to 4;
• Ar1—(CXY)m2—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VI
• wherein each of X, Y, X′, Y′, Z, n and p is defined as in Formula I above and Ar1 represents a polycyclic aromatic group m2 is an integer of from 0 to 4;
• (R1)q1—Ar1—(CXY)m2—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VIa
• wherein R1 is the same as defined above in Formula II;
• and each of X, Y, X′, Y′, Z, g, n and p is defined as in Formula I above;
• m2 is the same as defined above in Formula VI;
• q1 is an integer from 0 to 7;
• B—(CXY)m3—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VII
• wherein B is an optionally substituted alicyclic or heteroalicyclic group;
• each of T, X, Y, X′, Y′, Z, n and p is defined as in Formula I above, m3 is an integer of from 0 to 4;
• (R1)q2—B—(CXY)m3—(Het)0 or 1—(CX1Y1)n—C(Z)p—(T)3−p VIIa
• wherein R1 is the same as defined above in Formula II, each of X, Y, X′, Y′, Z, g, n and p is defined as in Formula I above, m3 is the same as defined above in Formula VIII, and q2 is an integer from 0 to 10;
• In a more preferred embodiment of the Formula VIIa shown above, R1 is hydroxyl;
• B is cyclohexyl or cyclopentyl;
• m3 and n are each 0;
• g is 1;
• Het is nitrogen;
• Z is hydrogen;
• q2 is 1;
• p is 2;
• (T′)q3—D—(T″)q4 VIII
• wherein T′ and T″ are each the same or different and are the same as defined for T in Formula I above;
• D is an optionally substituted imide, optionally with a C1-6 alkylene linkage between D and either or both T′ or T″ groups;
• (V)—(C═O)—(Het)0 or 1—Ar—(R1)q5 IX
• wherein V is a heteroalicyclic or heteroaromatic group having from 1 to 3 separate or fused rings, 5 to about 8 atoms in each ring, and 1-3 N, O or S atoms in each ring;
• Ar, Het are each the same as defined above in Formula I;
• R1 is the same as defined above in Formula II;
• q5 is an integer from 0 to 5;
• wherein each of R3a, R3b, R3c and R3d is the same as the R1 group defined in Formula II above with the proviso that each of R3a, R3b, R3c and R3d can be the same or different;
• Het1 and Het2 are each independently N, O or S the same or different;
• each of Ar2a, Ar2b, Ar2c, and Ar2d is independently an optionally substituted carbocyclic aryl or optionally substituted heteroaryl group the same or different;
• V is the same as defined in Formula IX above;
• q6 is an integer from 0 to 5;
• q7 is the same as q6 with the proviso that q6+q7 is not greater than 5;
• q8 is an integer from 0 to 5;
• q9 is the same as q8 with the proviso that q7+q8 is not greater than 5;
• wherein R3e is the same as the R1 group defined in Formula II above, with the proviso that each of R3a, R3b, R3c, R3d and R3e is the same or different;
• q10 is an integer from 0 to 5;
• q11 and q12 are each independently the same as q10 defined above with the proviso that q10+q11+q12 is not be greater than 5;
• q13 is an integer from 0 to 5;
• q14 is the same as q13 with the proviso that q13+q14 is not greater than 5;
• wherein R3f is the same as R1 as defined above in Formula II with the proviso that R3f can also be an optionally substituted cycloalkyl group having from about 5 to about 8 carbons, and R3f can be the same or different from each of R3a, R3b, and R3c as defined above;
• q7 is an integer from 0 to 5, with the proviso that q6+q7 in Formula IXc is not greater than 5;
• q15 is an integer from 0 to 2;
• m4 is an integer from 0 to 4;
• wherein each of (V2a) and (V2b) is independently the same as V defined above in Formula IXd with the proviso that each of (V2a) and (V2b) can be the same or different and with the proviso that both V2a and V2b are not both 0;
• m6 is an integer from 0 to 4;
• Ar3—(CXY)m7—(Het)0 or 1—(V) X
• wherein Ar3 is an optionally substituted carbocyclic aryl or heteroaryl group;
• each of X, Y, and Het is the same as defined above in Formula I with the proviso that X and Y can also join together to form a carbonyl group;
• m7 is an integer from 0 to 4;
• V is the same as defined above in Formula IXa;
• wherein R1, R2, R3, X and Y each may be independently the same as defined for R1 of Formula II above;
• or R1 and R2 of this Formula XI may be taken together to form a fused carbocyclic aryl, alicyclic or heteroalicyclic or heteroaromatic group having 1-3 fused or separate rings;
• Het is oxygen, optionally substituted N, S, S(O) or S(O)2;
• and X is an in integer of from 1 to 4;
• wherein each R1 is independently the same as defined for R1 of Formula II above;
• and x is an integer of from 1 to 10;
• or
• a pharmaceutically acceptable salt thereof.