Heterocyclic Amides Useful as Protein Modulators

Abstract

Disclosed are compounds having the formula:

##STR00001## wherein q, r, s, A, B, C, R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.C1, R.sup.C2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.14, R.sup.15, R.sup.16, and R.sup.17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

Claims

1. A compound according to Formula (I-N): ##STR00440## wherein: q is 0 or 1; r is 0 or 1; s is 0 or 1; wherein q+r+s=1 or 2; when q is 0, R.sup.A1 and R.sup.A2 are each independently H, halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —N(R.sup.e)(R.sup.f), —CO.sub.2R.sup.f, —N(R.sup.f)COR.sup.b, —N(R.sup.g)SO.sub.2(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —N(R.sup.g)CO(C.sub.1-C.sub.4alkyl)-N(R.sup.h)(R.sup.f), optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino-, and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino-, wherein the (C.sub.1-C.sub.6alkyl) of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino- and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, C.sub.1-C.sub.4alkoxy-, —N(R.sup.e)(R.sup.f), —CO.sub.2(R.sup.f), —CON(R.sup.e)(R.sup.f), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.6alkyl)amino-, (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)amino-, —(C.sub.1-C.sub.6alkyl)-NH.sub.2, halo(C.sub.1-C.sub.6alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, —C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkoxy) and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when r is 0, R.sup.B1 and R.sup.B2 are each independently H, optionally substituted C.sub.1-C.sub.6alkyl, halo(C.sub.1-C.sub.6alkyl), optionally substituted C.sub.2-C.sub.6alkenyl, optionally substituted C.sub.2-C.sub.6alkynyl, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl, wherein said optionally substituted C.sub.1-C.sub.6alkyl, optionally substituted C.sub.2-C.sub.6alkenyl, optionally substituted C.sub.2-C.sub.6alkynyl, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, —R.sup.c, —OH, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c; when s is 0, R.sup.C1 is H, halogen, or C.sub.1-C.sub.4alkyl and R.sup.C2 is optionally substituted C.sub.1-C.sub.4alkyl, wherein said optionally substituted C.sub.1-C.sub.4alkyl group is optionally substituted by a substituent selected from —OR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2R.sup.c, —CONR.sup.cR.sup.d, —SO.sub.2NR.sup.cR.sup.d, and —OCONR.sup.cR.sup.d; when q is 1, R.sup.A1 and R.sup.A2 are each independently —CH.sub.2—, —NR.sup.e—, or —O—, and A, taken together with R.sup.A1 and R.sup.A2, forms a linking group, wherein A is -halo(C.sub.1-C.sub.12alkyl)-, optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —O—P(O)(OH).sub.2, —O—P(O)(R.sub.IR.sub.II).sub.2, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —N R.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.1-C.sub.4alkoxy)-, —(C.sub.1-C.sub.4alkoxyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkoxyl)-O—P(O)(R.sup.IR.sup.II).sub.2 and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when r is 1, R.sup.B1 and R.sup.B2 are each independently —CH.sub.2—, and B, taken together with R.sup.B1 and R.sup.B2, forms a linking group, wherein B is a bond or B is -halo(C.sub.1-C.sub.10alkyl)-, optionally substituted —C.sub.1-C.sub.10alkyl-, optionally substituted —C.sub.2-C.sub.10alkenyl-, optionally substituted —C.sub.2-C.sub.10alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.4alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.10alkyl-, optionally substituted —C.sub.2-C.sub.10alkenyl-, optionally substituted —C.sub.2-C.sub.10alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSO R.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.4alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when s is 1, R.sup.C1 and R.sup.C2 are each independently —CH.sub.2—, and C, taken together with R.sup.C1 and R.sup.C2, forms a linking group, wherein C is -halo(C.sub.1-C.sub.12alkyl)-, optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; R.sup.3 and R.sup.5 are each independently —CON(R.sup.d)(R.sup.f), or one of R.sup.3 and R.sup.5 is —CON(R.sup.d)(R.sup.f), and the other of R.sup.3 and R.sup.5 is H, COOH or —CO.sub.2(R.sup.c); R.sup.4 and R.sup.6 are each independently selected from H, halogen, halo(C.sub.1-C.sub.6alkyl), halo(C.sub.1-C.sub.6alkoxy)-, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —COR.sup.c, —CO.sub.2R.sup.C, —N(R.sup.d)COR.sup.c, —N(R.sup.d)SO.sub.2R.sup.c, —N(R.sup.g)SO.sub.2(C.sub.1-C.sub.2alkyl)-N(R.sup.h)(R.sup.f), —N(R.sup.g) CO(C.sub.1-C.sub.2alkyl)-N(R.sup.h)(R.sup.f), optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino-, and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino-, wherein the (C.sub.1-C.sub.6alkyl) of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino- and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from —OH, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2H, —CO.sub.2R.sup.c, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, —NR.sup.dSO.sub.2R.sup.c, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; R.sup.14 is optionally substituted C.sub.1-C.sub.4alkyl, wherein said optionally substituted C.sub.1-C.sub.4alkyl is optionally substituted by a substituent selected from —OR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2R.sup.c, —CONR.sup.cR.sup.d, —SO.sub.2NR.sup.cR.sup.d, and —OCONR.sup.cR.sup.d; R.sup.16 is H, halogen, or C.sub.1-C.sub.4alkyl; R.sup.15 and R.sup.17 are each independently H, cyclopropyl, or C.sub.1-C.sub.4alkyl; R.sup.a is H, —R.sup.c, —COR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, or —SO.sub.2NR.sup.cR.sup.d; each R.sup.b is independently C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-OH, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, —(C.sub.1-C.sub.4alkyl)-O—(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —(C.sub.1-C.sub.4alkyl)-O—CO(C.sub.1-C.sub.4alkyl), or —(C.sub.1-C.sub.4alkyl)-CO—O—(C.sub.1-C.sub.4alkyl); each R.sup.c is independently C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-OH, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, —(C.sub.1-C.sub.4alkyl)-O—(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —(C.sub.1-C.sub.4alkyl)-O—CO(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-CO—O—(C.sub.1-C.sub.4alkyl), optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.6cycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl, optionally substituted —C.sub.1-C.sub.4alkyl-4-6 membered heterocycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-5-6 membered heteroaryl, or optionally substituted —C.sub.1-C.sub.4alkyl-9-10 membered heteroaryl, wherein the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or optionally substituted 9-10 membered heteroaryl moiety of said substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl optionally substituted —C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.6cycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl, optionally substituted —C.sub.1-C.sub.4alkyl-4-6 membered heterocycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-5-6 membered heteroaryl, or optionally substituted —C.sub.1-C.sub.4alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, —(C.sub.1-C.sub.4alkyl)NH.sub.2, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, —C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; each R.sup.d is independently H or C.sub.1-C.sub.4alkyl; each R.sup.e is independently H, C.sub.1-C.sub.4alkyl, —CO(C.sub.1-C.sub.4alkyl), —OCO(C.sub.1-C.sub.4alkyl), —CO.sub.2(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)NH.sub.2, —(C.sub.1-C.sub.4alkyl) C.sub.1-C.sub.4alkoxy, —CO-(optionally substituted 5-6 membered heterocycloalkyl), —CO(C.sub.1-C.sub.4alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), —CO(optionally substituted 5-6 membered heteroaryl), —CO(C.sub.1-C.sub.4alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy) O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; each R.sup.f is independently H or C.sub.1-C.sub.4alkyl; R.sup.g and R.sup.h are each independently H or C.sub.1-C.sub.4alkyl or R.sup.g and R.sup.h, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and each occurrence of R.sup.I and R.sup.II are independently (C.sub.1-C.sub.6alkyl)oxy-; or a tautomer thereof; or a salt thereof.

2. The compound or salt according to claim 1 has the structure of Formula (I) ##STR00441## wherein: q is 0 or 1; r is 0 or 1; s is 0 or 1; wherein q+r+s=1 or 2; when q is 0, R.sup.A1 and R.sup.A2 are each independently H, halogen, hydroxy, —N(R.sup.e)(R.sup.f), —CO.sub.2R.sup.f, —N(R.sup.f)COR.sup.b, —N(R.sup.g)SO.sub.2(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —N(R.sup.g)CO(C.sub.1-C.sub.4alkyl)-N(R.sup.h)(R.sup.f), optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino-, and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino-, wherein the (C.sub.1-C.sub.6alkyl) of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino- and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, C.sub.1-C.sub.4alkoxy-, —N(R.sup.e)(R.sup.f), —CO.sub.2(R.sup.f), —CON(R.sup.e)(R.sup.f), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.6alkyl)amino-, (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)amino-, halo(C.sub.1-C.sub.6alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when r is 0, R.sup.B1 and R.sup.B2 are each independently H, optionally substituted C.sub.1-C.sub.6alkyl, halo(C.sub.1-C.sub.6alkyl), optionally substituted C.sub.2-C.sub.6alkenyl, optionally substituted C.sub.2-C.sub.6alkynyl, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl, wherein said optionally substituted C.sub.1-C.sub.6alkyl, optionally substituted C.sub.2-C.sub.6alkenyl, optionally substituted C.sub.2-C.sub.6alkynyl, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, —R.sup.c, —OH, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c; when s is 0, R.sup.C1 is H, halogen, or C.sub.1-C.sub.4alkyl and R.sup.C2 is optionally substituted C.sub.1-C.sub.4alkyl, wherein said optionally substituted C.sub.1-C.sub.4alkyl group is optionally substituted by a substituent selected from —OR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2R.sup.c, —CONR.sup.cR.sup.d, —SO.sub.2NR.sup.cR.sup.d, and —OCONR.sup.cR.sup.d; when q is 1, R.sup.A1 and R.sup.A2 are each independently —CH.sub.2—, —NR.sup.e—, or —O—, and A, taken together with R.sup.A1 and R.sup.A2, forms a linking group, wherein A is -halo(C.sub.1-C.sub.12alkyl)-, optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSO R.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when r is 1, R.sup.B1 and R.sup.B2 are each independently —CH.sub.2—, and B, taken together with R.sup.B1 and R.sup.B2, forms a linking group, wherein B is a bond or B is -halo(C.sub.1-C.sub.10alkyl)-, optionally substituted —C.sub.1-C.sub.10alkyl-, optionally substituted —C.sub.2-C.sub.10alkenyl-, optionally substituted —C.sub.2-C.sub.10alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.4alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.10alkyl-, optionally substituted —C.sub.2-C.sub.10alkenyl-, optionally substituted —C.sub.2-C.sub.10alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl-C.sub.1-C.sub.4alkyl-, optionally substituted —C.sub.1-C.sub.4alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.4alkyl-, or optionally substituted —C.sub.1-C.sub.4alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.4alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; when s is 1, R.sup.C1 and R.sup.C2 are each independently —CH.sub.2—, and C, taken together with R.sup.C1 and R.sup.C2, forms a linking group, wherein C is -halo(C.sub.1-C.sub.12alkyl)-, optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl-, wherein the alkyl moiety of said optionally substituted —C.sub.1-C.sub.12alkyl-, optionally substituted —C.sub.2-C.sub.12alkenyl-, optionally substituted —C.sub.2-C.sub.12alkynyl-, optionally substituted —C.sub.1-C.sub.6alkyl-O—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-NR.sup.a—C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C.sub.1-C.sub.4alkyl), —OH, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.d, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, and —NR.sup.dSO.sub.2R.sup.c, and the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C.sub.1-C.sub.6alkyl-(C.sub.3-C.sub.6cycloalkyl)-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-phenyl-C.sub.1-C.sub.6alkyl-, optionally substituted —C.sub.1-C.sub.6alkyl-(4-6 membered heterocycloalkyl)-C.sub.1-C.sub.6alkyl-, or optionally substituted —C.sub.1-C.sub.6alkyl-(5-6 membered heteroaryl)-C.sub.1-C.sub.6alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; R.sup.3 and R.sup.5 are each independently —CON(R.sup.d)(R.sup.f), or one of R.sup.3 and R.sup.5 is —CON(R.sup.d)(R.sup.f), and the other of R.sup.3 and R.sup.5 is H or —CO.sub.2(R.sup.c); R.sup.4 and R.sup.6 are each independently selected from H, halogen, halo(C.sub.1-C.sub.6alkyl), halo(C.sub.1-C.sub.6alkoxy)-, hydroxy, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —COR.sup.c, —CO.sub.2R.sup.c, —N(R.sup.d)COR.sup.c, —N(R.sup.d)SO.sub.2R.sup.c, —N(R.sup.g)SO.sub.2(C.sub.1-C.sub.2alkyl)-N(R.sup.h)(R.sup.f), —N(R.sup.g)CO(C.sub.1-C.sub.2alkyl)-N(R.sup.h)(R.sup.f), optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino-, and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino-, wherein the (C.sub.1-C.sub.6alkyl) of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, optionally substituted (C.sub.1-C.sub.6alkyl)amino- and optionally substituted (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.4alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from —OH, —OR.sup.c, —NH.sub.2, —NR.sup.cR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2H, —CO.sub.2R.sup.c, —OCOR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH 2, —SO.sub.2NR.sup.cR.sup.d, —OCONH.sub.2, —OCONR.sup.cR.sup.d, —NR.sup.dCOR.sup.c, —NR.sup.dSOR.sup.c, —NR.sup.dCO.sub.2R.sup.c, —NR.sup.dSO.sub.2R.sup.c, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; R.sup.14 is optionally substituted C.sub.1-C.sub.4alkyl, wherein said optionally substituted C.sub.1-C.sub.4alkyl is optionally substituted by a substituent selected from —OR.sup.c, —NR.sup.cR.sup.d, —CO.sub.2R.sup.c, —CONR.sup.cR.sup.d, —SO.sub.2NR.sup.cR.sup.d, and —OCONR.sup.cR.sup.d; R.sup.16 is H, halogen, or C.sub.1-C.sub.4alkyl; R.sup.15 and R.sup.17 are each independently H, cyclopropyl, or C.sub.1-C.sub.4alkyl; R.sup.a is H, —R.sup.c, —COR.sup.c, —CO.sub.2H, —CO.sub.2R.sup.c, —SOR.sup.c, —SO.sub.2R.sup.c, —CONH.sub.2, —CONR.sup.cR.sup.d, —SO.sub.2NH.sub.2, or —SO.sub.2NR.sup.cR.sup.d; each R.sup.b is independently C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-OH, —(C.sub.1-C.sub.4alkyl)-O—(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —(C.sub.1-C.sub.4alkyl)-O—CO(C.sub.1-C.sub.4alkyl), or —(C.sub.1-C.sub.4alkyl)-CO—O—(C.sub.1-C.sub.4alkyl); each R.sup.c is independently C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-OH, —(C.sub.1-C.sub.4alkyl)-O—(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-N(R.sup.e)(R.sup.f), —(C.sub.1-C.sub.4alkyl)-O—CO(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-CO—O—(C.sub.1-C.sub.4alkyl), optionally substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted —C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.6cycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl, optionally substituted —C.sub.1-C.sub.4alkyl-4-6 membered heterocycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-5-6 membered heteroaryl, or optionally substituted —C.sub.1-C.sub.4alkyl-9-10 membered heteroaryl, wherein the C.sub.3-C.sub.6cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or optionally substituted 9-10 membered heteroaryl moiety of said substituted C.sub.3-C.sub.6cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl optionally substituted —C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.6cycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-phenyl, optionally substituted —C.sub.1-C.sub.4alkyl-4-6 membered heterocycloalkyl, optionally substituted —C.sub.1-C.sub.4alkyl-5-6 membered heteroaryl, or optionally substituted —C.sub.1-C.sub.4alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; each R.sup.d is independently H or C.sub.1-C.sub.4alkyl; each R.sup.e is independently H, C.sub.1-C.sub.4alkyl, —CO(C.sub.1-C.sub.4alkyl), —OCO(C.sub.1-C.sub.4alkyl), —CO.sub.2(C.sub.1-C.sub.4alkyl), —CO-(optionally substituted 5-6 membered heterocycloalkyl), —CO(C.sub.1-C.sub.4alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), —CO(optionally substituted 5-6 membered heteroaryl), —CO(C.sub.1-C.sub.4alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted 1-4 substituents each independently selected from halogen, hydroxy, amino, (C.sub.1-C.sub.4alkyl)amino-, (C.sub.1-C.sub.4alkyl)(C.sub.1-C.sub.4alkyl)amino-, C.sub.1-C.sub.4alkyl, halo(C.sub.1-C.sub.4alkyl), halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-, —COR.sup.d, —CON(R.sup.d)(R.sup.f), and —CO.sub.2R.sup.d; each R.sup.f is independently H or C.sub.1-C.sub.4alkyl; R.sup.g and R.sup.h are each independently H or C.sub.1-C.sub.4alkyl or R.sup.g and R.sup.h, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; or a tautomer thereof; or a salt thereof.

3. The compound or salt according to claim 1 wherein when s is 0, R.sup.C1 and R.sup.C2 are each independently H or C.sub.1-C.sub.4alkyl.

4. The compound or salt according to claim 1, wherein when s is 0, R.sup.c and R.sup.C2 are each independently ethyl.

5. The compound or salt according to claim 1, wherein r is 1, B, taken together with R.sup.B1 and R.sup.B2, form —CH.sub.2CH═CHCH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH(OH)CH(OH)CH.sub.2—, or —CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2— group.

6. The compound or salt according to claim 1, wherein r is 1, B, taken together with R.sup.B1 and R.sup.B2, form a —CH.sub.2CH═CHCH.sub.2—.

7. The compound or salt according to claim 1, wherein R.sup.4 and R.sup.6 are each H.

8. The compound or salt according to claim 1, wherein R.sup.16 is H.

9. The compound or salt according to claim 1, wherein R.sup.14, R.sup.15, and R.sup.17 are each independently C.sub.1-C.sub.3alkyl.

10. The compound or salt according to claim 1 having the structure of Formula (I-N-B′) ##STR00442## wherein R.sup.3 and R.sup.5 are each independently —CON(R.sup.d)(R.sup.f), or one of R.sup.3 and R.sup.5 is —CON(R.sup.d)(R.sup.f), and the other of R.sup.3 and R.sup.5 is H, COOH or —CO.sub.2(R.sup.c); R.sup.c is C.sub.1-C.sub.4alkyl; R.sup.B1 and R.sup.B2 are each independently —CH.sub.2—; B is -halo(C.sub.1-C.sub.5alkyl), unsubstituted —C.sub.1-C.sub.5allkyl, or unsubstituted —C.sub.2-C.sub.5alkenyl-; R.sup.A2 and R.sup.A1 are each independently H, halogen, hydroxyl, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, wherein C.sub.1-C.sub.6alkyl of said optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxyl, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, C.sub.1-C.sub.4alkoxyl, —N(R.sup.e)(R.sup.f), —CO.sub.2(R.sup.f), optionally substituted phenyl, and optionally substituted 5-6 membered heterocycloalkyl; wherein said optionally substituted phenyl, or 5-6 membered heterocycloalkyl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.6alkyl)amino-, (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)amino-, halo(C.sub.1-C.sub.6alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, —(C.sub.1-C.sub.6alkyl)-NH.sub.2, —C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkoxyl) and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; each R.sup.d is independently H or C.sub.1-C.sub.4alkyl; R.sup.e is selected from H, (C.sub.1-C.sub.4alkyl), —CO(C.sub.1-C.sub.4alkyl), —OCO(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-NH.sub.2, —(C.sub.1-C.sub.4alkyl) C.sub.1-C.sub.4alkoxy, or —CO.sub.2(C.sub.1-C.sub.4alkyl), each occurrence of R.sup.f is H or (C.sub.1-C.sub.4alkyl); R.sup.4 and R.sup.6 are H; R.sup.14 is C.sub.1-C.sub.4alkyl; R.sup.C1 is H or C.sub.1-C.sub.4alkyl; R.sup.C2 is C.sub.1-C.sub.4alkyl; R.sup.15 is H or C.sub.1-C.sub.4alkyl; R.sup.16 is H or C.sub.1-C.sub.4alkyl; R.sup.17 is H or C.sub.1-C.sub.4alkyl; and each occurrence of R.sup.I and R.sup.II are independently (C.sub.1-C.sub.6alkyl)oxy-, or a tautomer thereof.

11. The compound or salt according to claim 10, which has the structure of Formula (I-N-b′), ##STR00443## wherein B is -halo(C.sub.1-C.sub.5alkyl), unsubstituted —C.sub.1-C.sub.5allkyl, or unsubstituted —C.sub.2-C.sub.5alkenyl-; R.sup.A2 and R.sup.A1 are each independently H, halogen, hydroxyl, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, wherein C.sub.1-C.sub.6alkyl of said optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxyl, C.sub.1-C.sub.4alkoxyl, —N(R.sup.e)(R.sup.f), —CO.sub.2(R.sup.f), optionally substituted phenyl, and optionally substituted 5-6 membered heterocycloalkyl, and wherein said optionally substituted phenyl, or 5-6 membered heterocycloalkyl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH).sub.2, —O—P(O)(R.sup.IR.sup.II).sub.2, amino, (C.sub.1-C.sub.6alkyl)amino-, (C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)amino-, halo(C.sub.1-C.sub.6alkyl), hydroxy-(C.sub.1-C.sub.4alkyl)-, —(C.sub.1-C.sub.4alkyl)-O—P(O)(OH).sub.2, —(C.sub.1-C.sub.4alkyl)-O—P(O)(R.sup.IR.sup.II).sub.2, halo(C.sub.1-C.sub.4alkoxy)-, C.sub.1-C.sub.4alkoxy-, hydroxy-(C.sub.2-C.sub.4alkoxy)-, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(OH).sub.2, —(C.sub.2-C.sub.4alkoxy)-O—P(O)(R.sup.IR.sup.II).sub.2, —(C.sub.1-C.sub.6alkyl)-NH.sub.2, —C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkoxyl) and C.sub.1-C.sub.4alkoxy-(C.sub.1-C.sub.4alkoxy)-; R.sup.e is selected from H, (C.sub.1-C.sub.4alkyl), —CO(C.sub.1-C.sub.4alkyl), —OCO(C.sub.1-C.sub.4alkyl), —(C.sub.1-C.sub.4alkyl)-NH.sub.2, —(C.sub.1-C.sub.4alkyl) C.sub.1-C.sub.4alkoxy, or —CO.sub.2(C.sub.1-C.sub.4alkyl), each R.sup.f is H or (C.sub.1-C.sub.4alkyl); R.sup.14 is C.sub.1-C.sub.4alkyl; R.sup.C2 is C.sub.1-C.sub.4alkyl; R.sup.15 is C.sub.1-C.sub.4alkyl; and R.sup.17 is C.sub.1-C.sub.4alkyl; each occurrence of R.sup.I and R.sup.II are independently (C.sub.1-C.sub.6alkyl)oxy-, or a tautomer thereof.

12. The compound or salt according to claim 10, wherein R.sup.A2 and R.sup.A1 are each independently H, optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, and the C.sub.1-C.sub.6alkyl of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxyl, —N(R.sup.e)(R.sup.f), C.sub.1-C.sub.4alkoxyl, phenyl, optionally substituted 5-6 membered heterocycloalkyl containing at least one nitrogen or oxygen as a member of the ring, and R.sup.e and R.sup.f are each independently H or C.sub.1-C.sub.4alkyl.

13. The compound or salt according to claim 10, wherein at least one of R.sup.A2 or R.sup.A1 is each independently H, optionally substituted (C.sub.1-C.sub.6alkyl), or optionally substituted (C.sub.1-C.sub.6alkyl)oxy-, and the C.sub.1-C.sub.6alkyl of said optionally substituted (C.sub.1-C.sub.6alkyl), optionally substituted (C.sub.1-C.sub.6alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group consisting of —N(R.sup.e)(R.sup.f), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, and R.sup.e and R.sup.f are each independently H or C-C.sub.4alkyl.

14. A compound or a salt according to claim 10, which is (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide; (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide; (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide; (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide; (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; 3-(((2)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyldihydrogen phosphate; (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl dihydrogen phosphate; 3-(((Z)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl dihydrogen phosphate; or a tautomer thereof, or a salt thereof.

15. The compound or salt according to claim 1, wherein the salt is a pharmaceutically acceptable salt of said compound.

16. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 and at least one pharmaceutically acceptable excipient.

17. A method of treating a STING-mediated disease or disorder comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 15 to a human in need thereof.

18. The method according to claim 17, wherein the disease or disorder is cancer or pre-cancerous syndromes.

19. The method according to claim 18, wherein the disease or disorder is cancer.

20. The method according to claim 17, wherein the disease or disorder is infectious disease.

21. The method according to claim 20, wherein the disease or disorder is selected from Influenza, HIV, HCV, HPV or HBV infection.

22. The compound, or pharmaceutically acceptable salt thereof, according to claim 14 for use as a vaccine adjuvant.

Description

EXAMPLES

[0823] The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0824] It will be understood that certain compounds of the invention may be potent immunomodulators and accordingly, care should be exercised in their handling.

[0825] The reactions described herein are applicable for producing compounds of the invention having a variety of different substituent groups (e.g., R.sup.1, R.sup.2, etc.), as defined herein. The skilled artisan will appreciate that if a particular substituent is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. W. Greene ‘Protective Groups in Organic Synthesis’ (4th edition, 1. Wiley and Sons, 2006). Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0826] Certain intermediate compounds described herein form a yet further aspect of the invention.

General Synthetic Methods

[0827] The compounds of this invention may be prepared using synthetic procedures illustrated in the reaction schemes below, which can be readily adapted to prepare other compounds of the invention by drawing on the knowledge of a skilled organic chemist. The syntheses provided in these schemes are applicable for producing compounds of the invention having a variety of different R groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the schemes are shown with compounds only of Formula (I-N), (I-P) or (I), they are illustrative of processes that may be used to make the compounds of the invention. Intermediates (compounds used in the preparation of the compounds of the invention) may also be present as salts.

[0828] Method 1: An appropriate nitro-halo benzamide (1A) may be treated with an amine (allylamine used as an example) under base or metal-mediated coupling conditions to afford the aniline (1B). Subsequent reduction of the nitro group via appropriate conditions will provide dianiline (1C). Reaction with cyanogen bromide provides the aminobenzimidazole (1D). Peptide coupling between the aminobenzimiazole and pyrazole acid (1E) generates the amidobenzimidazole monomer (1F). Cross metathesis reaction between two molecules of (1F) affords the unsaturated dimer (1G), which can be hydrogenated to afford saturated dimer 1H.

Method 1

[0829] ##STR00041##

[0830] Method 2: Two molecules of an appropriate nitro-halo benzamide (2A) may be treated with a diamine under base or metal-mediated coupling conditions to afford the biscoupled aniline (2B). Subsequent bis-reduction of the nitro groups via appropriate conditions can provide the dianiline (2C). Reaction with cyanogen bromide provides the aminobenzimidazole dimer (2D). Peptide coupling between bis amine (2D) and two molecules of pyrazole acid (2E) generates the amidobenzimidazole dimer (2F).

Method 2

[0831] ##STR00042##

[0832] Method 3: Fluoronitrobenzamide (3A) is treated with a monoprotected diamine under base or metal-mediated coupling conditions to afford the aniline (3B). Subsequent reduction of the nitro group via appropriate conditions can provide the dianiline (3C). Reaction with cyanogen bromide provides the aminobenzimidazole (3D). Peptide coupling between amine (3D) and pyrazole acid (3E) generates the amidobenzimidazole (3I), which can be deprotected under appropriate conditions for the amine protecting group to afford amine (3G). Amine (3G) can be coupled with an appropriate halonitrobenzamide (3H) to provide (3I); reduction of the nitro group can provides dianiline (3J). Treatment of (3J) with cyanogen bromide generates aminobenzimidazole (3K), which can be treated with pyrazole acid (3E) under amide coupling conditions to afford the unsymmetrical dimer (3L).

Method 3

[0833] ##STR00043##

[0834] Method 4: An appropriate nitro-halo benzamide (4A) is treated with a monoprotected diamine under base or metal-mediated coupling conditions to afford the allylaniline (4B). Subsequent reduction of the nitro group via appropriate conditions will provide the dianiline (4C). Reaction with cyanogen bromide provides the aminobenzimidazole (4D). Peptide coupling between amine (4D) and pyrazole acid (4E) generates the amidobenzimidazole (4F), which can be deprotected under appropriate conditions for the amine protecting group to afford amine (4G). Amine (4G) can be coupled with fluoronitrobenzamide (4H) to provide (4I), and then reduction of the nitro group will provide dianiline (4J). Treatment of (4J) with cyanogen bromide generates aminobenzimidazole (4K), which can be treated with pyrazole acid (4E) under amide coupling conditions to afford the unsymmetrical dimer (4L).

Method 4

[0835] ##STR00044## ##STR00045## ##STR00046##

[0836] Method 5 Two molecules of an appropriate phenol (5A) are reacted with a bis-electrophile such as dibromopropane to provide ether linked dimer (5B). Dimer (5B) is then reacted with a suitable diamine to afford macrocycle (5C). Reduction of the nitro groups, followed by treatment with cyanogen bromide affords bisaminobenzimidazole (5D). Amide coupling with an appropriate acid (5E) affords bisamidobenzimidazole macrocycle (5F).

Method 5

[0837] ##STR00047##

[0838] Method 6: Bispyrazole acid 6A (Method 8) is reacted with Aminobenzimidazole dimer (6B) under amide coupling conditions to afford amidobenzimidazole macrocycle (6C), wherein each R may be the same or different.

Method 6

[0839] ##STR00048##

[0840] Method 7: Bispyrazole acid 7A (Method 8) is reacted with two molecules of aminobenzimidazole (7B) under amide coupling conditions to afford pyrazole-linked dimer (7C). Ring closing metathesis reaction will afford the unsaturated macrocycle (7D), which can be hydrogenated to provide the saturated amidobenzimidazole macrocycle (7E).

Method 7

[0841] ##STR00049##

[0842] Method 8: A substituted (pent-4-yn-1-yl)-1H-pyrazole-carboxylate (8C) may be formed by N-alkylation of a substituted 1H-pyrazole-carboxylate (8A) with (5-chloropent-1-yn-1-yl)trimethylsilane followed by de-silylation. A 4-iodo-1H-pyrazole-carboxylate (8F) may be formed by esterification of the corresponding 1H-pyrazole-carboxylic acid (8D), followed by iodination using 1-iodopyrrolidine-2,5-dione. Palladium catalyzed coupling of the substituted (pent-4-yn-1-yl)-1H-pyrazole-carboxylate (8C) with the 4-iodo-1H-pyrazole-carboxylate (8F) forms an alkynyl-linked bispyrazole (8G). Hydrogenation of the alkynyl-linked bispyrazole, followed by hydrolysis provided the bispyrazole acid used in Methods 6 and 7 (6A/7A), above.

Method 8

[0843] ##STR00050## ##STR00051##

[0844] Method 9: An appropriate nitro-halo benzamide (9A) may be treated with a monoprotected diamine (such as 9B) under base or metal-mediated coupling conditions to afford the coupled aniline (9C). Subsequent deprotection of the primary amine will provide amine 9D. A second nitro-halo benzamide (9E) may be reacted with amine 9D under base or metal-mediated coupling conditions to afford a bis-nitro dimeric benzamide (9F). Double reduction of the nitro groups via appropriate conditions can provide the dianiline (9G). Reaction with cyanogen bromide provides the aminobenzimidazole dimer (9H). Peptide coupling between bis amine 9H and two molecules of pyrazole acid (9I) generates the amidobenzimidazole dimer (9J).

Method 9

[0845] ##STR00052## ##STR00053##

[0846] Method 10: A tetraaniline (10A, prepared by method 9 or another general method) may be treated with isothiocyanate (10B) until completion of the reaction. Upon completion of step 1, EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) are added and the reaction stirred until completion to afford amidobenzimidazole dimer (10C).

Method 10

[0847] ##STR00054##

[0848] Method 11: All variables are as defined in Formula (I-N), (I-P) or Formula (I). A suitably substituted halonitrobenzamide (11A) is reacted with a monoprotected diamine such as 11B to provide nitroaniline 11C. Deprotection of the amine protecting group affords amine 11D, which can be reacted with a halo-nitrophenyl compound 11E to afford bis-nitro 11F. Reduction of both nitro groups will provide a bis-aniline 11G which is treated with cyanogen bromide to afford bisaminobenzimidazole 11H. Amide coupling with a pyrazole acid such as 11I will afford a substituted amidobenzimidazole dimer 11J. When suitable functional groups are present on 11J, further functionalization of these groups will be possible to afford additional compounds such as 11K.

Method 11

[0849] ##STR00055## ##STR00056## ##STR00057##

[0850] Method 12: In method 12, R.sup.C2═R.sup.14, R.sup.17═R.sup.15 and R.sup.16═R.sup.C1, all other variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A tetraaniline (12A, prepared by method 11, 16 or another general method) may be treated with an isothiocyanate such as 12B until completion of the reaction. Upon completion of step 1, EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) are added and the reaction stirred until completion to afford amidobenzimidazole dimer (12C).

Method 12

[0851] ##STR00058##

[0852] Method 13: In method 13, all variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). Macrocyclic compounds with substitutions can be prepared via this method. A substituted halonitrophenyl compound (13A) is treated with a suitable diamine (13B) containing a linker group (B) between the two amine groups to afford amine 13C. Reduction of the nitro group followed by treatment with cyanogen bromide can afford aminobenzimidazole 13D. Amide coupling between 13D and a mono-carboxylic acid bis-pyrazole (such as 13E) containing a linker group (C) between the two pyrazoles will afford an amidobenzimidazole (13F). Deprotection of the amine group enables addition to a second substituted halo-nitro-phenyl (13G) to provide nitro-ester 13H. Reduction of the nitro group of 13H followed by treatment with cyanogen bromide will provide aminobenzimidazole 13I. Hydrolysis of the pyrazole ester then enables a macrocyclic amide formation to provide the macrocyclic amidobenzimidazole 13J. When suitable functional groups are present on 13J, further functionalization of these groups will be possible to afford additional compounds such as 13K.

Method 13

[0853] ##STR00059## ##STR00060##

[0854] Method 14: —O-M.sup.1 is defined as optionally substituted (C.sub.1-C.sub.6alkyl)oxy as defined for R.sup.A1 when q is 0 in Formula (I) Formula (I-N), or Formula (I-P). All other variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A dimeric amidobenzimidazole containing a phenol, such as 14A, prepared via one of the general synthetic methods described here, can be alkylated on the phenol through the use of a suitable alkylating agent such as an alkyl bromide and base such as potassium carbonate. When suitable functional groups are present on 14B, further functionalization of these groups will be possible to afford additional compounds.

Method 14

[0855] ##STR00061##

[0856] Method 15: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted halo-nitrophenyl compound (15A) is reacted with a diamine containing a linker group (B) such as 15B to provide bis-nitro dimer 15C. Reduction of both nitro groups will provide a tetraaniline 15D which can be converted to an amidobenzimidazole dimer (15E) via one of two methods: 1) Treatment with cyanogen bromide to afford a bisaminobenzimidazole followed by amide coupling with a pyrazole acid such as 15F; or 2) Treatment with isothiocyanate (15G) until completion of the reaction, then addition of EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) and the reaction is stirred until completion. When suitable functional groups are present on 15E, further functionalization of these groups will be possible to afford additional compounds.

Method 15

[0857] ##STR00062## ##STR00063##

[0858] Method 16: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted halo-nitrophenyl compound (16A) is reacted with a monoprotected diamine containing a linker group (B) such as 16B to provide nitro-aniline 16C. Deprotection of the amine protecting group affords amine 16D, which can be reacted with a halo-nitrophenyl compound 16E to afford bis-nitro dimer 16F. Reduction of both nitro groups will provide a tetraaniline 16G which can be converted to an amidobenzimidazole dimer (16H) via one of two methods: 1) Treatment with cyanogen bromide to afford a bisaminobenzimidazole followed by amide coupling with a pyrazole acid such as 16I; or 2) Treatment with isothiocyanate (16J) until completion of the reaction, then addition of EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) and the reaction is stirred until completion. When suitable functional groups are present on 16H, further functionalization of these groups will be possible to afford additional compounds.

Method 16

[0859] ##STR00064## ##STR00065##

[0860] Method 17: M.sup.2 is C.sub.1-C.sub.6alkyl or COOM.sup.2 can be any ester that is inactive to hydrogenolysis of benzyl ester. All other variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A substituted pyrazole ester such as (pent-4-yn-1-yl)-1H-pyrazole-carboxylate (17D) may be formed by esterification of a substituted 1H-pyrazole-carboxylate (17A) to afford ester 17B followed by N-alkylation under mitsunobu conditions. A 4-iodo-pyrazole ester (17G) may be formed by esterification of the corresponding pyrazole-carboxylic acid (17E), followed by iodination using 1-iodopyrrolidine-2,5-dione (NIS). Palladium-catalyzed coupling of an alkylated pyrazole such as 17D with the 4-iodo-pyrazole-ester (17G) forms a linked bispyrazole (17H). Reduction and hydrogenolysis of the linked bispyrazole will provide a bispyrazole monoacid (17I).

Method 17

[0861] ##STR00066## ##STR00067##

[0862] Method 18: all variables are as defined in Formula (A). (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxy-propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (18A) may be treated with methanesulfonyl chloride and triethylamine. Upon completion of step 1, the resulting mesylate (18B) is treated with an amine (NHR.sup.AR.sup.B) and K.sub.2CO.sub.3 and the reaction heated at 50-80° C. until completion to afford the desired compounds (18C).

Method 18

[0863] ##STR00068##

[0864] Method 19: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted bis-aminobenzimidazole (19B) containing a linker group (B), prepared via one of the methods described here, is reacted with a bispyrazole (19A) incorporating a linker group (C) and amide coupling reagents to afford a macrocylic bisamidobenzimidazole.

Method 19

[0865] ##STR00069##

[0866] Method 20: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted halo-nitrophenyl compound (20A) is reacted with a monoprotected diamine containing a linker group (B) such as 20B to provide nitro-aniline 20C. Reduction of the nitro group under appropriate conditions will afford dianiline 20D, which can be converted to an amidobenzimidazole 20F via one of two methods: 1) treatment with cyanogen bromide followed by amide coupling with a pyrazole acid such as 20E; or 2) treatment with isothiocyanate (20L) until completion of the reaction, then addition of EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) and the reaction is stirred until completion. Deprotection of the amine protecting group affords amine 20G, which can be reacted with a halo-nitrophenyl compound 20H to afford dimeric nitro aniline 20I. Reduction of the nitro group will provide bis-aniline 20J which can be converted to an amidobenzimidazole dimer (20K) via one of two methods: 1) Treatment with cyanogen bromide to afford a bisaminobenzimidazole followed by amide coupling with a pyrazole acid such as 20M; or 2) Treatment with isothiocyanate (20N) until completion of the reaction, then addition of EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) and the reaction is stirred until completion. When suitable functional groups are present on 20K, further functionalization of these groups will be possible to afford additional compounds.

Method 20

[0867] ##STR00070## ##STR00071## ##STR00072##

[0868] Method 21: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). Two molecules of an appropriate functionalized nitro-halo-phenyl (21A) are dimerized to provide bis-nitro dimer 21B containing a linker group (A). 21B is then reacted with an amine or diamine to afford dianiline 21C. Reduction of the nitro groups, provides tetraaniline 21C which can be converted to an amidobenzimidazole dimer (21G) via one of two methods: 1) Treatment with cyanogen bromide to afford a bisaminobenzimidazole followed by amide coupling with a pyrazole acid such as 21E; or 2) Treatment with isothiocyanate (21F) until completion of the reaction, then addition of EDC (or other suitable coupling reagent) and triethylamine (or other suitable base) and the reaction is stirred until completion. When suitable functional groups are present on 21G, further functionalization of these groups will be possible to afford additional compounds. A general example of a dimerization would be the reaction of a suitable nitro-phenol (21H) with a bis-halide and a base to afford the bis-phenol dimer 21J.

Method 21

[0869] ##STR00073## ##STR00074##

[0870] Method 22: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted aminobenzimidazole (22A), prepared via one of the methods described here, is reacted with a bispyrazole (22B) incorporating a linker group (C) and amide coupling reagents to afford a dimeric bisamidobenzimidazole. When suitable functional groups are present on 22C, further functionalization of these groups will be possible to afford additional compounds.

Method 22

[0871] ##STR00075##

[0872] Method 23: All variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A suitably substituted aminobenzimidazole (23A), prepared via one of the methods described here, is reacted with a mono-carboxylic acid bispyrazole (23B) incorporating a linker group (C), and amide coupling reagents to afford an amidobenzimidazole ester such as 23C. Hydrolysis of the pyrazole ester will provide acid 23D, which can be coupled with a second aminobenzimidazole (23E) to provide a dimeric bisamidobenzimidazole (23F). When suitable functional groups are present on 23F, further functionalization of these groups will be possible to afford additional compounds.

Method 23

[0873] ##STR00076## ##STR00077##

[0874] Method 24: M.sup.2 is C.sub.1-C.sub.6alkyl or COOM.sup.2 can be any ester that is inactive to hydrogenolysis of benzyl ester. All other variables are as defined in Formula (I-N), Formula (I-P) or Formula (I). A substituted pyrazole ester such as (pent-4-yn-1-yl)-1H-pyrazole-carboxylate (24D) may be formed by esterification of a substituted 1H-pyrazole-carboxylate (24A) to afford ester 24B followed by N-alkylation under suitable conditions such as an alkyl halide and base. In the case of using with (5-chloropent-1-yn-1-yl)trimethylsilane, a subsequent desilation will afford pyrazole ester 24D. A 4-iodo-pyrazole ester (24G) may be formed by esterification of the corresponding pyrazole-carboxylic acid (24E), followed by iodination using 1-iodopyrrolidine-2,5-dione (NIS). Palladium-catalyzed coupling of an alkylated pyrazole such as 24D with the 4-iodo-pyrazole-ester (24G) forms a linked bispyrazole (24H). Reduction and hydrogenolysis of the linked bispyrazole will provide a bispyrazole monoacid (24I), which can be further hydrolyzed to afford a bispyrazole di acid 24J.

Method 24

[0875] ##STR00078## ##STR00079##

[0876] It will be appreciated that in any of the routes described above, the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.

[0877] Names for the intermediate and final compounds described herein were generated using the software naming programs ChemDraw Pro 12.0.2.1076 Plug-In inside of Perkin Elmer E-Notebook or MarvinSketch 5.11.4_b82 (Chemaxon).

[0878] It will be appreciated by those skilled in the art that in certain instances these programs may name a structurally depicted compound as a tautomer or isomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers or isomers of such compounds and any mixtures of tautomers and/or isomers thereof.

[0879] The definitions for LCMS analysis conditions listed below and apply to all compounds.

TABLE-US-00001 LCMS Method LCMS Method A Wavelength 214 nm and 254 nm Instrument Agilent 1200-6110 Column Halo C18 4.6 × 50 um Flow Rate 1.8 mL/min Gradient Method Time (min) ACN (0.05% FA) H.sub.2O (0.05% FA) 0 5 95 1 95 5 2 95 5 2.5 5 95

TABLE-US-00002 LCMS Method LCMS Method B Wavelength 214 nm and 254 nm Instrument Shimadzu 2020 Column Halo C18 4.6 × 50 um Flow Rate 1.5 mL/min Gradient Method Time (min) ACN (0.05% FA) H.sub.2O (0.05% FA) 0 5 95 1 95 5 4 95 5 4.5 5 95 5 5 95

[0880] LCMS Method: LCMS Method C

[0881] Instrumentation [0882] LC: Shimadzu 10Avp (controller, pumps, and UV detector) [0883] UV: Shimadzu 10AVp (214 nm) [0884] ELS: Sedere Sedex 75C (45C) [0885] MS: PE Sclex Single Quadrupole 150EX [0886] Polarity (positive); Mode (profile); Scan Time (0.33 s); Step (0.2 m/z) [0887] Capillary V (5500); Cone V (25-45) [0888] - - - [0889] or Waters ZQ Single Quadrupole [0890] Polarity (positive); Mode (continuum); Scan Time (0.25s) [0891] Capillary V (3500); Cone V (25-35) [0892] Autosampler: CTC Leap; 3 uL loop; default injection volume=2 uL (default) [0893] Column: Thermo Hypersil Gold (C18, 20×2.1 mm, 1.9 u particle diam.) [0894] Heater: Phenomenex 50-55° C. [0895] Solvent A: H.sub.2O, 0.02% TFA [0896] Solvent B: MeCN, 0.02% TFA

TABLE-US-00003 Time (min) Flow (mL/min) Sol. B Gradient: 0.02 1.4 4.0 1.90 95.0 1.91 4.0 2.00 Stop

[0897] LCMS Method: LCMS Method D

[0898] Instrumentation [0899] LC: Waters Acquity Binary Solvent Manager, Column Manager 55C [0900] Autosampler: CTC Leap PAL Autosampler [0901] UV: Waters Acquity PDA (210-360 nm) [0902] ELS: Waters Acquity ELSD (50C) or Sedere Sedex 75C (45C) [0903] MS: Waters Acquity SQD [0904] Polarity (positive or negative); Mode (continuum); Scan Time (0.15s) [0905] Capillary V (3500); Cone V (25-35); [0906] Column: Thermo Hypersil Gold (C18, 20×2.1 mm, 1.9 u particle diam.) [0907] Solvent A: H.sub.2O, 0.02% TFA [0908] Solvent B: MeCN, 0.02% TFA

TABLE-US-00004 Time (min) Flow (mL/min) Sol. B Gradient: 0.02 1.6 2.0 1.90 95.0 1.91 stop 4.0

[0909] LCMS Method: LCMS Method E

[0910] Instrumentation [0911] LC: Waters Acquity I-Class Binary Solvent Manager, Column Manager 55C [0912] Autosampler: CTC Leap PAL 3 Autosampler [0913] UV: Waters Acquity PDA (210-360 nm) [0914] ELS: Waters Acquity ELSD (50C) or Sedere Sedex 85C (45C) [0915] MS: Waters Acquity QDa Mass Detector [0916] Polarity (positive or negative); Mode (continuum); Scan Time (10 Hz) [0917] Capillary kV (0.8); Cone V (12); [0918] Column: Thermo Hypersil Gold (C18, 20×2.1 mm, 1.9 u particle diam.) [0919] Solvent A: H.sub.2O, 0.02% TFA [0920] Solvent B: MeCN, 0.02% TFA

TABLE-US-00005 Time (min) Flow (mL/min) Sol. B % Gradient: 0.02 1.6 0.5 1.90 90 to 95 1.91 stop 0.5

[0921] LCMS Method: LCMS Method F

[0922] Instrumentation [0923] LC: Waters Acquity Binary Solvent Manager, Column Manager 55C [0924] Autosampler: CTC Leap PAL Autosampler [0925] UV: Waters Acquity PDA (210-360 nm) [0926] ELS: Waters Acquity ELSD (50C) or Sedere Sedex 75C (45C) [0927] MS: Waters Acquity SQD [0928] Polarity (positive or negative); Mode (continuum); Scan Time (0.15s) [0929] Capillary V (3500); Cone V (25-35); [0930] Column: Waters BAH (C18, 30×2.1 mm, 1.7 u particle diam.) [0931] Solvent A: H.sub.2O, 0.02% TFA [0932] Solvent B: MeCN, 0.02% TFA

TABLE-US-00006 Time (min) Flow (mL/min) Sol. B Gradient: 0.02 1.5 1.0 4.90 85.0 4.91 1.0 5.00 stop 1.0

[0933] LCMS Method: LCMS Method G

[0934] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1 mm

[0935] i.d. 1.7 μm packing diameter) at 40 degrees centigrade.

[0936] The solvents employed were:

[0937] A=0.1% v/v solution of Formic Acid in Water.

[0938] B=0.1% v/v solution of Formic Acid in Acetonitrile.

[0939] The gradient employed was:

TABLE-US-00007 Time (min) Flow Rate (mL/min) % A % B 0 1 97 3 1.5 1 5 95 1.9 1 5 95 2.0 1 97 3

[0940] The UV detection was a summed signal from wavelength of 210 nm to 350 nm. [0941] Injection volume: 0.5 ul

[0942] MS Conditions [0943] MS: Waters ZQ [0944] Ionisation mode: Alternate-scan Positive and Negative Electrospray Scan

[0945] LCMS Method: LCMS Method H

[0946] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1 mm

[0947] i.d. 1.7 μm packing diameter) at 40 degrees centigrade.

[0948] The solvents employed were:

[0949] A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with ammonia solution.

[0950] B=Acetonitrile.

[0951] The gradient employed was:

TABLE-US-00008 Time (min) Flow Rate (mL/min) % A % B 0 1 97 3 0.05 1 97 3 1.5 1 5 95 1.9 1 5 95 2.0 1 97 3

[0952] The UV detection was a summed signal from wavelength of 210 nm to 350 nm. [0953] Injection volume: 0.3 ul

[0954] MS Conditions [0955] MS: Waters ZQ [0956] Ionisation mode: Alternate-scan Positive and Negative

[0957] Electrospray

[0958] LCMS Method: LCMS Method I [0959] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1 mm [0960] i.d. 1.7 μm packing diameter) at 40 degrees centigrade. [0961] The solvents employed were: [0962] A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with 25% ammonium hydroxide solution. [0963] B=Acetonitrile

[0964] The gradient employed was:

TABLE-US-00009 Time (min) Flow Rate (mL/min) % A % B 0 1 97 3 0.05 1 97 3 1.5 1 5 95 1.9 1 5 95 2.0 1 97 3

[0965] The UV detection was a summed signal from wavelength of 210 nm to 350 nm. [0966] Injection volume: 0.5 uL

[0967] MS Conditions [0968] MS: Waters Acquity SQD or QDa mass detector [0969] Ionisation mode: Alternate-scan Positive and Negative

[0970] LCMS Method: LCMS Method J [0971] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1 mm i.d. 1.7 μm packing diameter) at 40 degrees centigrade. [0972] The solvents employed were: [0973] A=0.1% v/v solution of Formic Acid in Water. [0974] B=0.1% v/v solution of Formic Acid in Acetonitrile. [0975] The gradient employed was:

TABLE-US-00010 Time (min) Flow Rate (mL/min) % A % B 0 1 97 3 1.5 1 5 95 1.9 1 5 95 2.0 1 97 3 [0976] The UV detection was a summed signal from wavelength of 210 nm to 350 nm. [0977] Injection volume: 0.5 uL

[0978] MS Conditions [0979] MS: Waters Acquity SQD or QDa mass [0980] detector [0981] Ionisation mode: Alternate-scan Positive and Negative

[0982] LCMS Method: LCMS Method K [0983] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1 mm i.d. 1.7 μm packing diameter) at 40 degrees centigrade. [0984] The solvents employed were: [0985] A=0.1% v/v solution of TFA in Water. [0986] B=0.1% v/v solution of TFA in Acetonitrile. [0987] The gradient employed was:

TABLE-US-00011 Time (min) Flow Rate (mL/min) % A % B 0 1 97 3 1.5 1 5 95 1.9 1 5 95 2.0 1 97 3 [0988] The UV detection was a summed signal from wavelength of 210 nm to 350 nm. [0989] Injection volume: 0.5 uL

[0990] MS Conditions [0991] MS: Waters Acquity SQD or QDa mass detector [0992] Ionisation mode: Alternate-scan Positive and Negative [0993] Electrospray

[0994] LCMS Method: LCMS Method L

[0995] Instrumentation [0996] LC: Waters Acquity I-Class Binary Solvent Manager, I-Class Column Manager [0997] 55C [0998] Autosampler: CTC PAL 3 Autosampler [0999] UV: Waters Acquity PDA (210-360 nm) [1000] ELS: Sedere Sedex 85C (45C) [1001] MS: Waters Acquity QDa Mass Detector [1002] Polarity (positive or negative); Mode (continuum); Scan Time (10 Hz) [1003] Capillary kV (0.8); Cone V (12); [1004] Column: Thermo Hypersil Gold (C18, 20×2.1 mm, 1.9 u particle diam.) [1005] Solvent A: H.sub.2O, 0.02% TFA [1006] Solvent B: MeCN, 0.02% TFA

TABLE-US-00012 Time (min) Flow (mL/min) Sol. B % Gradient: 0.02 1.6 0.5 1.90 95 1.91 0.5 2.00 stop

LCMS Method: LCMS Method M

[1007] The LCMS analysis was conducted on a Waters Sunfire C18 column (50 mm×3.0 mm i.d. 5 μm packing diameter) at Ambient temperature on an Agilent 1200 HPLC with a Model 6140 Quad MS The solvents employed were: A=0.1% v/v solution of TFA in Water. B=0.1% v/v solution of TFA in Acetonitrile.

[1008] The gradient employed was:

TABLE-US-00013 Time Flow % A % B 0 1 mL 90 10 2.5 1 mL 0 100 4.2 1 mL 0 100

[1009] The UV detection wavelength (Bandwidth 8): 220 nm and 254 nm. Injection volume: 1 ul

MS Conditions

[1010] MS: Agilent 6140 Quad MS

[1011] Ionisation mode: Positive

LCMS Method: LCMS Method N

[1012] The LCMS analysis was conducted on an Agilent Zorbax Eclipse XDB-C18 (150 mm×4.6 mm, i.d. 5 μm packing diameter) at Ambient temperature on an Agilent 1200 HPLC with a Model 6140 Quad MS

The solvents employed were: A=0.1% v/v solution of TEA in Water. B=0.1% v/v solution of TEA in Acetonitrile.

[1013] The gradient employed was:

TABLE-US-00014 Time Flow % A % B 0 1 mL 90 10 12 1 mL 0 100 13 1 mL 0 100

[1014] The UV detection wavelength (Bandwidth 8): 220 nm and 254 nm.

[1015] Injection volume: 1 ul

MS Conditions

[1016] MS: Agilent 6140 Quad MS

[1017] Ionisation mode: Positive

[1018] The following abbreviations may be used in this specification:

TABLE-US-00015 Abbreviation Meaning AcOH acetic acid aq. aqueous BBr.sub.3 boron tribromide BOC, tBOC tert-butoxycarbonyl brine saturated aqueous sodium chloride BuOH butanol CDCl.sub.3 deuterated chloroform CDI 1,1′-carbonyldiimidazole CH.sub.2Cl.sub.2 or DCM methylene chloride or dichloromethane CH.sub.3CN or MeCN acetonitrile CH.sub.3NH.sub.2 methylamine d day DAST diethylaminosulfur trifluoride DCE 1,2-dichloroethane DIEA or DIPEA diisopropyl ethylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv equivalents Et ethyl Et.sub.3N or TEA triethylamine Et.sub.2O diethyl ether EtOAc ethyl acetate EtOH ethanol FCC flash column chromatography h, hr hour(s) HATU O-(7-azabenzotriazol-1yl)-N,N,N′,N′- tetramethylyronium hexafluorophosphate HCl hydrochloric acid HOAt 1-hydroxy-7-azabenzotriazole HOBt hydroxybenzotriazole HPLC high-performance liquid chromatography ICl iodine monochloride IPA isopropyl alcohol i-Pr.sub.2NEt N′,N′-diisopropylethylamine K.sub.2CO.sub.3 potassium carbonate KHMDS potassium bis(trimethylsilyl)amide KOt-Bu potassium tert-butoxide KOH potassium hydroxide LCMS liquid chromatography-mass spectroscopy LiAlH.sub.4 lithium aluminum hydride LiHDMS lithium hexamethyldisilazide LiOH lithium hydroxide Me methyl MeOH or CH.sub.3OH methanol MgSO.sub.4 magnesium sulfate min minute(s) MS mass spectrum μw microwave NaBH.sub.4 sodium borohydride Na.sub.2CO.sub.3 sodium carbonate NaHCO.sub.3 sodium bicarbonate NaOH sodium hydroxide Na.sub.2SO.sub.4 sodium sulfate NBS N-bromosuccinimide N.sub.2H.sub.2 hydrazine NH.sub.4Cl ammonium chloride NH.sub.4OH ammonium hydroxide NiCl.sub.2•6H.sub.2O nickel (II) chloride hexahydrate NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd/C palladium on carbon Ph phenyl POCl.sub.3 phosphoryl chloride PSI pound-force per square inch RB round bottom rm or rxn mixture reaction mixture rt/RT room temperature satd. saturated sm starting material TBAF tetra-n-butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TMEDA tetramethylethylenediamine TMSI trimethylsilyl iodide TMSN.sub.3 trimethylsilyl azide T3P 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide t.sub.R or Rf or Rt retention time TsOH p-toluenesulfonic acid

Intermediate 1

[1019] ##STR00080##

Step 1: 4-chloro-3-methoxy-5-nitrobenzamide

[1020] ##STR00081##

[1021] Methyl 4-chloro-3-methoxy-5-nitrobenzoate (1000 mg, 4.07 mmol) was stirred in NH.sub.4OH (10 mL, 77 mmol) at RT for 24 h. The reaction temperature was then increased to 50° C. for 2 h. An additional 2 mL (˜3.7 eq) of NH.sub.4OH was added to the vessel. After an additional 2 h stirring at 50° C. (4 h total) the reaction was cooled to RT. The solid was filtered and rinsed with cold water. The solid was dried under house vacuum and lyophilized to give 4-chloro-3-methoxy-5-nitrobenzamide (710 mg, 2.99 mmol, 73% yield) as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.31 (br. s., 1H), 8.06 (d, J=1.77 Hz, 1H), 7.88 (d, J=1.77 Hz, 1 H), 7.81 (br. s., 1H), 4.02 (s, 3H). LCMS (LCMS Method D): Rt=0.71 min, [M+H].sup.+=230.9.

Step 2: 4-chloro-3-hydroxy-5-nitrobenzamide

[1022] ##STR00082##

[1023] 4-chloro-3-methoxy-5-nitrobenzamide (1 g, 4.34 mmol) was suspended in dry DCM (15 mL) and stirred at rt. To the reaction was added BBr.sub.3 (17.4 mL, 1M in DCM) dropwise. A slurry rapidly formed which was stirred overnight at rt under nitrogen. The reaction was poured into ice water (300 mL) and stirred vigorously for 30 min. The resulting suspension was filtered and the solids dried to afford the title compound (610 mg, 2.82 mmol, 65% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.53 (br. s., 1H), 8.17 (br. s., 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.66 (br. s., 1H). LC-MS (LCMS Method D) Rt=0.60 min, [M+H].sup.+=217.

Intermediate 2

4-(5-(5-Carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid

[1024] ##STR00083## ##STR00084##

Step 1

Ethyl 3-methyl-1-(5-(trimethylsilyl)pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate

[1025] ##STR00085##

[1026] A mixture of ethyl 3-methyl-1H-pyrazole-5-carboxylate (22 g, 143 mmol), (5-chloropent-1-yn-1-yl)trimethylsilane (24.94 g, 143 mmol), K.sub.2CO.sub.3 (39.4 g, 285 mmol), and DMF (4 mL) was stirred at 60° C. overnight under a nitrogen gas atmosphere. The mixture was then dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 3-methyl-1-(5-(trimethylsilyl)pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate (12.5 g, 42.7 mmol, 30% yield) as a colorless oil. LCMS (LCMS Method A): Rt=2.43 min, [M+H].sup.+=293.

Step 2

Ethyl 3-methyl-1-(pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate

[1027] ##STR00086##

[1028] A mixture of ethyl 3-methyl-1-(5-(trimethylsilyl)pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate (37.7 g, 129 mmol), K.sub.2CO.sub.3 (44.5 g, 322 mmol), and EtOH (800 mL) was stirred at rt overnight. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford ethyl 3-methyl-1-(pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate (20 g, 91 mmol, 70.4% yield) as a colorless oil. LCMS (LCMS Method A): Rt=2.08 min, [M+H].sup.+=221.

Step 3

Benzyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1029] ##STR00087##

[1030] A mixture of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (20 g, 130 mmol), (bromomethyl)benzene (22.2 g, 130 mmol), K.sub.2CO.sub.3 (26.9 g, 195 mmol), and DMF (200 mL) was stirred at 60° C. overnight. The mixture was then dissolved in DCM, washed with water, dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford benzyl 1-ethyl-3-methyl-pyrazole-5-carboxylate (31.4 g, 129 mmol, 99% yield) as a colorless oil. LCMS (LCMS Method A): Rt=2.09 min, [M+H].sup.+=245.

Step 4

Benzyl 1-ethyl-4-iodo-3-methyl-1H-pyrazole-5-carboxylate

[1031] ##STR00088##

[1032] A mixture of benzyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (31.6 g, 129 mmol), 1-iodopyrrolidine-2,5-dione (34.9 g, 155 mmol) and DMF (400 mL) was stirred at 90° C. for 2 days. The mixture was then allowed to cool to rt, dissolved in DCM, and washed with a saturated aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether/EtOAc=10:1) to afford benzyl 1-ethyl-4-iodo-3-methyl-1H pyrazole-5-carboxylate (42.6 g, 115 mmol, 89% yield). LCMS (LCMS Method A): Rt=2.31 min, [M+H].sup.+=371.

Step 5

Benzyl 4-(5-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1033] ##STR00089##

[1034] A mixture of ethyl 3-methyl-1-(pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate (10.0 g, 45.4 mmol), benzyl 1-ethyl-4-iodo-3-methyl-1H-pyrazole-5-carboxylate (16.8 g, 45.4 mmol), copper(I) iodide (0.864 g, 4.54 mmol), bis(triphenylphosphine)palladium(II) chloride (0.319 g, 0.454 mmol), and Et.sub.3N (200 mL) was stirred at 60° C. overnight under a nitrogen gas atmosphere. The mixture was then dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether/EtOAc=5:1) to afford benzyl 4-(5-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (9.5 g, 20.5 mmol, 45.3% yield) as a yellow solid. LCMS (LCMS Method B): Rt=2.66 min, [M+H].sup.+=463.

Step 6

4-(5-(5-(Ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid

[1035] ##STR00090##

[1036] A mixture of benzyl 4-(5-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (19.0 g, 41.10 mmol), 10% Pd/C (0.22 g, 2.05 mmol), and THF (500 mL) was stirred at rt under a hydrogen gas atmosphere (4 atm) for 2 days. The reaction mixture was then filtered and concentrated under reduced pressure. The residue obtained was recrystallized from EtOAc/petroleum ether (1:5, v/v) to afford 4-(5-(5-(ethoxycarbonyl)-3-methyl-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-pyrazole-5-carboxylic acid (10.5 g, 27.90 mmol, 67.9% yield). 1H-NMR (400 MHz, CDCl.sub.3) δ NMR (400 MHz, CDCl, v/v) to afford 4-(5-(5-(ethoxycarbonyl)-3-methyl-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-pyrazole-5-carboxylic acid (10.5 g, 27.90 mmol, 67.9% yield). 1H-NMR (400 MHz, CDCl.sub.3) δ ppm 6.63 (s, 1H), 4.57-4.48 (m, 4H), 4.38-4.32 (m, 2H), 2.74-2.62 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.91-1.86 (m, 2H), 1.59-1.54 (m, 2H), 1.45-1.37 (m, 8H). LCMS (LCMS Method A): Rt=1.59 min, [M+H].sup.+=377.

Step 7

4-4-(7-(5-Carboxy-3-methyl-1H-pyrazol-1-yl)heptyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid

[1037] ##STR00091##

[1038] To a suspension of 4-(5-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-/1H-pyrazole-5-carboxylic acid (9.0 g, 23.9 mmol) in MeOH (120 mL) and water (120 mL) stirred at rt was added a 2 M aq. NaOH solution (60 mL, 119.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was then acidified to pH 4 with the addition of a 6 M HCl solution upon which a solid precipitated from the reaction mixture. The solid was collected by filtration and dried under reduced pressure to afford 4-(5-(5-carboxy-3-methyl-1H pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (6.5 g, 18.7 mmol, 78.1% yield) as a white solid. 1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.57 (s, 1H), 4.40-4.34 (m, 4H), 2.53 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 1.74-1.67 (m, 2H), 1.44-1.37 (m, 2H), 1.27-1.16 (m, 5H). LCMS (LCMS Method A): Rt=1.40 min, [M+H].sup.+=349.

Intermediate 3

(3-Bromopropoxy)(tert-butyl)dimethylsilane

[1039] ##STR00092##

[1040] To 1H-imidazole (13.4 g, 197 mmol) in DCM (100 mL) was added 3-bromopropan-1-ol (13.7 g, 99 mmol) followed slowly by tert-butylchlorodimethylsilane (17.8 g, 118 mmol) in DCM (20 ml). After 3 hr at RT, the reaction was concentrated to ˜100 mL and poured in EtOAc (800 mL), washed with 5% aq citric acid (2×200 mL) and brine. The organic layer was dried over MgSO.sub.4, filtered and concentrated to yield the title compound (10.0 g, 39.5 mmol, 40% yield). .sup.1H NMR (400 MHz, chloroform-d) δ ppm 3.78 (t, J=5.70 Hz, 2H), 3.56 (t, J=6.46 Hz, 2H), 2.07 (t, J=5.83 Hz, 2H), 0.94 (s, 9H), 0.11 (s, 6H).

Intermediate 4

2,2,3,3-Tetrafluorobutane-1,4-diamine

[1041] ##STR00093##

Step 1: 2,2,3,3-Tetrafluorobutane-1L4-diylbis(4-methylbenzenesulfonate)

[1042] ##STR00094##

[1043] To 2,2,3,3-tetrafluorobutane-1,4-diol (10.0 g, 61.7 mmol) in pyridine (150 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (29.4 g, 154 mmol) over 5 min, and then the reaction was heated to 55° C. After 1 day, the reaction was quenched with ice water, and the resulting solid was collected by filtration, dissolved in DCM (200 mL) and washed with 5% aq H.sub.2SO.sub.4 (100 mL×3). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to yield the title compound (27.3 g, 58.0 mmol, 94% yield) as a white solid. LCMS (LCMS Method A): Rt=1.750 min, [M+H].sup.+=470.9

Step 2: 1,4-Diazido-2,2,3,3-tetrafluorobutane

[1044] ##STR00095##

[1045] 2,2,3,3-Tetrafluorobutane-1,4-diyl bis(4-methylbenzenesulfonate) (10.0 g, 21.3 mmol) and sodium azide (5.53 g, 85.0 mmol) in DMF (40 mL) was stirred at 110° C. overnight. The reaction was quenched with NaClO(aq) and extracted with DCM (5 mL×3). The combined organic layers were washed with water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated to yield the title compound (3.5 g, 16.5 mmol, 78% yield). LCMS (LCMS Method A): Rt=1.520 min, [M+H].sup.+=213.1

Step 3: 2,2,3,3-Tetrafluorobutane-1,4-diamine

[1046] ##STR00096##

[1047] To a solution of 1,4-diazido-2,2,3,3-tetrafluorobutane (36.0 g, 170 mmol) in MeOH (350 mL) was added 10% Pd on carbon (18.1 g, 17.0 mmol). The reaction mixture was stirred at 40° C. under hydrogen (4 atm) for 16 hrs. The mixture was filtered through a pad of Celite, washed with MeOH and the filtrate was concentrated in vacuo to yield the title compound (22.0 g, 124 mmol, 73% yield). .sup.1H NMR (400 MHz, chloroform-d) δ ppm 3.12-3.37 (m, 4H), 1.43 (br. s., 4H).

Intermediate 5

1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

[1048] ##STR00097##

[1049] To a 1L round bottom flask was added 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (25 g, 162 mmol) and DCM (500 mL). To this heterogeneous solution was added DMF (0.1 mL, 1.291 mmol) followed by the slow addition of oxalyl chloride (15.61 mL, 178 mmol). During the addition, bubbling was noticed. After stirring for 1 hr at room temperature, the volatiles were removed under vacuum and the crude was co-evaporated twice with dichloromethane (100 mL each). It was assumed 100% yield and the crude (1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (28.0 g, 162 mmol, 100% yield)) was used directly as it is in the next reaction.

[1050] To a dry 1L round bottom flask was added KSCN (18.92 g, 195 mmol) and acetone (463 ml). This clear homogenous solution was cooled to 0° C. After 5 min. stirring at 0° C., 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (28 g, 162 mmol) was added as a solution in acetone (25 mL). Once the addition was complete, the reaction was allowed to stir at 0° C. After 1 min. Additional KSCN was added (˜2 g) and the reaction was stirred for an additional 20 min. At this time, hexanes (200 mL) was added to the reaction mixture and the crude heterogeneous solution was concentrated in vacuo to one third of the volume. The process of hexanes addition and concentration was repeated twice (300 mL of Hexanes each). After the last concentration, hexanes (200 mL) were added and the solid was removed by filtration, rinsing with hexanes (100 mL). The resulting clear light yellow filtrate concentrated and purified by chromatography (330 g Gold silica column; eluting with 0-20% EtOAc/hexanes). The desired product elutes at ˜7% EtOAc/hexanes. The desired fractions were combined and concentrated yielding 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (27.5 g, 139 mmol, 86% yield) as a clear colorless liquid. 1H NMR (400 MHz, chloroform-d) δ ppm 6.77 (s, 1H), 4.54 (q, J=7.10 Hz, 2H), 2.34 (s, 3H), 1.44 (t, J=7.22 Hz, 3H); LCMS (LCMS Method D): Rt=1.16 min, [M+H].sup.+=196.1. The acylisothiocyanate product degrades over time, and so a ˜0.4 M 1,4-dioxane solution was prepared and frozen to avoid/slow decomposition. This solution was thawed and used directly in subsequent reactions.

Intermediate 6

(E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide hydrochloride

[1051] ##STR00098##

Step 1: (E)-tert-Butyl (4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)carbamate

[1052] ##STR00099##

[1053] A mixture of 4-fluoro-3-nitrobenzamide (10.0 g, 54.3 mmol), (E)-tert-butyl (4-aminobut-2-en-1-yl)carbamate (10.62 g, 57.0 mmol) and K.sub.2CO.sub.3 (15.01 g, 109 mmol) in DMSO (200 mL) was stirred at RT overnight. The reaction was poured into water (2000 mL) and stirred for 30 min. The resulting solid was collected by filtration to yield the title compound (18.3 g, 52.2 mmol, 96% yield). LCMS (LCMS Method A): Rt=1.38 min, [2M+H].sup.+=700.5

Step 2: (E)-tert-Butyl (4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamate

[1054] ##STR00100##

[1055] To (E)-tert-butyl (4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)carbamate (18.3 g, 52.2 mmol) in DMF (300 mL) was added stannous chloride dihydrate (58.9 g, 261 mmol). After stirring at RT overnight, the reaction was added to sat aq NaHCO.sub.3(2000 mL), dropwise, and extracted with EtOAc (5×500 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to yield the title compound (16.5 g, 51.5 mmol, 99% yield) as a yellow oil. LCMS (LCMS Method A): Rt=1.275 min, [M-BOC+H].sup.+=221.1

Step 3: (E)-tert-Butyl (4-(2-amino-5-carbamoyl-1Hbenzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate

[1056] ##STR00101##

[1057] A mixture of (E)-tert-butyl (4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamate (16.5 g, 51.5 mmol) and cyanogen bromide (8.18 g, 77 mmol) in THF (200 mL) was heated to reflux overnight. The reaction was cooled to room temperature, diluted with sat aq NaHCO.sub.3(500 mL), and extracted with EtOAc (5×300 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified over silica gel, eluting with 50:1 to 20:1 DCM in MeOH (+3% NH.sub.4OH) to yield the title compound (13.7 g, 39.7 mmol, 77% yield) as an off-white solid. LCMS (LCMS Method A): Rt=1.150 min, [M+H].sup.+=346.1

Step 4: (E)-tert-Butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate

[1058] ##STR00102##

[1059] To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (9.17 g, 59.5 mmol) in DCM (500 mL) at 0° C. was added EDC (20.53 g, 107 mmol) and HOBT (18.22 g, 119 mmol). After 15 min, a mixture of (E)-tert-butyl (4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate (13.7 g, 39.7 mmol) in DMF (50 mL) was added, followed by TEA (27.6 mL, 198 mmol). The reaction was warmed to RT, stirred overnight and concentrated. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL), and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified over silica gel, eluting with 50:1 to 20:1 DCM:MeOH to give the crude product, which was washed with DCM (300 mL) and collected by filtration to yield the title compound (14.0 g, 29.1 mmol, 73% yield) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (s, 1H), 8.00-7.97 (m, 2H), 7.80-7.78 (m, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 6.95 (t, J=5.5 Hz, 1H), 6.66 (s, 1H), 5.73-5.65 (m, 2H), 4.83 (d, J=4.3 Hz, 2 H), 4.62 (q, J=7.0 Hz, 2H), 3.52 (s, 2H), 2.18 (s, 3H), 1.38-1.33 (m, 12H); LCMS (LCMS Method A): Rt=1.409 min, [M+H].sup.+=482.0

Step 5: (E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide hydrochloride

[1060] ##STR00103##

[1061] To a suspension of (E)-tert-butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate (3.00 g, 6.23 mmol) in dioxane (60 mL) was added 4N HCl in dioxane (15.6 mL, 62.3 mmol), followed by MeOH (15 mL) to dissolve some remaining solid. After 30 min at RT, the reaction mixture became cloudy and was allowed to stir for approximately 3 days. The resulting solid was collected by filtration and washed with DCM to yield the title compound (2.0 g, 4.8 mmol, 77% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.97-8.09 (br. s., 1H), 7.82 (d, J=8.11 Hz, 1H), 7.50 (d, J=8.11 Hz, 1H), 7.38 (br. s., 1H), 6.70 (s, 1H), 5.97-6.08 (m, 1H), 5.68-5.80 (m, 1H), 4.91 (d, J=4.31 Hz, 2H), 4.60 (q, J=6.67 Hz, 2H), 3.42 (br. s., 2H), 2.18 (s, 3H), 1.36 (t, J=6.97 Hz, 3H); LCMS (LCMS Method D): Rt=0.53 min, [M+H].sup.+=382.2

Intermediate 7

1-(5-(5-(ethoxycarbonyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[1062] ##STR00104##

Step 1: benzyl 3-methyl-1H-pyrazole-5-carboxylate

[1063] ##STR00105##

[1064] A mixture of 3-methyl-1H-pyrazole-5-carboxylic acid (50 mg, 0.396 mmol) and KHCO.sub.3 (47.6 mg, 0.476 mmol) in DMSO (2 mL) was stirred for 30 min, and (bromomethyl) benzene (0.045 mL, 0.377 mmol) was added. The mixture was stirred for 4 h at RT, diluted with EtOAc (20 mL), washed with water and brine, and dried over Na.sub.2SO.sub.4. The mixture was filtered and concentrated, and the residue was purified by column chromatography (Combiflash, 0-50% EtOAc in hexane) to afford the title compound (66 mg, 0.305 mmol, 77% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.19 (br. s., 1H) 7.34-7.48 (m, 5H) 6.52 (s, 1H) 5.29 (s, 2H) 2.27 (s, 3H). LCMS (LCMS Method D): Rt=0.86 min, [M+H].sup.+=216.9.

Step 2: benzyl 3-methyl-1-(pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate

[1065] ##STR00106##

[1066] A mixture of DIAD (25.9 mL, 133 mmol) and triphenylphosphine (34.9 g, 133 mmol) in tetrahydrofuran (THF) (600 mL) was stirred for 30 min at 0° C., and pent-4-yn-1-ol (11.36 mL, 122 mmol) was then added. The mixture was stirred for 30 min, and benzyl 3-methyl-1H-pyrazole-5-carboxylate (24 g, 111 mmol) was added. It was allowed to warm to RT and stirred overnight. The reaction was diluted with EtOAc (1000 mL), washed with saturated NaHCO.sub.3, and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The oily residue was treated with 10% EtOAc in hexane (500 mL), and a white precipitate formed. The precipitate was filtered off and washed with 10% EtOAc in hexane. The combined filtrates were concentrated, and the residue was purified by column chromatography (Combiflash, 0-15% EtOAc in hexane) to afford the title compound (27.5 g, 97 mmol, 88% yield) as a white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34-7.47 (m, 5H) 6.68 (s, 1H) 5.33 (s, 2H) 4.63 (t, J=7.03 Hz, 2H) 2.30 (s, 3H) 2.19-2.26 (m, 2H) 2.09 (quin, J=7.09 Hz, 2H) 1.97 (br. s., 1H); LCMS (LCMS Method D): Rt=1.21 min, [M+H].sup.+=283.0.

Step 3: ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1067] ##STR00107##

[1068] Oxalyl chloride (5.68 ml, 64.9 mmol) was added to a suspension of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (5 g, 32.4 mmol) in DCM (40 mL) at RT under N2 and two drops of DMF were added. The mixture was stirred for 2 hours at RT, concentrated and dried in vacuo. Ethanol (50 ml, 856 mmol) was added, and the mixture was stirred for 1 hour at RT. The reaction was concentrated and dried in vacuo to give a light-yellow oil which was taken into EtOAc (100 mL), washed with saturated NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, filtered, concentrated and the resulting residue was dried in vacuo to give the title compound (5.5 g, 30.2 mmol, 93% yield) as a light-yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.63 (s, 1H) 4.56 (q, J=7.11 Hz, 2H) 4.35 (q, J=7.11 Hz, 2H) 2.30 (s, 3H) 1.44 (t, J=7.28 Hz, 3H) 1.39 (t, J=7.28 Hz, 3H). LCMS (LCMS Method E): Rt=0.81 min, [M+H].sup.+=183.1.

Step 4: ethyl 1-ethyl-4-iodo-3-methyl-1H-pyrazole-5-carboxylate

[1069] ##STR00108##

[1070] A mixture of ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (5.5 g, 30.2 mmol) and NIS (8.15 g, 36.2 mmol) in DMF (100 mL) was heated to 90° C. and stirred for 3 days under N2. The reaction was cooled to RT, diluted with EtOAc (200 mL), washed with saturated Na.sub.2S.sub.2O.sub.3, 5% LiCl, and brine, dried over Na.sub.2SO.sub.4, filtered, concentrated, and the resulting residue was purified by column chromatography (Combiflash, 0-7% EtOAc in hexane) to afford the title compound (9.1 g, 29.5 mmol, 98% yield) as a colorless oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.57 (q, J=7.03 Hz, 2H) 4.43 (q, J=7.03 Hz, 2H) 2.32 (s, 3H) 1.45-1.50 (m, 3H) 1.39-1.45 (m, 3H). LCMS (LCMS Method D): Rt=1.12 min, [M+H].sup.+=308.9.

Step 5: 1 ethyl 4-(5-(5-((benzyloxy)carbonyl)-3-methyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1071] ##STR00109##

[1072] A flask which was previously purged with nitrogen was charged with Cs.sub.2CO.sub.3 (23.08 g, 70.8 mmol), 1,10-phenanthroline (1.915 g, 10.63 mmol), copper(I) chloride (0.175 g, 1.771 mmol), benzyl 3-methyl-1-(pent-4-yn-1-yl)-1H-pyrazole-5-carboxylate (10 g, 35.4 mmol), ethyl 1-ethyl-4-iodo-3-methyl-1H-pyrazole-5-carboxylate (13.10 g, 42.5 mmol), Pd[P(o-tollyl).sub.3].sub.2 (0.760 g, 1.063 mmol), and degassed Toluene (100 mL). The mixture was degassed for 15 min, heated to 100° C. and stirred overnight (18 hr) under N2. The reaction was cooled to RT and diluted with EtOAc. The inorganic solids were filtered off and washed with EtOAc. The combined organics were concentrated and the residue was purified via silica gel chromatography (EtOAc/Hexanes 0-25%) to afford the title compound (11.38 g, 24.60 mmol, 69.5% yield) as a colorless oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34-7.47 (m, 5H) 6.68 (s, 1H) 5.31 (s, 2H) 4.67 (t, J=7.03 Hz, 2H) 4.51 (q, J=7.19 Hz, 2H) 4.39 (q, J=7.03 Hz, 2H) 2.51 (t, J=7.28 Hz, 2H) 2.31 (s, 3H) 2.29 (s, 3H) 2.17 (t, J=7.15 Hz, 2H) 1.40 (t, J=7.03 Hz, 6H). LCMS (LCMS Method D): Rt=1.43 min, [M+H].sup.+=463.3.

Step 6: 1-(5-(5-(ethoxycarbonyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[1073] ##STR00110##

[1074] To a flask charged with ethyl 4-(5-(5-((benzyloxy)carbonyl)-3-methyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (11.3 g, 24.43 mmol) and Pd/C (2.60 g, 2.443 mmol) was added ethanol (200 mL). The flask was purged with N2, then hydrogen (via balloon) and the mixture was stirred under a H.sub.2 atmosphere overnight (18 hr). The catalyst was filtered off and the filtrate was concentrated in vacuo to afford the title compound (8.89 g, 23.62 mmol, 97% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.14 (br. s., 1H) 6.57 (s, 1H) 4.33-4.43 (m, 4H) 4.28 (m, J=7.09 Hz, 2H) 2.51-2.56 (m, 2H) 2.16 (s, 3H) 2.10 (s, 3H) 1.72 (m, J=7.34 Hz, 2H) 1.41 (m, J=7.58 Hz, 2H) 1.25-1.31 (m, 6H) 1.16-1.24 (m, 2H). LCMS (LCMS Method D): Rt=1.07 min, [M+H].sup.+=377.2.

Example 1

1,1′-((2R,3R)-2,3-dihydroxybutane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

[1075] ##STR00111## ##STR00112##

Step 1: (4R,5R)-4,5-bis(azidomethyl)-2,2-dimethyl-1,3-dioxolane

[1076] ##STR00113##

[1077] A mixture of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (3.874 g, 8.23 mmol) and sodium azide (1.338 g, 20.58 mmol) in DMF (20 mL) was heated at 80° C. for 15 h. The reaction was concentrated in vacuo to remove DMF and the residue was dissolved in DCM/water. The biphasic solution was transferred to a separatory funnel and the layers were separated. The DCM layer was washed twice with water and once with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the title compound a pale yellow liquid (1.564 g; 7.37 mmol, 90% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.10 (dd, J=2.78, 1.26 Hz, 2H) 3.55-3.66 (m, 2H) 3.32-3.44 (m, 2H) 1.51 (s, 6H). LCMS (LCMS Method C): Rt.=0.89 min, [M+H].sup.+=214.0

Step 2: ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanamine

[1078] ##STR00114##

[1079] To a solution of (4R,5R)-4,5-bis(azidomethyl)-2,2-dimethyl-1,3-dioxolane (1.561 g, 7.36 mmol) in dry THF (30 mL) at rt in an open 250 mL RB flask was added 2M LiAlH.sub.4 in THE (3.68 mL, 7.36 mmol) dropwise over 10 min. The reaction was then diluted with THF (30 mL) and the mixture was stirred for 30 min. The reaction was quenched by added 1.24 mL of a saturated aqueous Na.sub.2SO.sub.4 solution dropwise to the reaction. The quenched yellow reaction was stirred for 10 min and then allowed to settle. The resulting solid was removed by filtration and the filtrate was dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound as a pale yellow oil (977 mg, 6.1 mmol, 83% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.72-3.91 (m, 2H) 2.71-3.11 (m, 4H) 1.18-1.65 (m, 6H). LCMS (LCMS Method C): Rt.=0.11 min, [M+H].sup.+=161.0

Step 3: 4,4′-((((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(azanediyl))bis(3-nitrobenzamide)

[1080] ##STR00115##

[1081] A mixture of 4-fluoro-3-nitrobenzamide (2.233 g, 12.13 mmol), ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanamine (0.9713 g, 6.06 mmol), and K.sub.2CO.sub.3 (1.843 g, 13.34 mmol) in DMSO (20 mL) was stirred at 70° C. for 90 min. The reaction was cooled slightly and diluted with 200 mL of water. The resulting orange suspension was stirred vigorously for 60 min, isolated by filtration, the filtered solid was dried in the Buchner funnel for 20 min. The slightly wet solid was transferred to a beaker containing Et.sub.20 and the solid was further crushed with a spatula in order to remove excess water from the solid. The resulting solid was isolated by filtration, transferred to a 250 mL RB flask, and dried for 3 days at 56° C. in a vacuum oven to give the title product (2.31 g, 4.73 mmol, 78% yield) as a yellow powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.66 (d, J=2.27 Hz, 2H) 8.50 (t, J=5.56 Hz, 2H) 7.98-8.10 (m, 4H) 7.34 (br. s., 2H) 7.19 (d, J=9.09 Hz, 2H) 4.22 (br. s., 2H) 3.64-3.86 (m, 4H) 1.38 (s, 6H). LCMS (LCMS Method C): Rt=0.78 min, [M+H].sup.+=489.2

Step 4: 4,4′-((((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(azanediyl))bis(3-aminobenzamide)

[1082] ##STR00116##

[1083] A mixture of 4,4′-((((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)) bis(azanediyl))bis(3-nitrobenzamide) (2.293 g, 4.69 mmol) and 10% wet Pd/C (230 mg) in NMP (25 mL) in a 250 mL RB flask was evacuated and placed under a balloon of hydrogen for 18 h at rt followed by heating at 80° C. for 20 h. The reaction was then cooled and filtered through Celite® while washing with 4 mL of NMP. The filtrate containing the product was used directly in the next reaction as a solution in NMP. LCMS (LCMS Method C): Rt.=0.50 min, [M+H].sup.+=429.2

Step 5: 1,1′-(((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(2-amino-1H-benzo[d]imidazole-5-carboxamide), 2Hydrobromide

[1084] ##STR00117##

[1085] A solution of 4,4′-((((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))-bis(azanediyl))bis(3-aminobenzamide) (1.0 g, 2.334 mmol) in NMP (16 mL) was treated with cyanogen bromide (0.618 g, 5.83 mmol) and the homogeneous reaction was stirred at rt for 3 hrs. Additional cyanogen bromide (0.618 g) was added and the reaction was stirred for 18 hrs at rt. Additional cyanogen bromide (1.236 gm, 5.0 eq.) was then added and the reaction was stirred at rt. After 5.5 hrs, the reaction was heated at 72° C. for 55 min, cooled, and diluted with 160 mL EtOAc. The resulting suspension was stirred for 20 min and the solid was isolated by filtration washing with EtOAc. The resulting dark green, hygroscopic solid was transferred to a vial and dried in a vacuum oven at 40° C. for 3 days to afford the title product (1.35 g, 2.11 mmol, 90% yield) as a dark brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.99 (br. s., 1H) 8.87 (br. s., 3H) 8.10 (br. s., 2H) 7.85-7.91 (m, 4H) 7.68 (d, J=9.09 Hz, 2H) 7.49 (br. s., 2H) 4.69-4.76 (m, 2H) 4.55-4.63 (m, 2H) 4.36 (br. s., 2H) 1.25 (s, 6H). LCMS (LCMS Method C): Rt.=0.40 min, [M+H].sup.+=479.2

Step 6: 1,1′-(((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

[1086] ##STR00118##

[1087] A mixture of 1,1′-(((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(2-amino-1H-benzo[d]imidazole-5-carboxamide), 2 hydrobromide (0.6647 g, 1.038 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.32 g, 2.076 mmol), HATU (0.868 g, 2.284 mmol), and DIPEA (1.088 mL, 6.23 mmol) in NMP (4 mL) was heated at 140° C. for 30 min in a microwave reactor. The reaction was purified directly via reverse phase HPLC (Gilson®, 13-43% MeCN/0.1% TFA water, 15 min gradient, Luna column). The desired fractions were combined, concentrated in vacuo, and placed under high vacuum for 15 h to afford the title product (140.0 mg, 0.143 mmol, 13.7% yield) as a dark green solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.94 (br. s., 2H) 7.98 (s, 4H) 7.66-7.76 (m, 2H) 7.47 (d, J=8.59 Hz, 2H) 7.38 (br. s., 2H) 6.86 (s, 2H) 4.75 (d, J=10.11 Hz, 2H) 4.55-4.69 (m, 6H) 4.40 (br. s., 2H) 2.05 (s, 6H) 1.37 (t, J=7.20 Hz, 6H) 1.14 (s, 6H). LCMS (LCMS Method C): Rt.=0.84 min, [M+H].sup.+=751.6

Step 7: 1,1′-((2R,3R)-2,3-dihydroxybutane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

[1088] ##STR00119##

[1089] 1,1′-(((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt (113.8 mg, 0.116 mmol) was dissolved in formic acid (3.0 mL) and water (0.3 mL) and stirred at rt for 4 days. The reaction was concentrated in vacuo at rt to give a green solid. The crude solid was diluted with 1.4 mL of DMSO and purified by HPLC (Gilson® Autoprep, acidic Luna column, 5-35% MeCN: 0.1% TFA water, 7 min gradient). The desired fractions were concentrated in vacuo and placed under high vacuum for 3 days to yield 1,1′-((2R,3R)-2,3-dihydroxybutane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt (27 mg, 0.029 mmol, 24.7% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.89 (br. s., 2H) 8.00 (s, 4H) 7.79 (d, J=8.34 Hz, 2H) 7.55 (d, J=8.34 Hz, 2H) 7.35 (br. s., 2H) 6.59 (s, 2H) 5.50 (br. s, 2H), 4.51-4.67 (m, 4H) 4.27-4.47 (m, 4H) 4.09 (br. s., 2H) 2.09 (s, 6H) 1.32 (t, J=7.07 Hz, 6H). LCMS (LCMS Method C): rt=0.67 min, [M+H].sup.+=711.6.

Example 2

(E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide)

[1090] ##STR00120##

Step 1: 1-allyl-2-amino-1H-benzo[d]imidazole-5-carboxamide, hydrobromide

[1091] ##STR00121##

[1092] To a solution of 4-fluoro-3-nitrobenzamide (10.0 g, 54.3 mmol) in DMF (60 mL) was added allylamine (36.6 mL, 489 mmol) dropwise at rt and the mixture was stirred for 5 min. After this period, K.sub.2CO.sub.3 (15.01 g, 109 mmol) was added in one portion and the mixture was stirred at rt for 30 min. DMF was then removed in vacuo, the residue was suspended in 500 mL of water, the resulting orange precipitate was filtered off, washed with water, and dried in vacuo.

[1093] The above precipitate was dissolved in AcOH (600.0 mL), the flask was placed into a 20° C. water bath, and zinc (10.65 g, 163 mmol) was added carefully in small portions. The reaction was monitored by LCMS and additional zinc (approximately 3 eq) was added in small portions as needed until the reduction was complete. Upon reaction completion by LCMS, the solids were filtered off and the filtrate concentrated in vacuo. The evaporation residue was taken up in DCM (500 mL) and EtOH (150 mL) and washed with 15% aq. K.sub.2CO.sub.3 (100 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.

[1094] The above evaporation residue was dissolved in MeOH (200.0 mL), 5.0 M cyanogen bromide in CH.sub.3CN (11.95 mL, 59.7 mmol) was added rapidly in one portion, and the mixture was stirred at rt for 18 hr. After this period, the reaction mixture was concentrated in vacuo, then dissolved again in MeOH (200.0 mL). A mixture of toluene (100 mL) and CH.sub.3CN (100 mL) was added and the resulting mixture was concentrated to dryness at 40° C. (0-1 mbar) and dried in vacuo for 16 hr. to afford 1-allyl-2-amino-1H-benzo[d]imidazole-5-carboxamide, hydrobromide (11.3 g, 38.0 mmol, 70.0% yield) as a dark purple powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.83 (s, 2H), 8.07 (br. s., 1H), 7.88 (d, J=1.00 Hz, 1H), 7.82 (dd, J=8.41, 1.38 Hz, 1H), 7.52 (d, J=8.53 Hz, 1H), 7.43 (br. s., 1H), 5.87-6.02 (m, 1H), 5.25 (dd, J=10.42, 0.88 Hz, 1H), 5.17 (dd, J=17.32, 1.00 Hz, 1H), 4.84 (d, J=5.02 Hz, 2H); LCMS (LCMS Method C): Rt=0.38 min, [M+H].sup.+=216.9.

Step 2: 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1095] ##STR00122##

[1096] A 100 mL RB flask was charged with 1-allyl-2-amino-1H-benzo[d]imidazole-5-carboxamide, hydrobromide (2.5 g, 8.41 mmol), HATU (3.52 g, 9.25 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.427 g, 9.25 mmol), and NMP (25 mL). After 1 minute of stirring at rt, DIPEA (7.33 mL, 42.1 mmol) was added and the mixture was stirred at rt for 40 hr. After this period, 2.0 mL of water were added and the mixture was stirred for 30 min at rt. It was then poured into 500 mL of ice-cold water and stirred vigorously for 1 h. The dark purple solid was filtered off, brine (100 mL) was added, and the next crop of somewhat lighter precipitate was filtered off. The resulting clear pink filtrate was allowed to stand at rt for 4 day whereupon the lightest pink precipitate crashed out of the solution. This final precipitate was filtered off, washed with water, and air-dried to afford 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (1.88 g, 5.33 mmol, 63.4% yield) as a pale pink powder. .sup.1H NMR (400 MHz, DMSO-) δ ppm 12.84 (br. s., 1H), 8.01 (s, 1H), 7.96 (br. s., 1H), 7.78 (dd, J=8.44, 1.59 Hz, 1H), 7.46 (d, J=8.31 Hz, 1H), 7.32 (br. s., 1H), 6.66 (s, 1H), 5.94-6.05 (m, 1H), 5.21 (dd, J=10.27, 1.22 Hz, 1H), 5.15 (dd, J=17.12, 1.22 Hz, 1 H), 4.86 (d, J=5.14 Hz, 2H), 4.61 (q, J=6.93 Hz, 2H), 2.17 (s, 3H), 1.35 (t, J=7.09 Hz, 3H) LCMS (LCMS Method E): Rt=0.75 min, [M+H].sup.+=353.2.

Step 3: (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide)

[1097] ##STR00123##

[1098] To a solution of 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.199 mmol) in DCM (1.0 mL) and MeOH (1.0 mL) was added dropwise a solution of p-toluenesulfonic acid monohydrate (37.8 mg, 0.199 mmol) in MeOH (1.0 mL) and the resulting clear solution was concentrated in vacuo. The glassy evaporation residue was stirred with DCM (4.0 mL) until a milky suspension was obtained. Hoveyda-Grubbs 2nd gen. catalyst (18.67 mg, 0.030 mmol) was added into a 5 mL Biotage® sealed tube under N2 atm. The above milky suspension was then added and the mixture was heated to 80° C. for 4 h in a microwave reactor. After this period, 5.0 mL of MeOH was added, followed by a solution of 1.0 M KHMDS in THF (0.25 mL) in MeOH (1.0 mL). The mixture was stirred for 5 min at rt, concentrated in vacuo, and subjected to normal phase silica gel chromatography (Biotage® Ultra SNAP 25 g silica gel cartridge; 0-40% gradient MeOH/DCM) to afford a greenish-white solid. The solid was then washed with 0.2 mL of MeOH to remove the dark green ruthenium residue to afford (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide) (14 mg, 0.02 mmol, 19.8% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.82 (br. s., 2H), 7.97 (s, 2H), 7.94 (br. s, 2H), 7.71 (dd, J=8.34, 1.26 Hz, 2H), 7.44 (d, J=8.34 Hz, 2H), 7.34 (br. s., 2H), 6.55 (s, 2H), 5.93 (br. s., 2H), 4.83 (br. s., 4H), 4.53 (q, J=6.82 Hz, 4H), 2.12 (s, 6H), 1.27 (t, J=7.07 Hz, 6H); LCMS (LCMS Method C): Rt=0.79 min, [M+H].sup.+=677.5.

[1099] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (2E,2′E)-1,1′-((E)-but-2-ene-1,4-diyl)bis(2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide)

##STR00124##

Example 3

1,1′-((Methylazanediyl)bis(ethane-2,1-diyl))bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide), trifluoroacetic acid salt

[1100] ##STR00125##

Step 1

4,4′-(((Methylazanediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(3-nitrobenzamide)

[1101] ##STR00126##

[1102] A mixture of M-(2-aminoethyl)-M-methylethane-1,2-diamine (0.318 g, 2.72 mmol), K.sub.2CO.sub.3 (1.501 g, 10.86 mmol) and 4-fluoro-3-nitrobenzamide (1 g, 5.43 mmol) in DMSO (20 mL) was stirred at rt overnight. Water was added and the resulting precipitate was collected by filtration and was dried under reduced pressure to afford 4,4′-(((methylazanediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(3-nitrobenzamide) (800 mg, 1.62 mmol, 59.6% yield) as a yellow solid. LCMS (LCMS Method A): Rt=1.01 min, [M+H].sup.+=446.

Step 2

1,1′-((Methylazanediyl)bis(ethane-2,1-diyl))bis(2-amino-1/benzo[d]imidazole-5-carboxamide)

[1103] ##STR00127##

[1104] 4,4′-(((Methylazanediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(3-nitrobenzamide) (700 mg, 1.572 mmol) and 10% Pd/C (84 mg, 0.079 mmol) in NMP (20 mL) and MeOH (30 mL) was stirred under a hydrogen gas atmosphere at rt overnight. The catalyst was removed by filtration and the MeOH was removed under reduced pressure. Cyanogen bromide (416 mg, 3.93 mmol) was then added and the reaction mixture was stirred at 60° C. for 4 hr. Et.sub.2O was added and the resulting precipitate was collected by filtration and dried under reduced pressure to afford 1,1′-((methylazanediyl)bis(ethane-2,1-diyl))bis(2-amino-benzo-1/+[d]imidazole-5-carboxamide) (500 mg, 1.03 mmol, 65.8% yield) as a red solid. LCMS (LCMS Method A): Rt=0.94 min, [M+H].sup.+=435.8.

Step 3

1,1′-((Methylazanediyl)bis(ethane-2,1-diyl))bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide) trifluoroacetic acid salt

[1105] ##STR00128##

[1106] To a mixture of 1,1′-((methylazanediyl)bis(ethane-2,1-diyl))bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (300 mg, 0.689 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (212 mg, 1.378 mmol), HOAt (281 mg, 2.067 mmol) and EDC hydrochloride (396 mg, 2.067 mmol) in DMF (25 mL) was added DIPEA (267 mg, 2.067 mmol). The reaction mixture was stirred at rt overnight. The reaction was quenched with water (30 mL) and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson®, Gemini® C18 column, gradient 35-95% MeCN:H.sub.2O 0.1% TFA) to afford 1,1′-((methylazanediyl)bis(ethane-2,1-diyl))bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide) trifluoroacetic acid salt (130 mg, 0.18 mmol, 26% yield) as a gray solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.82 (s, 1H), 7.98 (s, 4H), 7.74 (d, J=8.0 Hz, 2H), 7.47 (s, 2H), 7.37 (s, 2H), 6.59 (s, 2H), 4.56 (d, J=6.7 Hz, 4H), 4.18 (s, 4H), 3.35 (s, 8H), 2.09 (s, 6H), 1.32-1.25 (m, 6H). LCMS (LCMS Method A): Rt=1.14 min, [M+H].sup.+=708.

Example 4

Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate

[1107] ##STR00129## ##STR00130## ##STR00131##

Step 1: tert-butyl (4-((4-carbamoyl-2-nitrophenyl)amino)butyl)carbamate

[1108] ##STR00132##

[1109] A mixture of tert-butyl (4-aminobutyl)carbamate (5.00 g, 26.6 mmol), 4-fluoro-3-nitrobenzamide (4.89 g, 26.6 mmol), and K.sub.2CO.sub.3 (4.04 g, 29.2 mmol) in DMSO (25 mL) was stirred at 70° C. for 2 h. The reaction was cooled to rt and slowly diluted with 125 mL of water via addition funnel. The resulting solid was isolated by filtration, dried in a Buchner funnel, and placed in a vacuum oven at 56° C. for 3 days to give the title compound (9.2 g, 26.1 mmol, 98% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.67 (d, J=2.02 Hz, 1H) 8.40 (t, J=5.43 Hz, 1H) 8.01 (d, J=6.82 Hz, 2H) 7.30 (br. s., 1H) 7.12 (d, J=9.09 Hz, 1H) 6.87 (br. s., 1H) 3.42 (q, J=6.57 Hz, 2H) 2.91-3.01 (m, 2H) 1.60 (d, J=6.57 Hz, 2H) 1.43-1.54 (m, 2H) 1.38 (s, 9H). LCMS (LCMS Method C): Rt.=0.86 min, [M+H].sup.+=353.

Step 2: tert-butyl (4-((2-amino-4-carbamoylphenyl)amino)butyl)carbamate

[1110] ##STR00133##

[1111] A 500 mL RB flask was charged with tert-butyl (4-((4-carbamoyl-2-nitrophenyl)amino)butyl)carbamate (9.2 g, 26.1 mmol), 10% Pd/C (0.920 g, 8.64 mmol) (Degussa wet type), EtOH (100 mL) and MeOH (100 mL). The flask was evacuated and placed under a balloon of hydrogen with stirring. A condenser was placed on top of the flask and the hydrogen balloon was placed atop the condenser. The mixture was stirred at rt for 20 h, then the flask was evacuated and the suspension was filtered through a bed of Celite® using EtOH to aid in rinsing. The filtrate was concentrated in vacuo and placed under high vacuum to give the title compound (8.4 g, 26.1 mmol, 100% yield) as a black solid. .sup.1H NMR (400 MHz, DMSO-d) δ ppm 7.44 (br. s., 1H) 7.04-7.15 (m, 2H) 6.85 (t, J=5.43 Hz, 1H) 6.74 (br. s., 1H) 6.37 (d, J=8.08 Hz, 1H) 4.89 (t, J=5.18 Hz, 1H) 4.60 (br. s., 2H) 3.07 (q, J=6.48 Hz, 2H) 2.97 (q, J=6.40 Hz, 2H) 1.45-1.64 (m, 4H) 1.39 (s, 9H). LCMS (LCMS Method C): Rt.=0.68 min, [M+H].sup.+=323.1

Step 3: tert-butyl (4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)carbamate, hydrobromide

[1112] ##STR00134##

[1113] tert-Butyl (4-((2-amino-4-carbamoylphenyl)amino)butyl)carbamate (8.40 g, 26.1 mmol) was dissolved in MeOH (110 mL) and a solution of 5M cyanogen bromide in CH.sub.3CN (5.73 mL, 28.7 mmol) was added via syringe. The dark reaction was capped and stirred for 15 h at rt. The reaction was concentrated in vacuo and placed under high vacuum to give the title compound (11.17 g, 26.1 mmol, 100% yield) as a dark solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (br. s., 1H) 8.74 (br. s., 2H) 8.08 (br. s., 1H) 7.80-7.90 (m, 2H) 7.64 (d, J=8.34 Hz, 1H) 7.44 (br. s., 1H) 6.89 (t, J=5.56 Hz, 1H) 4.15 (t, J=7.20 Hz, 2H) 2.96 (q, J=6.32 Hz, 2H) 1.66 (d, J=7.07 Hz, 2H) 1.42-1.50 (m, 2H) 1.38 (s, 9H). LCMS (LCMS Method C): Rt.=0.62 min, [M+H].sup.+=348.1

Step 4: tert-butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)carbamate

[1114] ##STR00135##

[1115] A mixture of tert-butyl (4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)carbamate, hydrobromide (11.17 g, 26.1 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4.82 g, 31.3 mmol), HATU (11.90 g, 31.3 mmol), DIPEA (18.22 mL, 104 mmol), and HOBt (1.997 g, 13.04 mmol) in DMF (100 mL) was stirred at rt for 21 h. The reaction was diluted with 300 mL of water and 300 mL of EtOAc, transferred to a separatory funnel, and the layers were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined EtOAc layers were washed with saturated NH.sub.4Cl (2×200 mL), water (1×200 mL), and brine (2×200 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and placed under high vacuum. The solid was purified via chromatography on silica gel (Isco® Combiflash, 0-20% MeOH:DCM, 330 gm column, loaded in 50 mL of DCM). The desired fractions were combined, concentrated in vacuo, and placed under high vacuum to give the title compound as a purple solid, (9.53 g, 19.71 mmol, 76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (s, 1H) 8.01 (br. s., 2H) 7.81 (d, J=8.34 Hz, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.36 (br. s., 1H) 6.80-6.86 (m, 1H) 6.68 (s, 1H) 4.64 (q, J=6.82 Hz, 2H) 4.23 (t, J=6.44 Hz, 2H) 2.98 (d, J=5.81 Hz, 2H) 2.19 (s, 3H) 1.76 (d, J=6.57 Hz, 2H) 1.40-1.48 (m, 2H) 1.30-1.40 (m, 13H). LCMS (LCMS Method C): Rt.=0.89 min, [M+H].sup.+=484.3

Step 5: 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, 2 hydrochloride

[1116] ##STR00136##

[1117] An ice-cooled 500 mL RB flask containing tert-butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)carbamate (9.53 g, 19.71 mmol) was treated with 4M HCl in 1,4-dioxane (42.0 mL, 168 mmol). The ice bath was removed and the purple slurry was stirred at rt for 2.5 h. The reaction was then concentrated in vacuo, placed under high vacuum, and the resulting solid was placed in a vacuum oven at 50° C. for 15 hrs and cooled under high vacuum to afford impure title compound as a grey solid which also contained 1,4-dioxane (11.89 grams, assumed 19.7 mmol, 100% yield). Material was used as is without further purification. .sup.1H NMR (400 MHz, DMSO-) δ ppm 12.91 (br. s, 1H) 8.03 (d, J=1.26 Hz, 2H) 7.77-7.87 (m, 4H) 7.62 (d, J=8.34 Hz, 1H) 7.38 (br. s., 1H) 6.70 (s, 1H) 6-5 ppm (br. s, 1H), 4.63 (q, J=7.07 Hz, 2H) 4.28 (t, J=6.57 Hz, 2H) 2.77-2.87 (m, 2H) 2.20 (s, 3H) 1.81-1.91 (m, 2H) 1.52-1.60 (m, 2H) 1.38 (t, J=7.07 Hz, 3H). LCMS (LCMS Method C): Rt.=0.60 min, [M+H].sup.+=384.2

Step 6: Methyl 4-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)amino)-3-methoxy-5-nitrobenzoate

[1118] ##STR00137##

[1119] A 250 mL 3-neck RB flask equipped with a condenser, a large stir bar, and an internal thermometer was charged with 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, 2 hydrochloride (9.38 g, 20.55 mmol) and methyl 4-chloro-3-methoxy-5-nitrobenzoate (5.048 g, 20.55 mmol). DMSO (50 mL) was added followed by DIPEA (17.95 mL, 103 mmol) and the dark suspension was heated at 100° C. for approximately 24 h, cooled, and added dropwise to 500 mL of stirred water. After the addition was complete, the resulting orange suspension was stirred for 20 min and filtered. The isolated orange-red paste was washed with water and hexanes, dried in the Buchner funnel, and then in a vacuum oven at 56° C. for 20 hrs. The reddish solid was then triturated with Et.sub.20 (60 mL) and isolated by filtration. The trituration and filtration was repeated. The resulting solid was placed in a vacuum oven at 56° C. for 3 days to give afford the title compound (11.17 g, 18.85 mmol, 92% yield) as a reddish solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.78 (br. s., 1H) 8.12 (s, 1H) 7.99 (s, 1H) 7.93 (d, J=7.53 Hz, 2H) 7.79 (d, J=8.28 Hz, 1H) 7.53 (d, J=7.78 Hz, 1H) 7.36 (s, 1H) 7.31 (br. s., 1H) 6.60 (s, 1H) 4.60 (d, J=7.03 Hz, 2H) 4.23 (br. s., 2H) 3.84 (s, 3H) 3.80 (s, 3H) 3.53 (d, J=5.77 Hz, 2H) 2.15 (s, 3H) 1.82 (br. s., 2H) 1.62 (br. s., 2H) 1.35 (t, J=7.03 Hz, 3H). LCMS (LCMS Method D): Rt.=0.67 min, [M+H].sup.+=711.6

Step 7: Methyl 3-amino-4-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)amino)-5-methoxybenzoate

[1120] ##STR00138##

[1121] Methyl 4-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)amino)-3-methoxy-5-nitrobenzoate (5.0 g, 8.44 mmol) was mostly dissolved in DMF (50 mL) with stirring at rt in a 250 mL RB flask. Raney nickel (Raney 2800 nickel in water, ca. 10 mL of slurry, Aldrich) was added and a condenser was added atop the flask. A 3-way stopcock adapter with an attached hydrogen balloon was placed on top of the condenser and the setup was evacuated, filled with hydrogen, evacuated, and finally filled with hydrogen. The reaction was heated at 70° C. for 7 h. An additional 8 mL of Raney nickel slurry were added and the reaction was heated at 70° C. for 14 h. The reaction was cooled and filtered through Celite® while washing with DMF. The filtrate, a solution of ca. 100 mL DMF and 20 mL water from the Raney nickel slurry, containing the desired product was used as a solution directly in the next reaction. Assumed quantitative yield. LCMS (LCMS Method D): Rt.=0.73 min, [M+H].sup.+=563.4

Step 8: Methyl 2-amino-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate, Hydrobromide

[1122] ##STR00139##

[1123] Methyl 3-amino-4-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)amino)-5-methoxybenzoate (solution in DMF/water from previous step) was treated with 5M cyanogen bromide in CH.sub.3CN (1.875 mL, 9.37 mmol) and the resulting solution was stirred at rt for 22 hrs. The reaction was concentrated in vacuo and placed under high vacuum to give a brown semi-solid. The semi-solid was triturated with EtOAc, stirred vigorously for 30 min, and the resulting solid was isolated by filtration and dried in a Buchner funnel to provide impure title product as a tan solid (5.08 g). This impure material was used without purification. LCMS (LCMS Method D): Rt.=0.72 min, [M+H].sup.+=588.5.

Example 4

Step 9: Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate

[1124] ##STR00140##

[1125] A mixture of methyl 2-amino-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate, hydrobromide (5.073 g, 7.59 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.287 g, 8.35 mmol), HATU (3.46 g, 9.11 mmol), and DIPEA (3.98 mL, 22.76 mmol) in DMF (30 mL) was stirred at rt for 17 hrs. The reaction was concentrated in vacuo then the resulting residue was triturated with water (100 mL) and stirred for 30 min. The resulting suspension was filtered and partially dried in a Buchner funnel to give a dark tan solid. The solid was mostly dissolved in 150 mL of 10% IPA:chloroform, diluted with water and filtered. The filtrate layers were then separated and the organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated, and placed under high vacuum to give a tan solid. The solid was triturated with warm 10% IPA:chloroform (100 mL) and filtered. The filtrate layers were separated, the organic layer was dried over Na.sub.2SO.sub.4, filtered, added to the original tan solid, concentrated in vacuo and placed under high vacuum. The solid was purified via chromatography on silica gel (Biotage® Isolera, 120 gm Gold column, 0-10% MeOH:DCM over 30 min, loaded as a solution in DCM/MeOH). The desired product fractions were combined, concentrated, and placed under high vacuum to give a light tan solid. The solid was triturated with DCM (50 mL) and isolated by filtration, and placed in a vacuum oven at 56° C. for 30 h to provide methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate as a white solid (1.0 g, 1.4 mmol, 18% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.89 (s, 1H) 12.82 (s, 1H) 7.90-8.01 (m, 2H) 7.70-7.81 (m, 2H) 7.53 (d, J=8.28 Hz, 1 H) 7.30-7.40 (m, 2H) 6.59 (d, J=5.02 Hz, 2H) 4.50-4.64 (m, 4H) 4.38 (br. s., 2H) 4.27 (br. s., 2H) 3.87 (d, J=3.76 Hz, 6H) 2.10 (s, 6H) 1.86 (br. s., 4H) 1.23-1.39 (m, 6H).

[1126] LCMS (LCMS Method D): Rt.=1.00 min, [M+H].sup.+=724.5.

Example 5

1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2 trifluoroacetic acid salt

[1127] ##STR00141##

[1128] Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (0.1624 g, 0.224 mmol) was suspended in NH.sub.4OH (50 mL, 725 mmol) and the reaction was stirred for 6 days at rt. The reaction was concentrated in vacuo and the residue was purified via HPLC (Gilson® Autoprep, acidic Luna column, loaded as a solution in DMSO, 20%-50% MeCN:water w/0.1% TFA). The desired fractions were combined and concentrated to give a white solid. The solid was purified again (Gilson® Autoprep, acidic Luna column, loaded as a solution in DMSO, 20-50% MeCN:water w/0.1% TFA) and the desired fractions were combined, concentrated, placed under high vacuum, and then dried in the vacuum oven for 15 h at 56° C. to afford 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2 trifluoroacetic acid salt as a white solid (76 mg, 0.081 mmol, 36% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.79 (br. s., 1H) 7.97 (d, =1.47 Hz, 3H) 7.76 (dd, J=8.56, 1.47 Hz, 1H) 7.64 (d, J=1.22 Hz, 1H) 7.53 (d, J=8.31 Hz, 1H) 7.27-7.39 (m, 3H) 6.60 (d, J=8.31 Hz, 2H) 4.57 (quin, J=7.09 Hz, 4H) 4.37 (br. s., 2H) 4.28 (br. s., 2H) 3.82 (s, 3H) 2.11 (d, J=4.16 Hz, 6H) 1.86 (br. s., 4H) 1.31 (td, J=7.03, 4.52 Hz, 6H). LCMS (LCMS Method E): Rt.=0.85 min, [M+H].sup.+=709.5

Example 6

(E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

[1129] ##STR00142##

Step 1: 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide

[1130] ##STR00143##

[1131] (3-bromopropoxy)(tert-butyl)dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-5-nitrobenzamide (4.8 g, 22.16 mmol) was added followed by K.sub.2CO.sub.3 (6.13 g, 44.3 mmol) and stirred for 2 hr at 100° C. under nitrogen. The reaction was cooled to rt, poured into EtOAc (600 mL), washed with water (600 mL), brine, dried with MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-80% hexanes/EtOAc to afford the title compound (7.43 g, 19.1 mmol, 86% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.29 (br. s., 1H), 8.05 (d, J=1.71 Hz, 1H), 7.89 (d, J=1.71 Hz, 1H), 7.77 (br. s., 1H), 4.30 (t, J=5.99 Hz, 2H), 3.80 (t, J=5.99 Hz, 2H), 1.98 (quin, J=5.99 Hz, 2H), 0.80-0.90 (m, 9H), 0.02 (s, 6H). LCMS (LCMS Method E): Rt=1.40 min, [M+H].sup.+=389.

Step 2: 4-(allylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5-nitrobenzamide

[1132] ##STR00144##

[1133] 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide (2.05 g, 5.27 mmol) was dissolved in dry NMP (12 mL), allylamine (1.204 g, 21.08 mmol) was added and the reaction heated to 120° C. in a microwave reactor for 30 min. To the reaction was added additional allylamine (900 mg, 15.8 mmol) and heated at 120° C. for an additional 20 min. The reaction was poured into EtOAc (150 mL), washed with water (150 mL), brine, dried with MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-80% hexanes/EtOAc to afford the title compound (1.99 g, 4.86 mmol, 92% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.19 (s, 1H), 8.02 (br. s., 1H), 7.74 (t, J=6.02 Hz, 1H), 7.57 (s, 1H), 7.31 (br. s., 1H), 5.89 (ddt, J=16.53, 10.89, 5.36, 5.36 Hz, 1H), 5.05-5.19 (m, 2H), 4.09-4.22 (m, 4H), 3.79 (t, J=5.90 Hz, 2H), 1.99 (t, J=5.77 Hz, 2H), 0.87 (s, 9H), 0.04 (s, 6H). LC-MS (LCMS Method D): Rt=1.41 min, [M+H].sup.+=410.

Step 3: 4-(allylamino)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzamide

[1134] ##STR00145##

[1135] 4-(allylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5-nitrobenzamide (1.91 g, 4.66 mmol) was dissolved in AcOH (13.3 mL), zinc powder (1.220 g, 18.65 mmol) was added (in one portion) and the reaction stirred at rt under nitrogen. After 45 min an additional portion of zinc was added (610 mg, 9.32 mmol) and stirred an additional 2 hr at rt. The reaction was filtered, the filtrate poured into EtOAc (125 mL), washed with 10% aq Na.sub.2CO.sub.3 (125 mL), brine, dried with MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.60 (br. s., 1H), 6.93 (d, J=8.80 Hz, 1H), 6.85 (d, J=1.71 Hz, 1 H), 6.78 (d, J=1.96 Hz, 1H), 5.82-5.95 (m, 1H), 5.14 (dd, J=17.12, 1.96 Hz, 1H), 4.95-5.08 (m, 1H), 4.68 (br. s., 1H), 3.97-4.07 (m, 2H), 3.71-3.86 (m, 2H), 3.60 (d, J=5.87 Hz, 1H), 1.84-1.96 (m, 4H), 0.75-0.92 (m, 9H), −0.02-0.08 (m, 6H). LC-MS (LCMS Method D): Rt=1.04 min, [M+H].sup.+=380.

Step 4: 1-allyl-2-amino-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1H-benzo[d]imidazole-5-carboxamide, Hydrobromide

[1136] ##STR00146##

[1137] 4-(allylamino)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzamide (1.769 g, 4.66 mmol) was dissolved in dry MeOH (25 mL), cyanogen bromide (0.543 g, 5.13 mmol) was added and the reaction stirred overnight at rt under nitrogen. The reaction was concentrated in vacuo and the residue stirred with EtOAc (20 mL) at rt for 30 min. The solids were isolated by filtration and dried to afford the title compound (1.56 g, 3.21 mmol, 69% yield). .sup.1H NMR (400 MHz, DMSO-) δ ppm 12.94 (br. s., 1H), 8.60 (br. s., 2H), 8.08 (br. s., 1H), 7.51 (d, J=0.98 Hz, 1H), 7.43 (d, J=0.98 Hz, 2H), 5.92-6.08 (m, 1H), 5.21 (dd, J=10.51, 0.98 Hz, 1 H), 4.98-5.08 (m, 1H), 4.92 (d, J=4.65 Hz, 1H), 4.16-4.29 (m, 2H), 3.74-3.81 (m, 2H), 1.93-2.07 (m, 2H), 0.81-0.91 (m, 9H), −0.04-0.07 (m, 6H). LC-MS (LCMS Method D): Rt=1.02 min, [M+H].sup.+=405.

Step 5: 1-allyl-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1138] ##STR00147##

[1139] 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.579 g, 3.76 mmol), HATU (1.429 g, 3.76 mmol) and HOBt (0.240 g, 1.565 mmol) were combined with dry DMF (12 mL). Et.sub.3N (1.7 mL, 12.52 mmol) was added and the reaction stirred at rt for 5 min. To the reaction was added 1-allyl-2-amino-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1H-benzo[d]imidazole-5-carboxamide, hydrobromide (1.52 g, 3.13 mmol) and stirred at rt overnight under nitrogen. The reaction was poured into EtOAc (120 mL), washed with water (120 mL), brine, dried (MgSO.sub.4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 80-100% EtOAc/hexanes to afford the title compound (1.07 g, 1.98 mmol, 63% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (br. s., 1H), 7.91-8.05 (m, 1H), 7.67 (s, 1H), 7.37 (s, 1H), 7.32 (br. s., 1H), 6.63 (s, 1H), 5.96-6.13 (m, 1H), 5.14 (d, J=9.29 Hz, 1H), 4.91-5.03 (m, 3H), 4.61 (q, J=7.01 Hz, 2H), 4.24 (t, J=5.87 Hz, 2 H), 3.81 (t, J=6.11 Hz, 2H), 2.18 (s, 3H), 1.93-2.07 (m, 2H), 1.34 (t, −7.09 Hz, 3H), 0.80-0.92 (m, 9H), 0.04 (s, 6H). LC-MS (LCMS Method D): Rt=1.40 min, [M+H].sup.+=541.

Step 6: 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

[1140] ##STR00148##

[1141] 1-allyl-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (700 mg, 1.30 mmol) was dissolved in dry THF (6 mL), AcOH (0.15 mL, 2.60 mmol) was added followed by TBAF (2.6 mL, 1M in THF). The reaction was stirred overnight at rt under nitrogen and poured into EtOAc and water (40 mL each) and shaken vigorously. Insoluble material was filtered and dried to afford the 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide (460 mg, 1.08 mmol, 83%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (br. s., 1H), 7.99 (br. s., 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.32 (br. s., 1H), 6.62 (s, 1H), 5.98-6.12 (m, 1H), 5.15 (d, J=9.05 Hz, 1H), 4.92-5.04 (m, 3H), 4.54-4.68 (m, 3H), 4.24 (t, J=6.24 Hz, 2H), 3.63 (q, J=6.11 Hz, 2H), 2.18 (s, 3H), 1.97 (quin, J=6.17 Hz, 2H), 1.35 (t, J=7.09 Hz, 3H). LC-MS (LCMS Method D): Rt=0.79 min, [M+H].sup.+=427.

Example 6

Step 7: (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

[1142] ##STR00149##

[1143] 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide (100 mg, 0.23 mmol) was dissolved in 1:1 DCM:MeOH (5 mL). To the solution was added TsOH—H.sub.2O (45 mg, 0.23 mmol) as a solution in MeOH (1.5 mL) and the reaction was concentrated in vacuo. To the residue was added DCM (5 mL) and the fine suspension transferred to a microwave vial containing (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxy benzylidene)ruthenium(VI) chloride (22 mg, 0.035 mmol). The flask was degassed and heated at 80° C. in a microwave reactor for 3 h. The reaction was treated with MeOH (3 mL) and evaporated under nitrogen. The residue was purified by HPLC (Gilson®, eluting with 10-60% ACN/water/0.1% TFA) and the product-containing fractions were collected and lyophilized to afford (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt (57 mg, 23% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (br. s., 2H) 7.99 (br. s., 2H) 7.64 (s, 2H) 7.35 (br. s., 2H) 7.31 (s, 2H) 6.52 (s, 2H) 5.81 (br. s., 2H) 4.91 (br. s., 4H) 4.52 (q, J=6.93 Hz, 5H) 4.02 (t, J=6.36 Hz, 5H) 3.41 (t, J=5.99 Hz, 4H) 2.06-2.15 (m, 6H) 1.59-1.70 (m, 4H) 1.27 (t, J=7.09 Hz, 6H). LC-MS (LCMS Method D): Rt=0.81 min, [M+H].sup.+=825.

[1144] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (2E,2′E)-1,1′-((E)-but-2-ene-1,4-diyl)bis(2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide), 2 trifluoroacetic acid salt

##STR00150##

Example 7

8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1145] ##STR00151##

Step 1: 1-allyl-2-(1-(5-(5-((1-allyl-5-carbamoyl-1H-benzo[d]imidazol-2-yl)carbamoyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1146] ##STR00152##

[1147] A 5.0 mL Biotage® sealed tube was charged with 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (634 mg, 1.820 mmol), 1-allyl-2-amino-1H-benzo[d]imidazole-5-carboxamide, hydrobromide (1352 mg, 4.55 mmol), HATU (1730 mg, 4.55 mmol), and NMP (13 mL). After 1 minute of stirring at rt, DIPEA (3.17 mL, 18.20 mmol) was added and the mixture was stirred at rt for 5 min, then heated in a microwave reactor at 140° C. for 1 hr. After this period, 5.0 mL of water was added and the mixture was stirred at rt for 5 min. It was then poured into 250 mL of ice-cold water and stirred vigorously for 1 hr. The resulting solid was filtered off, washed with water, dissolved from the filter using MeOH/DCM, concentrated in vacuo, and subjected to silica gel chromatography (Biotage® Ultra SNAP 100 g SiO.sub.2 column: 0-40% MeOH/EtOAc) to yield 1-allyl-2-(1-(5-(5-((1-allyl-5-carbamoyl-1H-benzo[d]imidazol-2-yl)carbamoyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (840 mg, 1.128 mmol, 62% yield) as a pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.88 (s, 1H), 12.81 (s, 1H), 7.99-8.02 (m, 2H), 7.97 (br. s., 2H), 7.77 (ddd, J=8.34, 3.66, 1.39 Hz, 2H), 7.41 (dd, J=16.93, 8.34 Hz, 2H), 7.34 (br. s., 2H), 6.65 (s, 1H), 5.87-6.02 (m, 2H), 4.99-5.22 (m, 4H), 4.82 (dd, J=11.62, 4.80 Hz, 4H), 4.50-4.61 (m, 4H), 2.73 (t, J=7.45 Hz, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 1.71-1.85 (m, 2H), 1.45-1.55 (m, 2 H), 1.27-1.34 (m, 5H); LCMS (LCMS Method C): Rt=0.93 min, [M+H].sup.+=745.7.

Step 2: 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1148] ##STR00153##

[1149] Four 20 mL Biotage® microwave sealed tubes were charged with a total of 1-allyl-2-(1-(5-(5-((1-allyl-5-carbamoyl-1H-benzo[d]imidazol-2-yl)carbamoyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (160 mg, 0.215 mmol), Hoveyda-Grubbs II catalyst (26.9 mg, 0.043 mmol), and freshly degassed 1,2-dichloroethane (DCE) (80 mL). The sealed tubes were heated in a microwave reactor for 4 hr at 100° C. After the mixture cooled to rt, MeOH (1.0 mL) was added to each tube and the resulting clear solution was stirred at rt for 5 min. A solution of potassium 2-isocyanoacetate (15 mg in 1.5 mL of MeOH) was added to each tube and the resulting mixture was stirred at rt for 5 min. The tubes were combined, concentrated in vacuo, then the evaporation residue was taken up in a minimal volume of DCM/MeOH, and purified by silica gel chromatography (Biotage® Ultra SNAP 100 g SiO.sub.2 column; 0-40% MeOH/EtOAc) to afford the desired product (61 mg) as a pale green solid with a mixture of alkene isomers. The product was further purified (Biotage® Ultra SNAP 25 g SiO.sub.2 column; 0-20% MeOH/DCM gradient) to yield 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide as a 7:1 trans:cis mixture (54 mg, 0.075 mmol, 35% yield). Characterization of the trans isomer: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.87 (s, 1H), 12.84 (s, 1H), 7.98 (br. s., 4H), 7.77 (dd, J=7.71, 3.16 Hz, 2H), 7.33-7.48 (m, 4H), 6.55 (s, 1H), 5.89-5.98 (m, 1H), 5.66-5.75 (m, 1H), 4.90 (d, J=7.83 Hz, 4 H), 4.73 (t, J=6.95 Hz, 2H), 4.47 (q, J=6.99 Hz, 2H), 2.72-2.80 (m, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1.72 (br. s., 2H), 1.44 (br. s., 2H), 1.30 (t, J=7.07 Hz, 5H); LCMS (LCMS Method C): Rt=0.82 min, [M+H].sup.+=717.6.

Example 7

Step 3: 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1150] ##STR00154##

[1151] A RB flask was charged with 10% Pd/C (200 mg, 0.188 mmol) and purged with nitrogen. A solution of 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide (100 mg, 0.140 mmol, 7:1 trans:cis mixture) in a mixture of MeOH (20.0 mL) and THF (20.0 mL) was added, the flask was purged with hydrogen, and the reaction mixture was stirred under hydrogen atmosphere (1 atm) for 23 hr. The flask was then opened to air, stirred vigorously for 15 min and filtered, the Pd/C washed with MeOH/THF, the filtrate concentrated in vacuo, and subjected to silica gel chromatography (Biotage® Ultra SNAP 25 g SiO.sub.2 column; 0-20% MeOH/DCM) to yield 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-1][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide (56 mg, 0.078 mmol, 55.8% yield) as a pale pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.88 (br. s., 2H), 8.02 (s, 4 H), 7.79-7.87 (m, 2H), 7.67 (d, J=8.34 Hz, 1H), 7.63 (d, J=8.34 Hz, 1H), 7.37 (br. s., 2H), 6.57 (s, 1H), 4.74 (t, J=6.57 Hz, 2H), 4.48 (q, J=6.99 Hz, 2H), 4.19-4.31 (m, 4H), 2.78-2.86 (m, 2H), 2.16 (s, 3H), 2.08 (s, 3H), 1.91 (br. s., 4H), 1.77-1.86 (m, 2H), 1.44-1.54 (m, 2H), 1.35-1.42 (m, 2H), 1.29 (t, J=7.07 Hz, 3H); LCMS (LCMS Method C): Rt=0.81 min, [M+H].sup.+=719.7.

Example 8

8-Ethyl-10,18,30-trimethyl-7,20-dioxo-7,8,11,12,13,14,15,20,21,28,29,30,31,32-tetradecahydro-1/benzo[4,5]imidazo[2,1-b]benzo[4,5]imidazo[1,2-/]dipyrazolo[5,1-m:4′,3′-t][1,3,6,9,11,14]hexaazacyclodocosine-3,24-dicarboxamide

[1152] ##STR00155##

Example 8

8-Ethyl-10,18,30-trimethyl-7,20-dioxo-7,8,11,12,13,14,15,20,21,28,29,30,31,32-tetradecahydro-1H-benzo[4,5]imidazo[2,1-b]benzo[4,5]imidazo[1,2-i]dipyrazolo[5,1-m:4′,3′-t][1,3,6,9,11,14]hexaazacyclodocosine-3,24-dicarboxamide

[1153] ##STR00156##

[1154] To a solution of 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (576 mg, 1.516 mmol), 1,1′-((methylazanediyl)bis(ethane-2,1-diyl))bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (300 mg, 0.689 mmol, from Example 3) and 4-(5-(5-carboxy-3-methyl-1/pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (240 mg, 0.689 mmol) in NMP (10 mL) was added DIPEA (267 mg, 2.067 mmol). The reaction mixture was stirred at rt for 0.5 h and then the reaction was heated in a microwave reactor at 140° C. for 1 h (150 W). The reaction mixture was allowed to cool to rt, water was added and the mixture was extracted with DCM. The organic phase was washed with water (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson®, Gemini® C18 column, gradient 2-95% MeCN:H.sub.2O 0.1% TFA) to afford 8-ethyl-10,18,30-trimethyl-7,20-dioxo-7,8,11,12,13,14,15,20,21,28,29,30,31,32-tetradecahydro-benzo[4,5]imidazo[2,1-b]benzo[4,5]imidazo[1,2-/]dipyrazolo[5,1-m:4′,3′-t][1,3,6,9,11,14]hexaazacyclodocosine-3,24-dicarboxamide (25 mg, 0.03 mmol, 4.56% yield) as a brown solid. 1H-NMR (400 MHz, CD30D) δ ppm 8.00 (d, J=12.0 Hz, 2H), 7.92-7.87 (m, 2H), 7.57 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 4.79-4.77 (m, 2H), 4.70-4.67 (m, 2H), 4.57-4.51 (m, 4H), 3.98 (s, 2H), 3.78 (s, 2H), 3.15 (s, 3H), 2.78 (t, J=8.0 Hz, 2H), 2.18-2.15 (m, 6H), 1.81-1.74 (m, 2H), 1.39-1.33 (m, 6H), 1.17-1.07 (s, 2H). LCMS (LCMS Method A): Rt=1.26 min, [M+H].sup.+=748.

Example 9

1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,17,18,19-hexahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[1,2,3-cd:11,10,9-c′d′]diindene-4,12-dicarboxamide

[1155] ##STR00157##

Step 1: 5,5′-(propane-1,3-diylbis(oxy))bis(4-chloro-3-nitrobenzamide)

[1156] ##STR00158##

[1157] 4-chloro-3-hydroxy-5-nitrobenzamide (2 g, 9.23 mmol), 1,3-dibromopropane (932 mg, 4.62 mmol), DIPEA (3.23 mL, 18.47 mmol) were stirred in NMP (5 mL) in a 20 mL microwave vial. The reaction was then heated in microwave reactor at 100° C. for 15 min. Water (30 mL) was added to the reaction and the precipitate was isolated by filtration and washed with water. The solid was then dried in vacuo at 55° C. overnight to afford the title compound (3 g, 5.71 mmol, 61.8% yield). LCMS (LCMS Method D) Rt=0.99 mins, [M+H].sup.+=473.1.

Step 2: 1,13-dinitro-7,8,14,15,16,17,18,19-octahydro-6H-dibenzo[b,j][1,12,4,9]dioxadiazacyclopentadecine-3,11-dicarboxamide

[1158] ##STR00159##

[1159] 5,5′-(propane-1,3-diylbis(oxy))bis(4-chloro-3-nitrobenzamide) (2700 mg, 5.71 mmol), butane-1,4-diamine (503 mg, 5.71 mmol), DIPEA (2.491 mL, 14.26 mmol), were stirred in DMSO (8 mL) in a 20 mL microwave vial. It was then heated in microwave at 120° C. for 15 min. The reaction was diluted with water and filtered to afford the desired product as orange solid. The solid was then dried in vacuo at 55° C. overnight to give the orange solid (approximately 2.5 g, 5.12 mmol, 90% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.20-8.16 (m, 2H), 8.05-7.95 (m, 4H), 7.62 (d, J=1.71 Hz, 2H), 4.32 (t, J=5.26 Hz, 4H), 3.56-3.42 (m, 4H), 2.47-2.38 (m, 2H), 1.65 (br. s., 4H). LCMS (LCMS Method D) Rt=0.93 min, [M+H].sup.+=489.2.

Step 3: 1,13-diamino-7,8,14,15,16,17,18,19-octahydro-6H-dibenzo[b,j][1,12,4,9]dioxadiazacyclopentadecine-3,11-dicarboxamide

[1160] ##STR00160##

[1161] In a 50 mL RB flask, 1,13-dinitro-7,8,14,15,16,17,18,19-octahydro-6H-dibenzo[b,j][1,12,4,9] dioxadiazacyclopentadecine-3,11-dicarboxamide (2.5 g, 5.12 mmol) was stirred in AcOH (14.7 mL, 256 mmol). Zinc (1.67 g, 25.6 mmol) was then added in portions and the reaction was stirred at rt for 1 hr. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The material was purified by HPLC (Gilson®, Gemini® column: CH.sub.3CN, 0.1% NH.sub.4OH/water gradient 2-20%) to afford the title compound (90 mg, 0.2 mmol, 3.9% yield). LCMS (LCMS Method D) Rt=0.39 mins, [M+H].sup.+=429.3.

Step 4: 1,15-diamino-8,9,16,17,18,19-hexahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[1,2,3-cd:11,10,9-c′d′]diindene-4,12-dicarboxamide

[1162] ##STR00161##

[1163] In a 20 mL reaction vial, 1,13-diamino-7,8,14,15,16,17,18,19-octahydro-6H-dibenzo[b,j] [1,12,4,9]dioxadiazacyclopentadecine-3,11-dicarboxamide (140 mg, 0.327 mmol) was stirred in MeOH (5 mL) and treated with cyanogen bromide (69.2 mg, 0.653 mmol). The reaction mixture was stirred at rt overnight. Water (10 mL) was then added to the reaction mixture, the solid was isolated by filtration and was dried in vacuo overnight to afford the title compound (100 mg, 0.188 mmol, 57.6% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.04 (d, J=2.01 Hz, 2H), 6.97 (d, 1-1.76 Hz, 2H), 4.30 (s, 4H), 3.04 (br. s., 4H), 2.46-2.33 (m, 2H), 1.45 (br. s., 4H). LCMS (LCMS Method D) Rt=0.47 mins, [M+H].sup.+=479.3.

Example 9

Step 5: 1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,17,18,19-hexahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[1,2,3-cd:11,10,9-c′d′]diindene-4,12-dicarboxamide

[1164] ##STR00162##

[1165] To a 20 mL reaction vial was added 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (90 mg, 0.581 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluoro-phosphate(V) (221 mg, 0.581 mmol), DIPEA (0.135 mL, 0.775 mmol), DMF (5 mL), followed by the addition of 1,15-diamino-8,9,16,17,18,19-hexahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[1,2,3-cd:11,10,9-c′d′]diindene-4,12-dicarboxamide (90 mg, 0.194 mmol). The reaction vial was sealed and heated to 140° C. for 30 min. Water (20 mL) was added to the solution and the resulting solid was isolated by filtration and dried in air to give a brown solid. The crude product was then dissolved in DMSO (6 mL) and water was added (20 mL). The resulting solid was isolated by filtration and dried in vacuo to afford 1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,17,18,19-hexahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[1,2,3-cd:11,10,9-c′d′]diindene-4,12-dicarboxamide (50 mg, 0.063 mmol, 32.7% yield) as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (br. s., 2H), 8.00 (br. s., 2H), 7.67 (s, 2H), 7.46 (s, 2H), 7.37 (br. s., 2H), 6.59 (s, 2 H), 4.60 (d, J=6.78 Hz, 4H), 4.48 (d, J=4.52 Hz, 4H), 4.38 (br. s., 4H), 2.55 (s, 6H), 2.12 (s, 4H), 2.06 (d, J=6.02 Hz, 2H), 1.33 (t, J=7.03 Hz, 6H) LCMS (LCMS Method D) Rt=0.92 mins, [M+H].sup.+=751.5.

Example 10

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

[1166] ##STR00163## ##STR00164##

Step 1: (E)-1-(4-((2-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1167] ##STR00165##

[1168] A microwave tube containing (E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide hydrochloride (517 mg, 1.24 mmol, in DMSO (10 mL) was treated with TEA (0.28 mL, 2.0 mmol), followed by K.sub.2CO.sub.3 (274 mg, 1.98 mmol) and 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide (385 mg, 0.990 mmol). The reaction was heated to 75° C. After 7 hr, the mixture was concentrated, and the residue was purified over silica gel, eluting with 10-90% EtOAc to remove impurities, followed by 0-10% MeOH in DCM to yield the title compound (200 mg, 0.273 mmol, 28% yield) as an orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.16 (d, J=1.52 Hz, 1H), 7.94-8.08 (m, 3H), 7.74 (d, J=8.11 Hz, 2H), 7.50 (s, 1H), 7.31-7.43 (m, 3H), 6.62 (s, 1H), 5.74-5.81 (m, 2H), 4.80 (br. s., 2H), 4.59 (d, J=6.84 Hz, 2H), 4.13 (br. s., 2H), 4.01 (t, J=6.08 Hz, 2H), 3.63 (t, J=5.96 Hz, 2H), 2.16 (s, 3H), 1.76-1.88 (m, 2H), 1.33 (t, J=7.10 Hz, 3H), 0.74-0.82 (m, 9H), −0.06 (s, 6H); LCMS (LCMS Method D): Rt=1.23 min, [M+H].sup.+=734.6

Step 2: (E)-1-(4-((2-Amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1169] ##STR00166##

[1170] (E)-1-(4-((2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (1 g, 1.363 mmol) was suspended in MeOH (20 mL) and ammonium hydroxide (4.62 mL, 34.1 mmol) was added and stirred for 5 mins at RT. Sodium hydrosulfite (1.675 g, 8.18 mmol) in Water (5 mL) was then added. After 60 mins, EtOAc (300 ml) was added and the mixture was extracted with water (50 ml×3). The organic phase was separated, dried with Na.sub.2SO.sub.4, and concentrated in vacuo to afford title compound (710 mg, 1.009 mmol, 74.0% yield) as light yellow solid which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.80 (br. s., 1H), 8.00 (s, 1H), 7.97 (br. s., 1H), 7.75 (dd, J=8.49, 1.14 Hz, 1H), 7.63 (br. s., 1H), 7.28-7.41 (m, 2H), 7.00 (br. s., 1H), 6.84 (d, J=1.52 Hz, 1H), 6.74 (d, J=1.52 Hz, 1H), 6.65 (s, 1H), 5.79-5.96 (m, 1H), 5.64-5.78 (m, 1H), 4.81 (d, J=4.82 Hz, 2H), 4.68 (br. s., 2H), 4.61 (d, J=7.10 Hz, 2H), 3.92 (t, J=5.83 Hz, 2H), 3.84 (br. s., 1H), 3.63 (t, J=6.08 Hz, 2H), 3.57 (br. s., 2H), 2.17 (s, 3H), 1.70-1.82 (m, 2H), 1.34 (t, J=7.10 Hz, 3H), 0.68-0.83 (m, 9H), −0.06 (s, 6H); LCMS (LCMS Method J): Rt=1.05 min, [M+H].sup.+=704.3

Step 3: (E)-2-Amino-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide

[1171] ##STR00167##

[1172] To a solution of (E)-1-(4-((2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (120 mg, 0.170 mmol) in MeOH (5 mL) was added cyanogen bromide (36 mg, 0.34 mmol) at RT. After 2 hr, the reaction was concentrated, and EtOAc was added (10 mL). After stirring 30 min, the solid was isolated by filtration, and washed with EtOAc to yield the title compound (120 mg, 0.165 mmol, 97% yield) as a light brown solid, which was used without further purification. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.00 (d, J=1.27 Hz, 1H), 7.81 (dd, J=8.36, 1.77 Hz, 1H), 7.49 (d, J=1.27 Hz, 1H), 7.39-7.45 (m, 1H), 7.36 (d, J=1.27 Hz, 1H), 6.61 (s, 1H), 5.82-5.99 (m, 2H), 4.96-5.01 (m, 2 H), 4.56-4.65 (m, 2H), 4.12 (t, J=6.21 Hz, 2H), 3.62-3.75 (m, 2H), 2.18-2.29 (m, 3H), 1.79 (t, J=6.21 Hz, 2H), 1.24-1.54 (m, 5H), 0.84-0.98 (m, 9H), −0.01-0.11 (m, 6H); LCMS (LCMS Method D): Rt=0.97 min, [M+H].sup.+=729.5

Step 4: (E)-7-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1173] ##STR00168##

[1174] To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (33 mg, 0.21 mmol) in DMF (3 mL) was added HATU (75 mg, 0.20 mmol) and HOBt (12.6 mg, 0.082 mmol). After stirring at RT 10 min, triethylamine (0.09 mL, 0.66 mmol) was added, followed by (E)-2-amino-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide (120 mg, 0.165 mmol) and the reaction was continued at RT. After 3 days, a solid was precipitated out of the reaction by the dropwise addition of water. The solid was isolated by filtration and washed with water. The solid was then purified over silica gel (12 g HP Gold column), eluting with 0-20% MeOH in DCM. The desired fractions were combined and concentrated to yield the title compound (29 mg, 0.034 mmol, 20% yield) as an off-white solid. .sup.1H NMR (400 MHz, THF-d.sub.4) δ ppm 12.53 (br. s., 2H), 8.00 (d, J=1.01 Hz, 1H), 7.61 (d, J=1.01 Hz, 1H), 7.53 (dd, J=8.36, 1.52 Hz, 1H), 7.36 (d, J=6.84 Hz, 2H), 7.29 (d, J=1.01 Hz, 1H), 7.12 (d, J=8.36 Hz, 1H), 6.83 (br. s., 2H), 6.66 (d, J=2.28 Hz, 2H), 6.06 (dt, J=15.46, 5.58 Hz, 1H), 5.87 (dt, J=15.46, 5.83 Hz, 1H), 5.09 (d, J=5.32 Hz, 2H), 4.89 (d, J=5.58 Hz, 2H), 4.59-4.72 (m, 4H), 3.97 (t, J=6.21 Hz, 2H), 3.69 (t, J=5.96 Hz, 2H), 2.20 (s, 6H), 1.73-1.78 (m, 2H), 1.40 (td, J=7.03, 1.14 Hz, 6H), 0.82-0.94 (m, 9H), −0.03-0.09 (m, 6H); LCMS (LCMS Method D): Rt=1.21 min, [M/2+H].sup.+=433.6

Step 5: (E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

[1175] ##STR00169##

[1176] To a solution of (E)-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (25 mg, 0.029 mmol) and 1M TBAF in THF (0.058 mL, 0.058 mmol) in THF (2 mL) at RT was added acetic acid (3.3 μL, 0.058 mmol). After 12 hr the reaction was concentrated, triturated with diethyl ether and EtOAc, and further purified over silica gel (12 g Gold column) eluting with 0-25% methanol in DCM. The desired fractions were concentrated to yield the title compound (7 mg, 9 μmole, 32% yield) as an off-white solid. .sup.1H NMR (400 MHz, THF-d.sub.4) δ ppm 12.51 (br. s., 2H), 8.01 (d, J=1.01 Hz, 2H), 7.55-7.65 (m, 3H), 7.33 (d, J=1.01 Hz, 2H), 7.14-7.20 (m, 2H), 6.00-6.15 (m, 2H), 5.82-5.96 (m, 2H), 5.05-5.13 (m, 4H), 4.04 (t, J=6.59 Hz, 4H), 3.78-3.90 (m, 5H), 2.19 (d, J=2.03 Hz, 6H), 1.87-2.00 (m, 2H), 1.36-1.44 (m, 6 H); LCMS (LCMS Method D): Rt=0.79 min, [M+H].sup.+=751.4.

[1177] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00170##

or (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00171##

Example 11

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

[1178] ##STR00172##

Step 1: (E)-tert-Butyl (4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)carbamate

[1179] ##STR00173##

[1180] To a suspension of 4-chloro-3-methoxy-5-nitrobenzamide (1.50 g, 6.50 mmol) in EtOH (25 mL) was added (E)-tert-butyl (4-aminobut-2-en-1-yl)carbamate (1.454 g, 7.81 mmol) and DIEA (3.4 mL, 20 mmol). The reaction was stirred at 120° C. in a sealed tube overnight and allowed to cool to RT. The resulting orange solid was collected by filtration and washed with EtOH to afford the title compound (2.10 g, 5.52 mmol, 85% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.19 (d, J=1.77 Hz, 1H) 8.03 (br. s., 1H) 7.76 (t, J=6.08 Hz, 1H) 7.55 (d, J=1.52 Hz, 1H) 7.34 (br. s., 1H) 6.95 (t, J=5.45 Hz, 1H) 5.53 (br. s., 2H) 4.09 (br. s., 2H) 3.88 (s, 3H) 3.48 (br. s., 2H) 1.35 (s, 9H); LCMS (LCMS Method D): Rt=0.89 min, [M-t-Bu+H].sup.+=325.1

Step 2: (E)-4-((4-Aminobut-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide, hydrochloride

[1181] ##STR00174##

[1182] To a suspension of tert-butyl (E)-(4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)carbamate (20 g, 47.3 mmol) in methanol (50 mL) was added slowly 4M HCl in dioxane (100 mL, 400 mmol). The reaction mixture was stirred at RT for 1 hr, then the resulting solid was isolated by filtration, washed with Et.sub.2O 3 times (100 ml×3), and dried under high vacuum column to provide the title compound (13.90 g, 43.9 mmol, 93% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.22 (d, J=2.03 Hz, 1H), 7.76-8.16 (br. m., 5H), 7.60 (d, J=2.03 Hz, 1H), 7.37 (br. s., 1H), 5.87 (dt, J=15.52, 5.80 Hz, 1H), 5.62 (dt, J=15.65, 6.37 Hz, 1H), 4.18 (d, J=5.32 Hz, 2H), 3.90 (s, 3H), 3.40 (t, J=5.70 Hz, 2H); LCMS (LCMS Method K): Rt=0.41 min, [M+H].sup.+=281.1

Step 3: (E)-3-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-4-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)amino)-5-nitrobenzamide

[1183] ##STR00175##

[1184] To a suspension of (E)-4-((4-aminobut-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide, hydrochloride (9.77 g, 30.9 mmol) in 1-Butanol (90 mL) was added sodium bicarbonate (5.18 g, 61.7 mmol) and DIEA (22.45 mL, 129 mmol). The mixture was stirred at RT for 10 min, then 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide (10 g, 25.7 mmol) was added and the reaction mixture was stirred at 120° C. overnight. The solution was allowed to cool to RT and the resulting dark orange solid was isolated by filtration and washed EtOH (15 ml). The crude material was then stirred in water (100 mL) for 10 min., filtered and washed again with water (100 mL), EtOAc (50 mL) and EtOH (20 mL). The material was dried in vacuum oven to provide the title compound (10 g, 14.54 mmol, 56.5% yield). .sup.1H NMR (400 MHz, DMSO-o) δ ppm 8.16 (t, J=1.77 Hz, 2H), 8.04 (br. s., 2H), 7.72 (d, J=5.83 Hz, 2H), 7.53 (s, 2H), 7.35 (br. s., 2H), 5.53-5.68 (m, 2H), 3.99-4.16 (m, 6H), 3.74 (t, J=6.08 Hz, 2H), 3.43 (br. s., 3H), 1.92 (t, J=6.08 Hz, 2H), 0.74-0.88 (m, 9H), 0.00 (s, 6H); LCMS (LCMS Method K): Rt=1.32 min, [M+H].sup.+=633.4

Step 4: (E)-3-Amino-4-((4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)amino)-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzamide

[1185] ##STR00176##

[1186] To a solution of (E)-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)amino)-5-nitrobenzamide (5 g, 7.90 mmol) in methanol (120 mL) at 0° C., was added sodium hydrosulfite (16.19 g, 79 mmol) in water (50 mL) and ammonium hydroxide (25.6 mL, 198 mmol). The reaction mixture was allowed to warm to RT. After 10 min. at RT, the mixture was extracted with EtOAc (100×3), dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isco column) eluting with hexane: (EtOH:EtOAc 3:1) with 2% NH.sub.4OH additive (0-100% gradient) to yield the title compound (2.1 g, 3.34 mmol, 42.2% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.63 (br. s., 2H), 6.99 (d, J=5.58 Hz, 2H), 6.72-6.91 (m, 6 H), 5.62-5.73 (m, 2H), 4.66 (d, J=8.36 Hz, 4H), 4.00 (t, J=5.96 Hz, 2H), 3.69-3.84 (m, 4 H), 3.40-3.49 (m, 2H), 3.35 (s, 3H), 1.90 (t, J=6.08 Hz, 2H), 0.79-0.91 (m, 9H), −0.03-0.07 (m, 6H); LCMS (LCMS Method K): Rt=0.46 min, [M+H].sup.+=573.3

Step 5: (E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

[1187] ##STR00177##

[1188] To a solution of (E)-3-amino-4-((4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)amino)-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzamide (1.02 g, 1.78 mmol) in MeOH (15 mL) was added cyanogen bromide (943 mg, 8.90 mmol). After stirring at room temperature for 20 min, a light yellow solid precipitated, which was collected by filtration, washed with EtOAc and determined by LCMS to be a mixture of ˜⅔ of the TBDMS-protected compound (E)-2-amino-1-(4-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-1H-benzo[d]imidazole-5-carboxamide and ˜⅓ deprotected alcohol (E)-2-amino-1-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide. This mixture (ca. 900 mg) was added, after TEA (1.07 mL, 7.7 mmol), to a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.89 g, 5.78 mmol), HATU (2.2 g, 5.78 mmol) and HOBt (443 mg, 2.89 mmol) in DMF (10 mL) which had been stirred for 15 min at RT. After 20 hr, 5N aq NaOH (3 mL) was added. After 30 min at RT, water (30 mL) was added, and the resulting white precipitate was collected by filtration and purified over silica gel (40 g Isco column), eluting with 0-30% MeOH in DCM to yield the title compound (545 mg, 0.684 mmol, 38% yield for 2 steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.83 (br. s., 2H), 7.99 (br. s., 2H), 7.64 (d, J=3.04 Hz, 2 H), 7.28-7.42 (m, 4H), 6.52 (s, 2H), 5.84 (br. s., 2H), 4.91 (br. s., 4H), 4.53 (d, J=6.34 Hz, 4H), 4.06 (t, J=6.34 Hz, 2H), 3.75 (s, 3H), 3.45 (t, J=5.96 Hz, 2H), 2.10 (d, J=2.53 Hz, 6H), 1.71 (t, J=6.08 Hz, 2H), 1.27 (td, J=7.03, 1.90 Hz, 6H); LCMS (LCMS Method D): Rt=0.85 min, [M/2+H].sup.+=391.3833

[1189] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00178##

or (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-hydroxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00179##

Example 12

(E)-1,1′-(But-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide)

[1190] ##STR00180##

Step 1: 4-Chloro-3-(3-morpholinopropoxy)-5-nitrobenzamide

[1191] ##STR00181##

[1192] To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (1.00 g, 4.62 mmol), 3-morpholinopropan-1-ol (1.00 g, 6.89 mmol) and triphenylphosphine (1.82 g, 6.93 mmol) in DCM (46 mL) was added DIAD (1.35 mL, 6.93 mmol). After stirring 1 hr, additional triphenylphosphine (480 mg, 1.83 mmol) was added, and after an additional 30 min, DIAD (0.40 mL, 2.1 mmol) was added. After 1 hr, the reaction was partitioned between saturated aq. ammonium chloride and DCM. The organic layer was dry-loaded and purified on silica gel (ISCO-Rf 4 g column), eluting with 0-100% (3:1 EtOAc:EtOH) in hexane to afford the title compound (630 mg, 1.83 mmol, 40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.30 (s, 1 H), 8.05 (d, J=1.77 Hz, 1H), 7.88 (d, J=1.77 Hz, 1H), 7.80 (s, 1H), 4.28 (t, J=6.21 Hz, 2H), 3.57 (t, J=4.56 Hz, 4H), 2.41-2.47 (m, 2H), 2.37 (br. s., 4H), 1.97 (dd, J=13.94, 7.35 Hz, 2 H); LCMS (LCMS Method D): Rt=0.51 min, [M+H].sup.+=344.1

Step 2: (E)-4,4′-(But-2-ene-1,4-diylbis(azanediyl))bis(3-(3-morpholinopropoxy)-5-nitrobenzamide)

[1193] ##STR00182##

[1194] To a suspension of (E)-but-2-ene-1,4-diamine dihydrochloride (171 mg, 1.07 mmol) and 4-chloro-3-(3-morpholinopropoxy)-5-nitrobenzamide (630 mg, 1.65 mmol) in EtOH (4 mL) was added DIEA (1.0 mL, 5.8 mmol). The reaction was heated at 120° C. in a heating block, and after 47 hr, additional (E)-but-2-ene-1,4-diamine dihydrochloride (30 mg, 0.19 mmol) was added. Heating was continued at 120° C. for approximately 3 days, then the reaction was dry-loaded and purified on silica gel (ISCO-Rf 120 g column), eluting with 0-40% MeOH in DCM to afford the title compound (130 mg, 0.186 mmol, 11% yield) as a bright orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.18 (d, J=1.77 Hz, 2H), 8.04 (br. s., 2H), 7.76-7.85 (m, 2 H), 7.51 (d, J=1.52 Hz, 2H), 7.35 (br. s., 2H), 5.63 (br. s., 2H), 4.13 (br. s., 4H), 4.01 (t, J=6.34 Hz, 4H), 3.55 (t, J=4.56 Hz, 8H), 2.27-2.42 (m, 12H), 1.86 (t, J=6.72 Hz, 4H); LCMS (LCMS Method D): Rt=0.53 min, [M+H].sup.+=701.4623

Step 3: (E)-4,4′-(But-2-ene-1,4-diylbis(azanediyl))bis(3-amino-5-(3-morpholinopropoxy)benzamide) dihydrochloride

[1195] ##STR00183##

[1196] To tin (II) chloride (40.6 mg, 0.214 mmol) in conc. aq HCl (892 μL, 10.7 mmol) was added (E)-4,4′-(but-2-ene-1,4-diylbis(azanediyl))bis(3-(3-morpholinopropoxy)-5-nitrobenzamide) (15 mg, 0.021 mmol). After 20 min, the reaction was allowed to cool in a refrigerator and after 15 min the resulting solid was collected by filtration to afford the title compound (12 mg, 0.017 mmol, 79% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.07 (br. s., 2H), 7.99 (br. s., 2H), 7.41 (br. s., 2H), 7.05 (s, 2H), 6.91 (br. s., 2H), 5.94 (br. s., 2H), 3.97-4.08 (m, 8H), 3.78-3.88 (m, 8H), 3.48 (d, J=12.17 Hz, 4H), 3.35-3.43 (m, 4H), 3.05-3.19 (m, 4H), 2.21 (br. s., 4H); LCMS (LCMS Method D): Rt=0.34 min, [M/2+H].sup.+=321.3990

Step 4: (E)-1,1′-(But-2-ene-1,4-diyl)bis(2-amino-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide) dihydrobromide

[1197] ##STR00184##

[1198] To a solution of (E)-4,4′-(but-2-ene-1,4-diylbis(azanediyl))bis(3-amino-5-(3-morpholinopropoxy)benzamide) dihydrochloride (102 mg, 0.143 mmol) in water (1.4 mL) was added cyanogen bromide (136 mg, 1.29 mmol). After 2 days at RT the reaction was added dropwise to acetonitrile (˜100 mL), and the resulting white solid was collected by filtration to afford the title compound (76 mg, 0.09 mmol, 62% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.21 (br. s., 2H), 11.16 (br. s., 2H), 8.88 (br. s., 2H), 8.13 (br. s., 2H), 7.55 (s, 2H), 7.50 (br. s., 2H), 7.42 (s, 2H), 5.71 (br. s., 2H), 4.91 (br. s., 4H), 4.13 (br. s., 4H), 3.97 (br. s., 4H), 3.82 (br. s., 4H), 3.29-3.40 (m, 4H), 3.17 (br. s., 4H), 2.99-3.09 (m, 4H) 2.08 (br. s., 4H); LCMS (LCMS Method D): Rt=0.28 min, [M+H].sup.+=691.6058

Step 5: (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imid-azole-5-carboxamide)

[1199] ##STR00185##

[1200] To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (133 mg, 0.862 mmol), HATU (328 mg, 0.862 mmol) and HOBt (66.0 mg, 0.431 mmol) in N,N-dimethylformamide (DMF) (1150 μL) was added a suspension of (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-amino-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide), dihydrobromide (209 mg, 0.245 mmol) and TEA (240 μL, 1.724 mmol) in N,N-dimethylformamide (DMF) (4598 μL). The reaction was stirred at rt overnight. The reaction was concentrated to dryness under a stream of nitrogen. The resulting residue was dissolved in methanol and dry-loaded onto silica gel for purification viaISCO-Rf, 40 g, 0%-50% methanol, DCM. Desired fractions were concentrated to dryness to afford (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imid-azole-5-carboxamide) (112 mg, 0.115 mmol, 47% yield) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (br. s., 2H), 7.98 (br. s., 2H), 7.66 (d, J=1.01 Hz, 2H), 7.36 (br. s., 2H), 7.25 (s, 2H), 6.58 (s, 2 H), 5.82 (br. s., 2H), 4.92 (br. s., 4H), 4.57 (q, J=7.10 Hz, 4H), 3.85 (t, J=5.96 Hz, 4H), 3.45 (t, J=4.18 Hz, 8H), 2.09-2.24 (m, 18H), 1.54 (t, J=6.72 Hz, 4H), 1.32 (t, J=7.10 Hz, 6 H); LCMS (LCMS Method D): Rt=0.65 min, [M+H].sup.+=963.938

Example 13

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide

[1201] ##STR00186##

[1202] Step 1: To(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxy-propoxy)-1H-benzo[d]imidazole-5-carboxamide (17 mg, 0.023 mmol) in THF (3 mL) was added triethylamine (9.5 μL, 0.068 mmol). After 10 min at RT, methanesulfonyl chloride (2.1 μL, 0.027 mmol) was added. After 2 hr, LCMS indicated presence of (E)-3-((5-Carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl methanesulfonate, and the reaction mixture was used directly in the next reaction. LCMS (LCMS Method D): Rt=0.80 min, [M+H].sup.+=751.6010.

[1203] Step 2: To a solution of (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl methanesulfonate (18 mg, 0.022 mmol) in THF (5 mL) was added morpholine (9.5 μL, 0.11 mmol) and K.sub.2CO.sub.3 (9.0 mg, 0.065 mmol). After 5 hr at RT, the reaction was heated to 45° C. for 2 hr and then concentrated. The residue was purified over silica gel eluting with 0-20% MeOH in DCM to yield the title compound (7 mg, 9 μmole, 39% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.99 (d, J=1.27 Hz, 1H), 7.73 (dd, J=8.36, 1.52 Hz, 1H), 7.59 (d, J=1.27 Hz, 1H), 7.36 (d, J=8.62 Hz, 1H), 7.28 (d, J=1.27 Hz, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 5.92-6.05 (m, 1H), 5.73-5.88 (m, 1H), 4.51-4.71 (m, 4H), 4.00 (t, J=6.21 Hz, 2H), 3.56-3.67 (m, 8H), 2.27-2.46 (m, 6H), 2.22 (d, J=10.39 Hz, 6H), 1.83 (dt, J=14.19, 6.84 Hz, 2H), 1.26-1.44 (m, 6 H); LCMS (LCMS Method D): Rt=0.73 min, [M/2+H].sup.+=410.9876

[1204] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00187##

or (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00188##

Example 14

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide tris hydrochloride

[1205] ##STR00189##

Step 1: (E)-4-((4-((4-Carbamoyl-2-(3-morpholinopropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide

[1206] ##STR00190##

[1207] (E)-4-((4-aminobut-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide, hydrochloride (1.7 g, 5.37 mmol), 4-chloro-3-(3-morpholinopropoxy)-5-nitrobenzamide (1.655 g, 4.81 mmol) i-PrOH(15 ml) and DIPEA (2.94 ml, 16.85 mmol) were divided into two 24 mL vials, then the vials were capped heated to 120° C. for 42 hrs. The solid was isolated by filtration, rinsed with i-PrOH (2×3 mL) to afford (E)-4-((4-((4-carbamoyl-2-(3-morpholinopropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide (1.95 g, 2.79 mmol, 51.9% yield) as a brick red solid. LCMS (LCMS Method K): Rt=0.60 min, [M+H].sup.+=588.2

Step 2: (E)-3-Amino-4-((4-((2-amino-4-carbamoyl-6-(3-morpholinopropoxy)phenyl)amino)but-2-en-1-yl)amino)-5-methoxybenzamide

[1208] ##STR00191##

[1209] To (E)-4-((4-((4-carbamoyl-2-(3-morpholinopropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide (4.6 g, 6.65 mmol) in MeOH (83.0 mL) at RT was added sodium hydrosulfite (19.08 g, 93.0 mmol) in water (70 mL). After 15 min, solid sodium bicarbonate (24 grams) was added. After 10 min., the reaction was filtered, and the solid was rinsed with MeOH (4×20 mL). The combined filtrates were concentrated onto Celite, and the was purified by dry-loading onto silica gel (80 g Gold column), eluting with 2-40% (10:1 MeOH:aq NH.sub.4OH) in DCM to afford the title compound (1.81 g, 3.26 mmol, 49% yield) as a dark yellow film. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.64 (br. s., 2H), 6.99 (br. s., 2H), 6.85 (dd, J=5.07, 1.77 Hz, 2H), 6.78 (dd, J=4.31, 1.77 Hz, 2H), 5.63-5.72 (m, 2H), 4.66 (d, J=8.11 Hz, 4H), 3.96 (t, J=6.21 Hz, 2H), 3.74 (s, 3H), 3.51-3.60 (m, 6H), 3.17 (br. s., 4H), 2.43 (t, J=7.10 Hz, 2H), 2.35 (br. s., 4H), 1.87 (t, J=6.72 Hz, 2H); LCMS (LCMS Method K): Rt=0.37 min, [M+H].sup.+=528.4

Step 3: (E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide tris hydrochloride

[1210] ##STR00192##

[1211] To (E)-3-amino-4-((4-((2-amino-4-carbamoyl-6-(3-morpholinopropoxy)phenyl)amino)-but-2-en-1-yl)amino)-5-methoxybenzamide (368 mg, 0.697 mmol) in DMF (6.97 mL) at 0° C. was added 0.4 M 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate in dioxane (2.0 mL, 0.80 mmol). After ˜10 min, another portion of 0.4 M 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate in dioxane (0.5 mL, 0.20 mmol) was added, followed ˜15 min later by a final portion (0.5 mL, 0.20 mmol). After 35 min total reaction time, EDC (334 mg, 1.74 mmol) was added followed by triethylamine (0.486 mL, 3.49 mmol). The mixture was allowed to warm to RT and stirred overnight (˜14 hours). The reaction was quenched with 3:1 water:saturated aqueous NH.sub.4Cl solution (40 mL) and extracted with 3:1 chloroform:ethanol (2×40 mL). The combined organic phases were washed with water (20 mL), dried over MgSO.sub.4 and concentrated. The resulting residue was purified over silica gel (40 g Gold column), eluting with 2-40% (10:1 MeOH:aq NH.sub.4OH) in DCM to give pure material as the free base. This product was partially dissolved in MeOH and treated with 4M HCl in dioxane (0.35 mL, 1.40 mmol), then concentrated. The residue was taken up in MeCN-water and lyophilized to yield the title compound (403.6 mg, 0.421 mmol, 60% yield) as an off-white solid. .sup.1H NMR (400 MHz, methanol-d.sub.4) δ 7.70 (dd, J=2.66, 1.14 Hz, 2H), 7.42 (d, J=1.27 Hz, 2H), 6.72 (d, J=3.04 Hz, 2H), 5.79-6.12 (m, 2H), 5.19 (dd, J=11.03, 5.45 Hz, 4H), 4.61-4.81 (m, 4H), 4.00-4.25 (m, 4H), 3.79-3.96 (m, 5H), 3.45 (d, J=12.42 Hz, 2H), 3.28-3.36 (m, 2H), 3.14 (td, J=12.23, 3.68 Hz, 2H), 2.28 (s, 6H), 2.07-2.25 (m, 2H), 1.46 (td, J=7.10, 3.80 Hz, 6H); LCMS (LCMS Method K): Rt=0.68 min, [M+H].sup.+=850.6. The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as

(E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide tris hydrochloride

[1212] ##STR00193##

[1213] or (Z)-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-morpholinopropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide tris hydrochloride

##STR00194##

Example 15

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((4-methoxybenzyl)oxy)-1H-benzo[d]imidazole-5-carboxamide

[1214] ##STR00195##

##STR00196##

Step 1: 4-chloro-3-((4-methoxybenzyl)oxy)-5-nitrobenzamide

[1215] ##STR00197##

[1216] 4-chloro-3-hydroxy-5-nitrobenzamide (942 mg, 4.35 mmol) was dissolved in DMF (7 mL), Cs.sub.2CO.sub.3 (1.559 g, 4.78 mmol) was added followed by 4-methoxybenzyl chloride (0.622 mL, 4.57 mmol) and the reaction mixture was stirred for 24 hours at RT. With vigorous stirring, water (15 mL) was added dropwise and the resulting solid was stirred for 5 minutes, collected by filtration and rinsed with water to afford the title compound (1.26 g, 3.74 mmol, 82% yield) as a light orange solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 7.80 (d, J=1.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 6.13 (br. s., 1H), 5.82 (br. s., 1H), 5.25 (s, 2H), 3.87 (s, 3H); LCMS (LCMS Method D): Rt=1.03, [M+H].sup.+=337.1.

Step 2: (E)-1-(4-((4-carbamoyl-2-((4-methoxybenzyl)oxy)-6-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1217] ##STR00198##

[1218] To a mixture of (E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride (1.543 g, 3.69 mmol, Intermediate 6) and TEA (1.871 mL, 13.42 mmol) stirred in EtOH (7 mL) for 5 minutes was added 4-chloro-3-((4-methoxybenzyl)oxy)-5-nitrobenzamide (1.13 g, 3.36 mmol) and the mixture was heated in a sealed microwave vial at 120° C. for 18 hours. After cooling to RT, the mixture was diluted with DCM (50 mL) and water (50 mL) and a dark residue appeared. The layers were separated and the residue was combined with the organics and concentrated. To the crude mixture was added 10% MeOH in DCM and the resulting solid was collected by filtration and rinsed with DCM. To the concentrated filtrate 10% MeOH in DCM was again added and the resulting solid was collected by filtration and rinsed with DCM. Both batches of solid were combined to afford the title compound (559 mg, 0.82 mmol, 22% yield) as an orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 12.86 (br. s., 1H), 8.19 (d, J=2.0 Hz, 1H), 7.93-8.05 (m, 3H), 7.86 (t, J=6.3 Hz, 1H), 7.72 (dd, J=8.4, 1.3 Hz, 1H), 7.62 (s, 1H), 7.29-7.40 (m, 3H), 7.25 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.62 (s, 1H), 5.65-5.75 (m, 1H), 5.49-5.58 (m, 1H), 4.93 (s, 2H), 4.75 (d, J=5.1 Hz, 2H), 4.58 (q, J=7.1 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.69 (s, 3H), 2.16 (s, 3H), 1.31 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.98, [M+H].sup.+=682.5.

Step 3: (E)-1-(4-((2-amino-4-carbamoyl-6-((4-methoxybenzyl)oxy)phenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1219] ##STR00199##

[1220] To (E)-1-(4-((4-carbamoyl-2-((4-methoxybenzyl)oxy)-6-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (557 mg, 0.817 mmol) in DMF (10 mL) was added ammonium hydroxide (1.136 mL, 8.17 mmol) followed by a dropwise addition of sodium hydrosulfite (837 mg, 4.09 mmol) in water (5 mL). After 1 hour at RT, the reaction was diluted with EtOAc and water. The aqueous was extracted with EtOAc, the combined organics were washed with saturated NH.sub.4Cl and brine and concentrated to afford the title compound (335 mg, 0.51 mmol, 57% yield) as an orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 12.85 (br. s., 1H), 8.00 (s, 2H), 7.75 (dd, J=8.4, 1.5 Hz, 1H), 7.66 (br. s., 1H), 7.36 (br. s., 2H), 7.25-7.31 (m, 4H), 7.03 (br. s., 1H), 6.83-6.91 (m, 4H), 6.64 (s, 1H), 5.75-5.84 (m, 1H), 5.64-5.73 (m, 1H), 4.89 (s, 2H), 4.78 (d, J=5.1 Hz, 2H), 4.69 (br. s., 2H), 4.59 (q, J=7.0 Hz, 2H), 3.91 (t, J=7.0 Hz, 1H), 3.71 (s, 3H), 3.56 (br. m., 2H), 2.17 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.76, [M+H].sup.+=652.5.

Step 4: (E)-2-amino-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-((4-methoxybenzyl)oxy)-1H-benzo[d]imidazole-5-carboxamide dihydrobromide

[1221] ##STR00200##

[1222] To a suspension of (E)-1-(4-((2-amino-4-carbamoyl-6-((4-methoxy-benzyl)oxy)phenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo-[d]imidazole-5-carboxamide (333 mg, 0.460 mmol) in MeOH (3 mL) was added cyanogen bromide (97 mg, 0.920 mmol) and the reaction was stirred at RT for 2 hours. The resulting solid was collected by filtration and rinsed with MeOH to afford the title compound (235 mg, 0.28 mmol, 58% yield) as a light orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 13.07 (br. s., 1H), 12.90 (s, 1H), 8.70 (br. s., 1H), 8.09 (br. s., 1H), 7.98-8.04 (m, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.51 (s, 2H), 7.46 (br. s., 1H), 7.32-7.40 (m, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.54 (s, 1H), 5.83-5.92 (m, 1H), 5.53-5.62 (m, 1H), 5.01 (s, 2H), 4.79 (s, 2H), 4.78 (s, 2H), 4.53 (q, J=7.2 Hz, 2H), 3.66 (s, 3H), 2.13 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.72, [M+H].sup.+=677.5.

Step 5: (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((4-methoxybenzyl)oxy)-1H-benzo[d]imidazole-5-carboxamide

[1223] ##STR00201##

[1224] A solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (51.4 mg, 0.333 mmol) and CDI (63.1 mg, 0.389 mmol) in DMF (3 mL) was stirred at 60° C. for 10 minutes, then (E)-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((4-methoxybenzyl)oxy)-1H-benzo[d]imidazole-5-carboxamide dihydrobromide (233 mg, 0.278 mmol) and DIPEA (0.194 mL, 1.111 mmol) were added. After heating at 90° C. for 4 hours, additional CDI (20 mg) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (20 mg) were added and heating was continued for 1.5 hours. After cooling to RT and adding small ice chunks while stirring, water (5 mL) was added dropwise. The resulting solid was collected by filtration and rinsed with water to afford the title compound (225 mg, 0.27 mmol, 95% yield) as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 12.88 (br. s., 2H), 8.00 (m, 2H), 7.64-7.72 (m, 2H), 7.46 (br. s., 1H), 7.29-7.42 (m, 3H), 7.20 (d, J=7.9 Hz, 2H), 6.75 (d, J=7.6 Hz, 2H), 6.54 (s, 2H), 5.94 (m, 1H), 5.49 (m, 1H), 4.97 (s, 2H), 4.85 (br. s., 2H), 4.78 (br. s., 2H), 4.53 (br. m., 4H), 3.65 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.22-1.33 (m, 6H); LCMS (LCMS Method F): Rt=2.27 min, [M+H].sup.+=813.9.

Example 16

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazole-5-carboxamide dihydrochloride

[1225] ##STR00202##

[1226] To (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]-imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((4-methoxy-benzyl)oxy)-1H-benzo[d]imidazole-5-carboxamide (210 mg, 0.258 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (0.258 mL, 1.03 mmol). After 30 min at RT, the reaction was heated to 50° C. for 18 hours. Additional 4N HCl in dioxane (0.2 mL) was added, and after heating another 5 hr, the reaction was cooled, and the resulting solid was collected by filtration and rinsed with DCM to afford the title compound (168 mg, 0.219 mmol, 81% yield) as a light tan solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.01 (d, J=1.3 Hz, 1H), 7.82 (dd, J=8.5, 1.6 Hz, 1H), 7.49-7.55 (m, 2H), 7.29 (d, J=1.5 Hz, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 6.08-6.18 (m, 1H), 5.89-5.99 (m, 1H), 5.30 (d, J=5.6 Hz, 2H), 4.98-5.04 (m, 2H), 4.65 (dq, J=14.6, 7.2 Hz, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 1.37-1.46 (m, 6H); LCMS (LCMS Method F): Rt=1.73 min, [M+H].sup.+=693.4.

Example 17

1,1′-(2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide)

[1227] ##STR00203##

Step 1: 4,4′-((2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(azanediyl))bis(3-nitrobenzamide)

[1228] ##STR00204##

[1229] To 2,2,3,3-tetrafluorobutane-1,4-diamine (Intermediate 4) (1.25 g, 7.81 mmol), and potassium carbonate (3.24 g, 23.4 mmol) in DMF (50 mL) at RT was added 4-fluoro-3-nitrobenzamide (3.59 g, 19.5 mmol) over 5 min, and the reaction was stirred overnight. The mixture was quenched with water, and the resulting solid was collected by filtration and triturated with MeOH to afford the title compound (600 mg, 1.23 mmol, 16% yield) as a yellow solid. LCMS (LCMS Method A): Rt=1.367 min, [M+H].sup.+=489.0

Step 2: 4,4′-((2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(azanediyl))bis(3-aminobenzamide)

[1230] ##STR00205##

[1231] 4,4′-((2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(azanediyl))bis(3-nitrobenzamide) (1.15 g, 2.36 mmol) and Pd on carbon (0.251 g, 2.36 mmol) in MeOH (100 mL) were stirred under H.sub.2 at 30° C. overnight. The reaction was filtered, and the filtrate concentrated to afford the title compound (250 mg, 0.584 mmol, 25% yield). LCMS (LCMS Method A): Rt=1.165 min, [M+H].sup.+=429.1

Step 3: 1,1′-(2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide)

[1232] ##STR00206##

[1233] To 4,4′-((2,2,3,3-tetrafluorobutane-1,4-diyl)bis(azanediyl))bis(3-aminobenzamide) (20 mg, 0.047 mmol) in MeOH (1 mL) and water (2 mL) was added cyanogen bromide (29.7 mg, 0.280 mmol), and the reaction was stirred at 30° C. overnight. The MeOH was removed in vacuo and the resulting solid was collected by filtration to afford the title compound (15 mg, 0.031 mmol, 67% yield). LCMS (LCMS Method A): Rt=0.629 min, [M+H].sup.+=479.0

Step 4: 1,1′-(2,2,3,3-Tetrafluorobutane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide)

[1234] ##STR00207##

[1235] To HATU (763 mg, 2.01 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (227 mg, 1.47 mmol) in DMF (20 mL) at RT was added EDC (385 mg, 2.01 mmol), 1,1′-(2,2,3,3-tetrafluorobutane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (320 mg, 0.667 mmol) and DIEA (0.467 mL, 2.68 mmol) in one charge. The reaction was heated to 70° C. for 12 hr, concentrated and purified to yield the title compound (8 mg, 0.01 mmol, 2% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.05 (s, 2H), 8.01 (d, J=8.6 Hz, 4H), 7.81 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.38 (s, 2H), 6.73 (s, 2H), 5.32 (t, J=16.0 Hz, 4H), 4.59 (dd, J=14.0, 6.9 Hz, 4H), 2.06 (s, 6H), 1.33 (t, J=7.1 Hz, 6H); LCMS (LCMS Method A): Rt=1.367 min, [M+H].sup.+=751.1

Example 18

Di-tert-butyl (3-(((2)-6-carbamoyl-3-((E)-4-((2)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl) phosphate

[1236] ##STR00208##

Di-tert-butyl (3-(((2)-6-carbamoyl-3-((E)-4-((2)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl) phosphate

[1237] ##STR00209##

[1238] A suspension of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (1.00 g, 1.28 mmol) and 0.45 M 2H-tetrazole in acetonitrile (14.2 mL, 6.40 mmol) in DMF (5 mL) was concentrated on a rotary evaporator to remove acetonitrile. The resulting heterogeneous mixture in DMF was cooled to 0° C. then a solution of di-tert-butyl diisopropylphosphoramidite (1.617 mL, 5.12 mmol) in 5 mL DMF was added. Soon after addition, the solution becomes homogeneous but again becomes heterogeneous as the reaction is stirred at RT for 2 additional hours. The temperature was lowered to 0° C. and H.sub.2O.sub.2 (30% Wt in water, 2.62 mL, 25.6 mmol) was added. After stirring for 20 min, an additional 10 eq of H.sub.2O.sub.2 was added and the reaction stirred until homogeneous (30 min). A 2 mL portion of aqueous NaHCO.sub.3 and Na.sub.2S.sub.2O.sub.3 (0.4M in NaHCO.sub.3, 2M in Na.sub.2S.sub.2O.sub.3) was added to 200 mL water. When the reaction mixture was poured into this solution, a precipitate was formed. The precipitate was then collected on a filter, dissolved in 200 mL THE, dried with MgSO.sub.4 and concentrated to provide the title compound as an off-white solid (1.1 g, 1.13 mmol, 88% yield. 5H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.8 (s, 2H), 10.2 (5, 1H), 7.98 (i, 2H), 7.65 (d, J=2.5 Hz, 2H), 7.34 (m, 4H), 6.51 (d, J=2.5 Hz, 2H), 5.83 (m, 2H), 4.91 (m, 4H), 4.52 (m, 4H), 4.09 (m, 2H), 3.93 (m, 2H), 3.74 (s, 3H), 3.60 (m, 2H), 2.11 (s, 6H), 1.90 (m, 2H), 1.76 (m, 2H), 1.4-1.3 (m, 18H, 1.27 (m, 6H); LCMS (LCMS Method I): Rt=1.09 min, [M+H].sup.+=973.3.

Example 19

3-(((2)-6-Carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl dihydrogen phosphate

[1239] ##STR00210##

[1240] To di-tert-butyl (3-(((2)-6-carbamoyl-3-((E)-4-((2)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)-propyl) phosphate (18 mg, 0.018 mmol) suspended in dioxane (1 mL) at RT was added 4N HCl in dioxane (0.028 mL, 0.11 mmol). Some precipitate formed immediately. The reaction was stirred for 2 hr and additional 4N HCl in dioxane (0.028 mL, 0.11 mmol) was added. After 2 hr, the reaction was placed in freezer, and after 16 hr, the reaction was diluted with diethyl ether. The mixture was adjusted to pH of 2˜3 with conc. ammonium hydroxide. The precipitate was collected by filtration and washed with ether to yield the title compound (15 mg, 0.017 mmol, 92% yield) as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ ppm 12.85 (br s, 1H), 8.02 (br, d, J=6.6 Hz, 2H), 7.65 (d, J=5.7 Hz, 2H), 7.35-7.41 (m, 2H), 7.34 (br. d, J=10.6 Hz, 2H), 6.51 (d, J=12.8 Hz, 2H), 5.74-5.89 (m, 2H), 4.92 (br. dd, J=12.0, 4.9 Hz, 4H), 4.50 (quin, J=7.0 Hz, 4H), 4.10 (br. t, J=6.1 Hz, 2H), 3.91-3.94 (m, 2H), 3.75 (s, 3 H), 2.10 (d, J=3.1 Hz, 6H), 1.84-1.93 (m, 2H), 1.22-1.28 (m, 6H); LCMS (LCMS Method I): Rt=0.68 min, [M+H].sup.+=861.2

[1241] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl dihydrogen phosphate

##STR00211##

or 3-(((E)-6-carbamoyl-3-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl dihydrogen phosphate

##STR00212##

Example 20

Step 8: (E)-7-Bromo-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1242] ##STR00213##

Step 1: 4-Chloro-3-(3-methoxypropoxy)-5-nitrobenzamide

[1243] ##STR00214##

[1244] To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (1.00 g, 4.62 mmol) in DMF (15 mL) was added 1-bromo-3-methoxypropane (1.06 g, 6.93 mmol) and K.sub.2CO.sub.3 (1.91 mg, 13.9 mmol). The reaction mixture was stirred at 60° C. in a sealed tube. After 3 hr, the reaction was cooled to RT and poured into water. The resulting light yellow precipitate was collected by filtration and washed with diethyl ether to provide the title compound (1.1 g, 3.8 mmol, 83% yield). LCMS (LCMS Method D): Rt=0.84 min, [M+H].sup.+=289.0

Step 2: (E)-tert-Butyl (4-((4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)carbamate

[1245] ##STR00215##

[1246] To a suspension of 4-chloro-3-methoxy-5-nitrobenzamide (1.50 g, 6.50 mmol) in EtOH (25 mL) was added (E)-tert-butyl (4-aminobut-2-en-1-yl)carbamate (1.45 g, 7.81 mmol) and DIEA (3.41 mL, 19.5 mmol). The reaction was heated to 120° C. in a sealed tube overnight and allowed to cool to RT. The resulting orange precipitate was collected by filtration and washed with EtOH to provide the title compound (2.1 g, 5.5 mmol, 85% yield). LCMS (LCMS Method D): Rt=0.96 min, [M+H].sup.+=439.2

Step 3: (E)-4-((4-Aminobut-2-en-1-yl)amino)-3-(3-methoxypropoxy)-5-nitrobenzamide dihydrochloride

[1247] ##STR00216##

[1248] To (E)-tert-butyl (4-((4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)carbamate (1.43 g, 3.26 mmol) in dioxane (10 mL) was added 4N HCl in dioxane (12.2 mL, 48.9 mmol). After 1 hr at RT, the reaction was concentrated, and the residue was triturated with diethyl ether to provide the title compound (1.3 g, 3.1 mmol, 96% yield). LCMS (LCMS Method D): Rt=0.52 min, [M+H].sup.+=339.2

Step 4: (E)-3-Bromo-4-((4-((4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)amino)-5-nitrobenzamide

[1249] ##STR00217##

[1250] To a solution of (E)-4-((4-aminobut-2-en-1-yl)amino)-3-(3-methoxypropoxy)-5-nitrobenzamide dihydrochloride (361 mg, 0.878 mmol) in DMF (5 mL) was added 3-bromo-4-fluoro-5-nitrobenzamide (220 mg, 0.836 mmol) and TEA (0.47 mL, 3.4 mmol). After stirring at RT overnight, water (20 mL) was added, and the resulting light brown solid was collected by filtration to provide the title compound (475 mg, 0.719 mmol, 86% yield). LCMS (LCMS Method D): Rt=0.91 min, [M+H].sup.+=583.2

Step 5: (E)-3-Amino-4-((4-((2-amino-4-carbamoyl-6-(3-methoxypropoxy)phenyl)amino)but-2-en-1-yl)amino)-5-bromobenzamide

[1251] ##STR00218##

[1252] To a solution of (E)-3-bromo-4-((4-((4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenyl)amino)but-2-en-1-yl)amino)-5-nitrobenzamide (400 mg, 0.585 mmol) in conc. aq 12M HCl (5 mL, 60 mmol) was added tin (II) chloride (665 mg, 3.51 mmol). After 5 min at RT, 6N aq NaOH was added to neutralize the reaction, and the resulting solid was collected by filtration to provide the title compound (150 mg, 0.288 mmol, 49% yield). LCMS (LCMS Method D): Rt=0.55 min, [M+H].sup.+=521.2

Step 6: (E)-2-Amino-1-(4-(2-amino-5-carbamoyl-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-bromo-1H-benzo[d]imidazole-5-carboxamide

[1253] ##STR00219##

[1254] To a solution of (E)-3-amino-4-((4-((2-amino-4-carbamoyl-6-(3-methoxypropoxy)phenyl)amino)but-2-en-1-yl)amino)-5-bromobenzamide (150 mg, 0.288 mmol) in MeOH (3 mL) and DMSO (1 mL) was added cyanogen bromide (183 mg, 1.73 mmol). The reaction mixture was stirred at RT overnight, during which time a solid precipitated out. This solid was collected by filtration to provide the crude title compound (120 mg, 0.210 mmol, 73% yield). LCMS (LCMS Method D): Rt=0.47 min, [M+H].sup.+=573.2

Step 8: (E)-7-Bromo-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1255] ##STR00220##

[1256] To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (97 mg, 0.63 mmol) in DMF (2 mL) was added HATU (240 mg, 0.630 mmol) and HOBt (48 mg, 0.32 mmol). After 15 min at RT, TEA (0.18 mL, 1.3 mmol) was added, followed by (E)-2-amino-1-(4-(2-amino-5-carbamoyl-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-bromo-1H-benzo[d]imidazole-5-carboxamide (120 mg, 0.210 mmol). After stirring overnight, water (5 mL) was added, and the resulting light yellow precipitate was collected by filtration. This crude material was purified over silica gel (Isco Rf 25 g column eluting with 0-20% MeOH in DCM) to provide the title compound (45 mg, 0.050 mmol, 24% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.06 (br. s., 1H), 12.83 (br. s., 1H), 8.07 (br. s., 1H), 8.00 (d, J=8.62 Hz, 2H), 7.88-7.96 (m, 1 H), 7.64 (s, 1H), 7.47 (br. s., 1H), 7.28-7.39 (m, 2H), 6.49-6.59 (m, 2H), 5.70-5.92 (m, 2H), 5.09 (br. s., 2H), 4.93 (br. s., 2H), 4.44-4.60 (m, 4H), 4.03 (t, J=6.46 Hz, 2H), 3.23-3.30 (m, 2H), 3.14 (s, 3H), 2.11 (d, J=12.17 Hz, 6H), 1.71-1.83 (m, 2H), 1.27 (q, J=7.10 Hz, 6H); LCMS (LCMS Method D): Rt=0.96 min, [M/2+H].sup.+=422.1.

[1257] The compound prepared by the above process may exist in a tautomeric or an isomeric form, e.g., as (E)-7-bromo-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-methoxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00221##

or (Z)-7-bromo-1-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-methoxypropoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

##STR00222##

Example 21

Step 9: Ethyl (E)-3-(5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)propanoate

[1258] ##STR00223##

[1259] A mixture of (E)-7-bromo-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (50 mg, 0.059 mmol), Pd(amphos)Cl.sub.2 (20 mg, 0.028 mmol) and (3-ethoxy-3-oxopropyl)zinc(II) bromide (1.5 ml, 0.750 mmol) was heated in the microwave at 100° C. After 15 min, the reaction was cooled, concentrated and the crude material was purified by reverse phase HPLC (Gilson HPLC (CH.sub.3CN/H.sub.2O 10 to 60%) to provide the title compound (20 mg, 0.023 mmol, 38.2% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.85 (d, J=1.52 Hz, 1H), 7.59 (d, J=1.01 Hz, 1H), 7.54 (d, J=1.52 Hz, 1H), 7.32 (d, J=1.01 Hz, 1H), 6.61 (d, J=7.10 Hz, 2H), 5.92 (d, J=15.72 Hz, 1 H), 5.61-5.77 (m, 1H), 4.99-5.23 (m, 4H), 4.50-4.69 (m, 4H), 4.08 (t, J=6.34 Hz, 2H), 4.00 (q, J=7.18 Hz, 2H), 3.41 (t, J=6.21 Hz, 2H), 3.28 (s, 3H), 3.12 (t, J=7.86 Hz, 2H), 2.53-2.65 (m, 2H), 2.22 (s, 6H), 1.85 (quin, J=6.27 Hz, 2H), 1.24-1.47 (m, 9H), 1.15 (t, J=7.10 Hz, 3H); LCMS (LCMS Method K): Rt=0.87 min, [M+H].sup.+=865.2

Example 22

Step 10: Ethyl (E)-3-(5-Carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)propanoic acid

[1260] ##STR00224##

[1261] To (E)-ethyl 3-(5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)propanoate (15 mg, 0.014 mmol, Example 21) in THF (0.3 mL) was added 1M aq LiOH (0.042 mL, 0.042 mmol) in water (0.3 mL). After 1 hr at RT, the THF was removed in vacuo, and 5N aq HCl was added to neutralize the reaction. The resulting white solid was collected by filtration, and this crude material was purified by HPLC (Gilson, Sunfire C18 OBD 30×100 mm column with a gradient of 10-60% acetonitrile (0.1% TFA)/water (0.1% TFA) and a flow rate of 30 mL/min., gradient time:15 min.) to provide the title compound (2.4 mg, 3 μmol, 20% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) δ ppm 7.86 (d, J=1.52 Hz, 1H), 7.58 (dd, J=3.55, 1.27 Hz, 2H), 7.31 (d, J=1.01 Hz, 1H), 6.60 (d, J=5.83 Hz, 2H), 5.92 (d, J=15.46 Hz, 1H), 5.69 (d, J=15.46 Hz, 1H), 5.12 (br. s., 2H), 5.06 (d, J=4.82 Hz, 2H), 4.60 (dq, J=14.61, 7.21 Hz, 4H), 4.09 (t, J=6.46 Hz, 2 H), 3.42 (t, J=6.08 Hz, 2H), 3.28 (s, 3H), 3.09-3.18 (m, 2H), 2.56-2.65 (m, 2H), 2.21 (d, J=4.82 Hz, 6H), 1.86 (t, J=6.21 Hz, 2H), 1.35 (dt, J=12.42, 7.10 Hz, 6H); LCMS (LCMS Method D): Rt=1.90 min, [M+H].sup.+=838.0

Example 23

Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylate, bis trifluoroacetic acid salt

[1262] ##STR00225##

Step 1: 4-((4-((tert-Butoxycarbonyl)amino)butyl)amino)-3-nitrobenzoic acid hydrochloride

[1263] ##STR00226##

[1264] To tert-butyl (4-aminobutyl)carbamate (4.00 g, 21.3 mmol) and potassium carbonate (8.81 g, 63.7 mmol) in DMSO (70.8 ml) at RT was added 4-fluoro-3-nitrobenzoic acid (3.93 g, 21.3 mmol). The reaction was heated to 80° C. for 18 hr, cooled to RT and diluted with EtOAc and water. The mixture was stirred vigorously and carefully brought to pH 5 with HCl. The organic layer was isolated, washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford the crude title compound (11.86 g, 21.3 mmol, quantitative yield) as a yellow amorphous solid, which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.89 (br. s., 1H), 8.63 (d, J=2.02 Hz, 1H), 8.50-8.60 (m, 1H), 7.97 (d, J=9.09 Hz, 1H), 7.16 (d, J=9.35 Hz, 1H), 6.88 (br. s., 1H), 3.44 (q, J=6.57 Hz, 2H), 3.38 (br. s., 1H), 2.98 (d, J=6.06 Hz, 2H), 1.61 (d, J=6.57 Hz, 2H), 1.43-1.54 (m, 2H), 1.39 (s, 9H); LCMS (LCMS Method C): Rt=0.91 min, [M+H].sup.+=354.1

Step 2: tert-Butyl (4-((4-carbamoyl-2-nitrophenyl)amino)butyl)carbamate

[1265] ##STR00227##

[1266] To 4-((4-((tert-butoxycarbonyl)amino)butyl)amino)-3-nitrobenzoic acid hydrochloride (10.7 g, 27.4 mmol) and HATU (12.5 g, 32.9 mmol) in DCM (91 ml) at RT was added DIEA (10.5 ml, 60.3 mmol) followed by 7 M ammonia in MeOH (7.83 ml, 54.8 mmol). After 3 hr, the resulting yellow solid was collected by filtration and washed with DCM to yield the title compound (8.52 g, 21.8 mmol, 79% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.41 (t, J=5.68 Hz, 1H), 8.34 (dd, J=4.04, 1.26 Hz, 1H), 8.13 (dd, J=8.34, 1.26 Hz, 1H), 7.31 (br. s., 2H), 7.07-7.15 (m, 1H), 3.39-3.46 (m, 2H), 3.36 (br. s., 1H), 2.97 (q, J=6.57 Hz, 2H), 1.55-1.67 (m, 2H), 1.42-1.53 (m, 2H), 1.38 (s, 9H); LCMS (LCMS Method C): Rt=0.84 min, [M+H].sup.+=353.1

Step 3: 4-((4-Aminobutyl)amino)-3-nitrobenzamide dihydrochloride

[1267] ##STR00228##

[1268] To tert-butyl (4-((4-carbamoyl-2-nitrophenyl)amino)butyl)carbamate (4.42 g, 12.6 mmol) in dioxane (126 ml) at RT was added 4 M HCl in dioxane (62.8 ml, 251 mmol). After 24 hr, the reaction was concentrated to yield the title compound (4.08 g, 11.9 mmol, 95% yield) as a yellow-orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.78 (dd, J=4.42, 1.39 Hz, 1H), 8.68 (d, J=2.02 Hz, 1H), 8.55 (dd, J=8.34, 1.52 Hz, 1H), 8.03 (dd, J=9.09, 2.02 Hz, 2 H), 7.90 (br. s., 3H), 7.09-7.17 (m, 2H), 3.46 (d, J=6.06 Hz, 2H), 2.78-2.91 (m, 2H), 1.67 (br. s., 4H); LCMS (LCMS Method C): Rt=0.40 min, [M+H].sup.+=253.0

Step 4: Methyl 4-((4-((4-carbamoyl-2-nitrophenyl)amino)butyl)amino)-3-nitrobenzoate

[1269] ##STR00229##

[1270] To a suspension of 4-((4-aminobutyl)amino)-3-nitrobenzamide dihydrochloride (1.84 g, 5.66 mmol) and K.sub.2CO.sub.3 (2.346 g, 16.97 mmol) in DMSO (11.32 ml) at 23° C. was added methyl 4-fluoro-3-nitrobenzoate (1.13 g, 5.66 mmol). After 30 min, a bright yellow precipitate formed. The reaction was diluted with water (25 mL), and the solid was collected by filtration and dried under vacuum to yield the title compound (4.1 g, 5.6 mmol, 99% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.64 (d, J=2.28 Hz, 1H), 8.61 (d, J=2.28 Hz, 2H), 8.42 (t, J=5.70 Hz, 1H), 7.93-8.03 (m, 3H), 7.30 (br. s., 1H), 7.17 (d, J=9.38 Hz, 1H), 7.12 (d, J=9.12 Hz, 1H), 3.83 (s, 3H), 3.48 (d, J=6.08 Hz, 4H), 1.73 (br. s., 4H); LCMS (LCMS Method D): Rt=0.97 min, [M+H].sup.+=432.2

Step 5: Methyl 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-1H-benzo[d]imidazole-5-carboxylate dihydrobromide

[1271] ##STR00230##

[1272] To methyl 4-((4-((4-carbamoyl-2-nitrophenyl)amino)butyl)amino)-3-nitrobenzoate (3.18 g, 7.37 mmol) and 10% Pd/C (1.2 g, 1.128 mmol) at RT was added NMP (35 ml). The flask was evacuated and charged with nitrogen, then evacuated once more and charged with 1 atm H.sub.2 delivered via balloon. The mixture was stirred at 70° C. for 18 hr, then filtered through Celite warm. The filtrate was cooled to RT and treated with cyanic bromide (2.95 ml, 14.7 mmol). After 2 hr, the reaction was heated to 70° C. for 2 hr, cooled to RT and diluted with EtOAc (120 mL) with vigorous stirring. The resulting grey solid was collected by filtration to yield the title compound (4.91 g, 5.90 mmol, 80% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (br. s., 2H), 8.91 (br. s., 2H), 8.78 (s, 2H), 8.08 (br. s., 1H), 7.82-7.99 (m, 4H), 7.60-7.75 (m, 2H), 7.47 (br. s., 1H), 4.13-4.28 (m, 4H), 3.89 (s, 3H), 1.74-1.84 (m, 4 H); LCMS (LCMS Method C): Rt=0.49 min, [M+H].sup.+=422.2

Example 23

Step 6: Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylate, bis trifluoroacetic acid salt

[1273] ##STR00231##

[1274] A microwave vial of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.502 g, 3.26 mmol), HATU (1.27 g, 3.34 mmol) and DIEA (1.497 ml, 8.57 mmol) in NMP (5.71 ml) was allowed to stir at RT for 10 min. A separate solution of methyl 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-1H-benzo[d]imidazole-5-carboxylate dihydrobromide (1.0 g, 1.7 mmol) dissolved in a minimal amount of NMP was added, and the vial was sealed and microwaved to 140° C. After 30 min, the reaction was cooled to RT and diluted with water (˜50 mL). The resulting grey solid was collected by filtration, dissolved in a minimal amount of DMSO and purified by reverse-phase HPLC (C18 50×30 mm Luna column, 47 mL/min), eluting with 10-40% acetonitrile in water (0.1% TFA) to yield the title compound (400 mg, 0.412 mmol, 24% yield) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.89 (s, 1H), 12.83 (s, 1H), 8.09 (s, 1H), 7.93-8.01 (m, 2H), 7.84 (d, J=8.59 Hz, 1H), 7.77 (d, J=8.08 Hz, 1H), 7.58 (dd, J=17.68, 8.34 Hz, 2H), 7.35 (br. s., 1H), 6.60 (d, J=7.83 Hz, 2H), 4.58 (q, J=6.74 Hz, 4H), 4.22-4.34 (m, 4H), 3.88 (s, 3H), 2.11 (s, 6 H), 1.82-1.94 (m, 4H), 1.31 (t, J=6.82 Hz, 6H); LCMS (LCMS Method C): Rt=0.86 min, [M+H].sup.+=694.6

Example 24

(E)-1,1′-(But-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide)

[1275] ##STR00232##

[1276] Example 24 can be prepared according to method 1 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1277] A solution of 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (20 mg, 0.052 mmol) in 1,2-dichloroethane (2.1 ml) was degassed with N.sub.2 at 90° C. (heat was needed for dissolution) for 5 min., then Zhan catalyst 1B (CAS 918870-76-5, 5.76 mg, 7.84 μmol) was added. After heating 18 hr, the reaction was stirred at RT 2 days. Another 10 mg Zhan catalyst 1B was added, and the reaction was re-heated to 90° C. After 1 hr, the mixture was cooled and the resulting solid was collected by filtration to yield the title compound (4 mg, 5 μmole, 10% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (s, 2H), 7.91-8.24 (m, 2H), 7.64 (s, 2H), 7.33 (s, 4H), 6.53 (s, 2H), 5.70-6.16 (m, 2H), 4.91 (br. s., 4H), 4.29-4.64 (m, 4H), 3.77 (s, 6H), 2.10 (s, 6H), 1.27 (s, 6 H); LCMS (LCMS Method L): Rt=0.85 min, [M+H].sup.+=737.5.

Example 25

1,1′-(Butane-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide), dihydrochloride

[1278] ##STR00233##

[1279] Example 25 can be prepared according to method 2 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1280] To 1,1′-(butane-1,4-diyl)bis(7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide) (12 mg, 0.011 mmol) in 1,4-dioxane (1.5 mL) was added 4N HCl in dioxane (0.011 mL, 0.045 mmol). After 60 min, the reaction was concentrated and triturated with EtOAc, then the solid was isolated by filtration and dried to afford the title compound (10 mg, 0.011 mmol, 98% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.77 (br. s., 2H), 8.02 (br. s., 2H), 7.57 (s, 2H), 7.29-7.39 (m, 4H), 6.58 (s, 2H), 4.56 (d, J=7.10 Hz, 4H), 4.36 (br. s., 4H), 4.15 (t, J=6.21 Hz, 4H), 3.48-3.54 (m, 6H), 2.10 (s, 6H), 1.86 (br. s., 4H), 1.74-1.83 (m, 4H), 1.30 (t, J=7.10 Hz, 6H); LCMS (LCMS Method D): Rt=0.78 min, [M+H].sup.+=827.4.

Example 26

(E)-8-ethyl-1,26-bis(3-hydroxypropoxy)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,-13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo-[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide, bis hydrochloride

[1281] ##STR00234##

[1282] Example 26 can be prepared according to method 6 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1283] To (E)-4,26-bis(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-2,24-dicarboxamide (269 mg, 0.246 mmol) in THF (20 mL) at 0° C. was added dropwise 4N HCl in dioxane (0.31 mL, 1.23 mmol). After 2 hr, the resulting white solid was collected by filtration and washed with Et.sub.20 to afford the title compound (226 mg, 0.241 mmol, 98% yield). .sup.1H NMR (600 MHz, MeOH-d.sub.4) δ ppm 7.71-7.74 (m, 2H), 7.38-7.41 (m, 2H), 6.82 (s, 1H), 5.72 (s, 2H), 5.00-5.07 (m, 4H), 4.77-4.83 (m, 2H), 4.67 (q, J=7.2 Hz, 2H), 3.88-3.98 (m, 4H), 3.39-3.44 (m, 4H), 2.85-2.92 (m, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.93-2.02 (m, 2 H), 1.67 (br. t., J=7.6 Hz, 2H), 1.49 (t, J=7.2 Hz, 5H), 1.34-1.44 (m, 4H); LCMS (LCMS Method L): Rt=0.73 min, [M+H].sup.+=865.7017.

Example 27

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide, dihydrochloride

[1284] ##STR00235##

[1285] Example 27 can be prepared according to a combination of methods 2, 3 and 4 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1286] 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (216 mg, 1.40 mmol) and CDI (227 mg, 1.40 mmol) were stirred in DMF (0.7 mL) at 100° C. After 10 min, (E)-2-amino-1-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide dihydrobromide (255 mg, 0.350 mmol) was added, and the reaction was heated at 110° C. After 18 hr, a solution of 10M NaOH (350 μl, 3.50 mmol) was added and the reaction mixture heated for 1h at 75° C. to hydrolyze a small amount of ester byproduct (˜15%). The mixture was then poured into sat'd aq NH.sub.4Cl (10 mL) and the resulting solid was collected by filtration. The solid was suspended in hot MeOH and filtered to give a white powder. This solid was suspended in dioxane (10 mL), and 4N HCl in dioxane (74 μL, 0.30 mmol) was added. After 10 min, the solid was collected by filtration and washed with diethyl ether to afford the title compound (110 mg, 0.121 mmol, 35% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.66 (dd, J=5.32, 1.01 Hz, 2H), 7.39 (dd, J=13.18, 1.27 Hz, 2H), 6.68 (d, J=17.24 Hz, 2H), 5.93 (br. s., 2H), 5.17 (br. s., 4H), 4.61-4.75 (m, 4H), 4.06-4.22 (m, 4H), 3.61-3.72 (m, 2H), 3.45 (t, J=6.08 Hz, 2H), 3.31 (s, 3H), 2.28 (d, J=4.06 Hz, 6H), 1.88 (td, J=6.21, 2.28 Hz, 4H), 1.35-1.50 (m, 6H); LCMS (LCMS Method L): Rt=0.78 min, [M+H].sup.+=839.6204.

Example 28

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1Hbenzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-methoxyethoxy)-1H-benzo[d]imidazole-5-carboxamide

[1287] ##STR00236##

[1288] Example 28 can be prepared according to a combination of methods 2 and 3 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1289] A mixture of HATU (894 mg, 2.35 mmol), DIEA (425 mg, 3.29 mmol), (E)-2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(2-methoxyethoxy)-1H-benzo[d]imidazole-5-carboxamide (450 mg, 0.940 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (362 mg, 2.35 mmol) in DMF (8 mL) was stirred at 65° C. After 12 hr, the reaction was cooled and treated with water. The resulting solid was collected by filtration and further purified by HPLC to yield the title compound (350 mg, 0.466 mmol, 50% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (s, 2H), 7.95-7.99 (m, 4H), 7.65-7.67 (m, 1H), 7.60 (s, 1H), 7.45-7.48 (m, 1H), 7.28-7.35 (m, 2H), 6.55 (d, J=4.0 Hz, 2H), 5.99 (dd, J=13.2, 7.7 Hz, 1H), 5.85 (dd, J=13.3, 7.5 Hz, 1H), 4.94 (d, J=5.3 Hz, 2H), 4.83 (d, J=4.9 Hz, 2H), 4.58-4.49 (m, 4H), 4.15-4.12 (m, 2H), 3.58-3.49 (m, 2H), 3.16 (s, 3H), 2.12 (s, 6H), 1.26-1.35 (m, 6H); LCMS (LCMS Method A): Rt=1.353 min, [M+H].sup.+=751.1.

Example 29

(E)-1,1′-(But-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1H-benzo[d]imidazole-5-carboxamide)

[1290] ##STR00237##

[1291] Example 29 can be prepared according to method 2 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1292] 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (89 mg, 0.58 mmol) and CDI (107 mg, 0.659 mmol) in DMF (2 mL) were stirred for 10 minutes. (E)-1,1′-(But-2-ene-1,4-diyl)bis(2-amino-7-isopropoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrobromide (180 mg, 0.264 mmol) and DIEA (0.18 mL, 1.1 mmol) were added, and the reaction was heated at 90° C. After 3 hr, ice was added, and the resulting solid was collected by filtration, stirred vigorously for 3 hr in EtOAc and isolated. The solid was found by LC/MS to contain ˜5% mono-amide and was treated with CDI (14 mg, 0.086 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (12 mg, 0.078 mmol) and DIEA (0.1 mL, 0.6 mmol) in DMF (1.5 mL). The reaction was heated to 90° C. 2 hr, and another portion of reagents was added. After 4 more hr, the reaction was cooled to RT, ice was added, and the resulting solid was collected by filtration to yield the title compound (122 mg, 0.154 mmol, 58% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.80 (s, 2H), 7.94 (br. s., 2H), 7.59 (s, 2H), 7.32 (s, 2H), 7.28 (s, 2H), 6.55 (s, 2H), 5.85 (br. s., 2H), 4.94 (br. s., 4H), 4.74 (dt, J=12.0, 5.8 Hz, 2H), 4.55 (q, J=7.0 Hz, 4H), 2.14 (s, 6H), 1.28 (t, J=7.0 Hz, 6H), 1.10 (d, J=6.1 Hz, 12H); LCMS (LCMS Method D): Rt=1.03 min, [M/2+H].sup.+=397.4557.

Example 30

(E)-7-(Benzyloxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1293] ##STR00238##

[1294] Example 30 can be prepared according to a combination of methods 2, 3 and 4 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1295] 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (20.2 mg, 0.131 mmol) and CDI (23.1 mg, 0.142 mmol) in DMF (1 mL) were stirred for 10 minutes. (E)-2-Amino-1-(4-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(benzyloxy)-1Hbenzo[d]imidazole-5-carboxamide dihydrobromide (40 mg, 0.057 mmol) and DIEA (0.07 mL, 0.4 mmol) were added, and the reaction was heated at 90° C. After 22 hr, ice was added with vigorous stirring, and the resulting solid was collected by filtration, rinsed with water and triturated sequentially with ethyl acetate and methanol to yield the title compound (10 mg, 0.012 mmol, 21% yield) as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.86 (d, J=5.8 Hz, 2H), 7.99 (br. s., 2H), 7.67 (d, J=2.3 Hz, 2H), 7.45 (s, 1H), 7.37 (br. s., 2H), 7.19-7.30 (m, 6H), 6.53 (s, 1H), 6.49 (s, 1H), 5.74-5.84 (m, 1H), 5.53-5.62 (m, 1H), 5.05 (s, 2H), 4.86 (dd, J=11.8, 4.9 Hz, 4H), 4.44-4.58 (m, 4H), 3.64 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3 H), 1.19-1.31 (m, 6H); LCMS (LCMS Method D): Rt=1.02 min, [M/2+H].sup.+=407.4811.

Example 31

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1Hbenzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1Hbenzo[d]imidazole-5-carboxamide

[1296] ##STR00239##

[1297] Example 31 can be prepared according to a combination of methods 2 and 4 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1298] A mixture of HATU (568 mg, 1.49 mmol), DIEA (0.31 mL, 1.8 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (203 mg, 1.31 mmol) in NMP (5 mL) was stirred at RT. After 1 hr, (E)-2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide (250 mg, 0.597 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction was treated with water, and the resulting solid was collected by filtration and further purified by HPLC (Gemini-C18, 150×21.2 mm, 5 um, 20-50% CH.sub.3CN in H.sub.2O, 0.1% TFA) to yield the title compound (3 mg, 4 μmol, 0.7% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.08-12.70 (m, 2H), 7.97 (d, J=10.4 Hz, 2H), 7.87 (d, J=13.0 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.32 (d, J=17.7 Hz, 2H), 6.54 (d, J=7.9 Hz, 2H), 5.96 (d, J=15.3 Hz, 1H), 5.52 (d, J=15.6 Hz, 1 H), 4.99 (s, 2H), 4.83 (s, 2H), 4.53 (d, J=4.7 Hz, 4H), 2.51 (s, 3H), 2.12 (d, J=2.8 Hz, 6H), 1.27 (t, J=7.1 Hz, 6H); LCMS (LCMS Method A): Rt=1.321 min, [M+H].sup.+=691.3.

Example 32

(E)-1,1′-(But-2-ene-1,4-diyl)bis(7-butoxy-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide)

[1299] ##STR00240##

[1300] Example 32 can be prepared according to method 2 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1301] To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (17.4 mg, 0.113 mmol) and CDI (18.3 mg, 0.113 mmol) in DMF (650 uL) at 60° C. were added (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-amino-7-(3-hydroxypropoxy)-1H-benzo[d]imidazole-5-carboxamide) (25 mg, 0.045 mmol) and TEA (38 μL, 0.27 mmol), and the reaction was heated to 120° C. After 18 hr, a solution of additional CDI (30 mg, 0.19 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (30 mg, 0.19 mmol) (heated in DMF for 10 min at 60° C.) was then added to the reaction. The reaction was cooled, water was added, and the resulting precipitate was collected by filtration and triturated with hot MeOH (1 mL) to yield the title compound (6.9 mg, 8.4 μmol, 13% yield) as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.87 (s, 2H), 7.96 (br. s., 2 H), 7.65 (s, 2H), 7.35 (br. s., 2H), 7.26 (s, 2H), 6.56 (s, 2H), 5.81 (br. s., 2H), 4.91 (br. s., 4H), 4.49-4.62 (m, 4H), 3.84 (t, J=6.46 Hz, 4H), 2.14 (s, 6H), 1.37-1.48 (m, 5H), 1.30 (t, J=6.97 Hz, 6H), 1.20 (dd, J=14.95, 7.60 Hz, 4H), 0.74 (t, J=7.48 Hz, 6H); LCMS (LCMS Method L): Rt=1.06 min, [M+H].sup.+=821.7039.

Example 33

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1Hbenzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1H-benzo[d]imidazole-5-carboxamide

[1302] ##STR00241##

[1303] Example 33 can be prepared according to a combination of methods 2 and 4 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1304] A mixture of HATU (190 mg, 0.500 mmol), DIEA (0.16 mL, 0.93 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (70 mg, 0.45 mmol) in NMP (3 mL) was stirred at RT. After 15 min, (E)-2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-isopropoxy-1H-benzo[d]imidazole-5-carboxamide (86 mg, 0.19 mmol) was added, and the mixture was stirred at 60° C. 16 hr. The reaction was treated with water, and the resulting solid was collected by filtration and further purified by HPLC (Gemini-C18, 150×21.2 mm, 5 um, 30-50% CH.sub.3CN in H.sub.2O, 0.1% TFA, 15 min run) to yield the title compound (23 mg, 0.031 mmol, 17% yield) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.82 (s, 2H), 7.96 (d, J=14.3 Hz, 3H), 7.72 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.31 (d, J=11.6 Hz, 3H), 6.55 (s, 2H), 5.96 (dd, =13.5, 7.7 Hz, 1H), 5.80 (d, J=15.7 Hz, 1H), 4.94 (d, J=5.4 Hz, 2H), 4.84 (d, J=4.9 Hz, 2H), 4.73-4.79 (m, 1H), 4.54 (td, J=14.3, 7.1 Hz, 4H), 2.13 (d, J=5.8 Hz, 6H), 1.28 (dt, J=12.1, 7.1 Hz, 6H), 1.14 (d, J=6.0 Hz, 6H); LCMS (LCMS Method A): Rt=1.413 min, [M+H].sup.+=735.2.

Example 34

(E)-1,1′-(But-2-ene-1,4-diyl)bis(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-isopropoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride

[1305] ##STR00242##

[1306] Example 34 can be prepared according to method 2 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1307] To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (110 mg, 0.711 mmol), HATU (271 mg, 0.711 mmol) and HOBt (54.5 mg, 0.356 mmol) in DMF (0.9 mL) was added a suspension of (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-amino-7-(3-isopropoxypropoxy)-1H-benzo[d]-imidazole-5-carboxamide) (151 mg, 0.237 mmol) and TEA (0.20 mL, 1.4 mmol) in DMF (3.8 mL). After stirring at RT overnight, the reaction was diluted with water, extracted with EtOAc (2X), and the combined organic extracts were washed with brine and concentrated. The resulting residue was purified over silica gel (Isco R.sup.f 40 g column), eluting with 0-20% MeOH in DCM to yield the free base of title compound (105 mg, 0.116 mmol, 49% yield) as a pale yellow solid. A portion of this material (80 mg, 0.088 mmol) was dissolved in MeOH (2 mL) and DCM (2 mL) and treated with 4N HCl in dioxane (0.044 mL, 0.18 mmol). After 5 min, the reaction was added to MeCN (A very small amount of solid precipitated), and the mixture was concentrated. The resulting residue was triturated with EtOAc to give the title compound (68 mg, 0.069 mmol, 79% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.00 (br. s., 2H), 7.65 (d, =1.01 Hz, 2H), 7.35 (br. s., 2H), 7.30 (d, J=1.01 Hz, 2H), 6.55 (s, 2H), 5.83 (br. s., 2H), 4.94 (br. s., 4H), 4.54 (q, J=7.10 Hz, 4H), 4.00 (t, J=6.21 Hz, 4H), 3.32-3.41 (m, 2H), 3.21-3.31 (m, 4H), 2.13 (s, 6H), 1.69 (t, J=6.21 Hz, 4H), 1.29 (t, J=7.10 Hz, 6H), 0.98 (d, J=6.08 Hz, 12H); LCMS (LCMS Method D): Rt=1.10 min, [M/2+H].sup.+=455.5857.

Example 35

(E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(morpholinomethyl)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide, trifluoroacetic acid salt

[1308] ##STR00243##

[1309] Example 35 can be prepared according to a combination of methods 2 and 3 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1310] A mixture of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (117 mg, 0.760 mmol), HATU (347 mg, 0.912 mmol) and DIEA (0.319 mL, 1.824 mmol) in DMF (6 mL) was stirred at RT. After 30 min, (E)-2-amino-1-(4-(2-amino-7-(morpholinomethyl)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide (140 mg, 0.304 mmol) was added, and the reaction was stirred at 50° C. overnight. Water was added, and the resulting solid was collected by filtration and purified by prep-HPLC to afford the title compound (10 mg, 12 μmole, 3.9% yield) as a gray solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.98 (br. s., 2H), 10.59 (br. s., 1H), 7.91-8.01 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.24-7.39 (m, 3H), 6.56 (d, J=5.6 Hz, 2H), 5.93 (d, J=16 Hz, 2H), 5.38-5.50 (m, 2H), 5.10 (br. s., 2H), 4.79 (br. s., 2H), 4.48-4.55 (m, 4H), 3.69-3.85 (m, 4H), 3.03-3.32 (m, 4H), 2.13 (s, 6H), 1.21-1.40 (m, 6H); LCMS (LCMS Method A): Rt=1.328 min, [M+H].sup.+=733.2

Example 36

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperidin-4-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride

[1311] ##STR00244##

Step 1: tert-butyl 4-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)piperidine-1-carboxylate

[1312] ##STR00245##

[1313] 4-chloro-3-hydroxy-5-nitrobenzamide (1 g, 4.62 mmol)), tert-butyl 4-(3-hydroxypropyl) piperidine-1-carboxylate (1.348 g, 5.54 mmol) and triphenylphosphine (2.059 g, 7.85 mmol) were mixed in THF (20 mL) at 0° C., and then diisopropyl (E)-diazene-1,2-dicarboxylate (1.545 ml, 7.85 mmol) was added. The reaction was maintained at RT for 16 hrs, then the yellow solution was then concentrated and the residue was partitioned between sat. aq. NaHCO.sub.3 and EtOAc. The organic layer was washed by brine, dried over MgSO.sub.4 and concentrated to a yellow residue. This residue was purified by Isco Combiflash (10%-50% (3:1 EtOAc/EtOH)/Hexane, with 2% NH.sub.4OH; 40 g RediSep column). Collected fractions containing the product were combined and concentrated to give the title compound as a yellow solid (2.83 g, 61% pure, 3.91 mmol, 85% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.29 (s, 1H), 8.04 (d, J=1.77 Hz, 1H,) 7.87 (d, J=1.52 Hz, 1H), 7.80 (s, 1H), 4.22 (t, J=6.34 Hz, 2H), 3.93 (d, J=10.90 Hz, 2H), 2.68 (br. s., 2H), 1.77-1.88 (m, 2H), 1.67 (d, J=11.41 Hz, 2H), 1.47 (br. s., 1H), 1.34-1.42 (m, 11H), 0.89-1.05 (m, 2H); LCMS (LCMS Method K): Rt=1.25 min, [M−100].sup.+=342.0.

Step 2: tert-butyl (E)-4-(3-(5-carbamoyl-2-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)amino)-3-nitrophenoxy)propyl)piperidine-1-carboxylate

[1314] ##STR00246##

[1315] (E)-4-((4-aminobut-2-en-1-yl)amino)-3-methoxy-5-nitrobenzamide, Trifluoroacetic acid salt (1 g, 2.54 mmol) was suspended in n-butanol (10 mL) at RT, and then DIPEA (2.66 ml, 15.22 mmol) and tert-butyl 4-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)piperidine-1-carboxylate (2.021 g, 2.79 mmol) were added. The reaction mixture was then maintained at 120° C. for 48 hrs, then the reaction mixture was cooled to RT. The brown solid was collected by filtration, and purified by Isco Combiflash (20%-80% (3:1 EtOAc/EtOH)/Hexane, with 2% NH.sub.4OH; 40 g RediSep column). Collected fractions containing the product were combined and concentrated to give the title compound as a red solid (204 mg, 12% yield). LCMS (LCMS Method K): Rt=1.25 min, [M−100].sup.+=586.2.

Step 3: tert-butyl (E)-4-(3-(3-amino-2-((4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)amino)-5-carbamoylphenoxy)propyl)piperidine-1-carboxylate

[1316] ##STR00247##

[1317] Sodium hydrosulfite (609 mg, 2.97 mmol) was dissolved in H2O (5 mL) at rt, and then this solution was added to a stirring solution of tert-butyl (E)-4-(3-(5-carbamoyl-2-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)amino)-3-nitrophenoxy)propyl)piperidine-1-carboxylate (204 mg, 0.297 mmol) and ammonium hydroxide (0.799 mL, 5.95 mmol) in 20 ml MeOH. The reaction mixture was then maintained at RT for 2 hrs then the mixture was filtered and the filtrate was partially concentrated to remove MeOH. The resulting yellow aqueous mixture was partitioned between sat. NaHCO.sub.3(aq) and EtOAc. The organic layer was washed by brine, dried over MgSO.sub.4, concentrated and purified by Isco Combiflash (2%-20% MeOH/CH.sub.2Cl.sub.2, 10% TEA in MeOH; 40 g RediSep column). Collected fractions containing the product were combined and concentrated to give the title compound as a colorless oil (77 mg, 42% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 6.94 (t, J=2.15 Hz, 2 H), 6.89 (dd, J=4.56, 1.77 Hz, 2H), 5.74 (d, J=4.56 Hz, 2H), 4.05 (d, J=13.43 Hz, 2 H), 3.96 (t, J=6.34 Hz, 2H), 3.80 (s, 3H), 3.52-3.62 (m, 4H), 2.62-2.83 (m, 2H), 1.77-1.88 (m, 2H), 1.71 (d, J=11.91 Hz, 2H), 1.35-1.52 (m, 12H), 0.99-1.16 (m, 2H). LCMS (LCMS Method K): Rt=0.64 min, [M+H].sup.+=626.3.

Step 4: tert-butyl (E)-4-(3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)piperidine-1-carboxylate

[1318] ##STR00248##

[1319] tert-Butyl (E)-4-(3-(3-amino-2-((4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)amino)-5-carbamoylphenoxy)propyl)piperidine-1-carboxylate (77 mg, 0.123 mmol) was dissolved in DMF (3 mL) at 0° C., and then 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (0.308 ml, 0.123 mmol) was added. The reaction mixture was then maintained at 0° C. for 15 min. then EDC (28.3 mg, 0.148 mmol) and TEA (0.043 ml, 0.308 mmol) were then added to the reaction mixture. The reaction mixture was then maintained at RT for 16 hrs. The reaction mixture was concentrated and the yellow residue was purified on silica gel (20%-50% MeOH/CH.sub.2Cl.sub.2, 10% TEA in MeOH; 40 g RediSep column). Collected fractions containing the product were combined and concentrated to afford the title compound as a white solid (87 mg, 52% yield). LCMS (LCMS Method K): Rt=1.11 min, [M+H].sup.+=948.3.

Example 36

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperidin-4-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride

[1320] ##STR00249##

[1321] Step 5: tert-butyl (E)-4-(3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)piperidine-1-carboxylate (87 mg, 0.092 mmol) was suspended in MeOH (40 ml), and HCl (4N in 1,4-dioxane) (0.575 ml, 2.30 mmol) was added. The reaction mixture was maintained at RT for 48 hrs, then the mixture was concentrated and the residue was purified by HPLC (XSELECT CSH C18 column, 150 mm×30 mm, i.d. 5 um packing diameter, 15%-85% 10 mM ammonium bicarbonate in water with acetonitrile). The desired fractions were combined and partially concentrated and the white precipitate collected to yield the title compound as a white solid (30 mg, 37% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 8.57 (s, 1H), 7.63 (d, J=1.01 Hz, 1H), 7.57 (s, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 5.85 (br. s., 2 H), 5.03 (br. s., 4H), 4.54-4.73 (m, 4H), 3.81 (t, J=6.46 Hz, 2H), 3.71 (s, 3H), 3.23 (d, J=12.93 Hz, 2H), 2.72-2.85 (m, 2H), 2.24 (d, J=12.17 Hz, 6H), 1.74 (d, J=13.69 Hz, 2H), 1.12-1.54 (m, 13H). LCMS (LCMS Method K): Rt=0.72 min, [M+H].sup.+=848.6.

Example 37

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

[1322] ##STR00250##

##STR00251##

Step 1: tert-butyl 4-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)piperazine-1-carboxylate

[1323] ##STR00252##

[1324] Triphenylphosphine (2.059 g, 7.85 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (1.692 g, 6.93 mmol) and diisopropyl (E)-diazene-1,2-dicarboxylate (1.587 g, 7.85 mmol) were mixed in THF (20 mL) at 0° C., and then 4-chloro-3-hydroxy-5-nitrobenzamide (1 g, 4.62 mmol) was added. The reaction solution was maintained at RT for 16 hrs then the brown reaction solution was partitioned between sat. NaHCO.sub.3(aq) and EtOAc. The organic layer was washed with brine, dried over MgSO.sub.4, concentrated and purified on silica gel (20%-80% (3:1 EtOAc/EtOH)/Hexane, with 2% NH.sub.4OH; 330 g RediSep column). Desired fractions were combined and concentrated to give the title compound as a white solid (970 mg, 47% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.30 (s, 1H), 8.05 (d, J=1.77 Hz, 1H), 7.88 (d, J=1.77 Hz, 1H), 7.80 (s, 1H), 4.28 (t, J=6.21 Hz, 2H), 3.31 (br. s., 4H), 2.48 (t, J=7.10 Hz, 2H), 2.33 (t, J=4.94 Hz, 4H), 1.96 (t, J=6.59 Hz, 2H), 1.40 (s, 9H). LCMS (LCMS Method K): Rt=0.69 min, [M+H].sup.+=443.4.

Step 2: tert-butyl (E)-4-(3-(5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenoxy) propyl)piperazine-1-carboxylate

[1325] ##STR00253##

[1326] (E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2Hydrochloride (242 mg, 0.499 mmol) was dissolved in n-butanol (10 mL) at RT, and then DIPEA (0.476 mL, 2.72 mmol) was added, followed by tert-butyl 4-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)piperazine-1-carboxylate (201 mg, 0.454 mmol). The reaction mixture was maintained at 120° C. for 16 hrs. The reaction mixture was cooled to RT and the red solid was collected by filtration (296 mg, 73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.14 (d, J=1.77 Hz, 1H), 8.00 (br. s., 2H), 7.84 (t, J=6.46 Hz, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.30-7.41 (m, 3H), 6.59 (s, 1H), 5.61-5.87 (m, 2H), 4.89 (d, J=5.58 Hz, 2H), 4.58 (q, J=7.35 Hz, 2H), 4.14 (br. s., 2H), 3.89 (t, J=6.34 Hz, 2H), 3.84 (s, 3H), 3.25 (br. s., 4H), 2.27 (t, J=6.72 Hz, 2H), 2.21 (br. s., 4H), 2.16 (s, 3H), 1.75 (d, J=6.08 Hz, 2H), 1.39 (s, 9H) 1.23-1.35 (m, 3H). LCMS (LCMS Method K): Rt=0.78 min, [M+H]+=818.4.

Step 3: tert-butyl (E)-4-(3-(3-amino-5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenoxy)propyl) piperazine-1-carboxylate

[1327] ##STR00254##

[1328] Sodium hydrosulfite (371 mg, 1.81 mmol) was dissolved in H.sub.2O (2 mL) at RT, and then a solution of tert-butyl (E)-4-(3-(5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenoxy) propyl)piperazine-1-carboxylate (296 mg, 0.362 mmol) and ammonium hydroxide (0.486 mL, 3.62 mmol) in 5 mL MeOH was added. The reaction mixture was maintained at room temperature for 2 hrs, then the reaction mixture was filtered and the filtrate was partially concentrated to remove MeOH. The resulting yellow aqueous mixture was then extracted with EtOAc 3 times, the organic extracts were combined and concentrated to provide the title compound as a yellow solid (114 mg, 40% yield). .sup.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.60 (d, J=1.27 Hz, 1H), 7.31 (d, J=1.27 Hz, 1H), 6.81 (d, J=1.77 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J=1.77 Hz, 1H), 5.74-5.84 (m, 1H), 5.53-5.65 (m, 1H), 4.12 (q, J=7.18 Hz, 2H), 3.84-3.91 (m, 3H), 3.61-3.71 (m, 4H), 3.38 (br. s., 4H), 2.31-2.36 (m, 6H), 2.26 (s, 3H), 2.03 (s, 2H), 1.68-1.78 (m, 2H), 1.47 (s, 9H), 1.42 (t, J=7.10 Hz, 3 H). LCMS (LCMS Method K): Rt=0.65 min, [M+H]+=788.5.

Step 4: tert-butyl (E)-4-(3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)piperazine-1-carboxylate

[1329] ##STR00255##

[1330] Tert-butyl (E)-4-(3-(3-amino-5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenoxy)propyl) piperazine-1-carboxylate (114 mg, 0.145 mmol) was dissolved in DMF (10 mL) at 0° C., and then 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (0.362 mL, 0.145 mmol) was added. The reaction mixture was maintained at 0° C. for 15 min. then TEA (0.050 ml, 0.362 mmol) and EDC (33.3 mg, 0.174 mmol) were added to the reaction mixture. The reaction mixture was maintained at RT for 16 hrs. The reaction mixture was then added into a stirring solution of sat. NaHCO.sub.3(aq). The resulting white precipitate was collected by filtration to provide the title compound (103 mg, 75% yield). LCMS (LCMS Method K): Rt=0.82 min, [M+H].sup.+=950.5.

Example 37

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

[1331] ##STR00256##

[1332] Step 5: tert-butyl (E)-4-(3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)piperazine-1-carboxylate (103 mg, 0.109 mmol) was dissolved in MeOH (2 mL) and DCM (2 mL), and then HCl (4N in 1,4-dioxane) (0.271 mL, 1.085 mmol) was added. The reaction mixture was maintained at RT for 16 hrs. DMSO (2 mL) was then added to the reaction mixture, and this mixture was filtered and the filtrate was concentrated and purified by HPLC (XSELECT CSH C18 column, 150 mm×30 mm, i.d. 5 um packing diameter, 30%-85% 10 mM ammonium bicarbonate in water with acetonitrile). The clean fractions after HPLC were combined and partially concentrated to yield the title compound as a white precipitate (25 mg, 27% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.57 (d, J=16.48 Hz, 2H), 7.14-7.30 (m, 2H), 6.50-6.70 (m, 2H), 5.81 (d, J=3.04 Hz, 2H), 4.99 (br. s., 4H) 4.50-4.69 (m, 4H) 3.86 (t, J=5.70 Hz, 2H) 3.69 (s, 3H) 2.81 (t, J=4.69 Hz, 4H) 2.32-2.36 (m, 6H) 2.20 (d, J=12.93 Hz, 6H), 1.70 (br. s., 2H), 1.25-1.45 (m, 6H). LCMS (LCMS Method K): Rt=0.67 min, [M+H].sup.+=849.8.

Example 38

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-ethoxy-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1333] ##STR00257##

[1334] Example 38 can be prepared according to method 20 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: (E)-1-(4-((2-amino-4-carbamoyl-6-(3-morpholinopropoxy)phenyl)amino)but-2-en-1-yl)-7-ethoxy-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide (46 mg, 0.065 mmol) was dissolved in DMF (655 uL) at 0° C., and then 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (196 μl, 0.079 mmol) was added. The reaction solution was maintained at 0° C. for 15 min., then EDC (15.06 mg, 0.079 mmol) and TEA (22.81 μl, 0.164 mmol) were added and the reaction solution was maintained at RT. After 16 hrs, the reaction was concentrated and the yellow residue was purified by HPLC (XSELECT CSH C18 column, 150 mm×30 mm, i.d. 5 um packing diameter, 15%-55% 10 mM ammonium bicarbonate in water with acetonitrile). The desired fractions were combined and concentrated to provide the title compound as a white solid (19.2 mg, 34% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.62 (d, J=1.27 Hz, 1H), 7.58 (d, J=1.27 Hz, 1H), 7.24 (d, J=1.27 Hz, 1H), 7.20 (d, J=1.27 Hz, 1H), 6.64 (s, 1H), 6.62 (s, 1H), 5.78 (d, J=3.30 Hz, 2H), 5.01 (d, J=2.79 Hz, 4 H), 4.63 (q, J=7.10 Hz, 4H), 3.86-4.08 (m, 6H), 3.69-3.81 (m, 2H), 3.37 (br. s., 2H), 3.16-3.23 (m, 2H), 2.97-3.13 (m, 2H), 2.23 (s, 6H), 1.96-2.04 (m, 2H), 1.39 (t, J=7.10 Hz, 6H), 1.15 (t, J=6.97 Hz, 3H). LCMS (LCMS Method K): Rt=0.76 min, [M+H].sup.+=864.5.

Example 39

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-(dimethylamino)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, 2Hydrochloride

[1335] ##STR00258##

[1336] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, hydrochloride (150 mg, 0.184 mmol) in DMF (2 mL) was added TEA (0.20 mL, 1.435 mmol). The solution was cooled to 0° C. Methanesulfonyl chloride (42.0 mg, 0.367 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 1 hr then another 1 eq. of methanesulfonyl chloride (21.0 mg, 0.183 mmol) was then added, and the reaction was continued at 0° C. for 1 hr. K.sub.2CO.sub.3 (127 mg, 0.918 mmol) was then added to reaction mixture followed by 1 ml of dimethyl amine (2 M in THF, 2.0 mmol). The reaction mixture was stirred at 80° C. in a sealed tube for 2 hours then allowed to cool to room temperature, and the crude material was purified by mass directed HPLC. The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia, B=MeCN B %: 15-55. Collected desired MW peaks. Solvent was removed and the residue was dissolved in 1 mL MeOH. 4N HCl in dioxane (1 mL) was added. The solution was stirred at room temperature for 10 min. Removed solvent and the solid washed with ethyl ether (5 ml×2) to provide the title compound (76 mg, 0.082 mmol, 44.7% yield). .sup.1H NMR (DMSO-d6, 600 MHz): δ (ppm) 12.89 (br s, 2H), 10.18-10.41 (m, 1H), 7.96-8.04 (m, 2H), 7.66 (d, J=10.0 Hz, 2H), 7.35-7.41 (m, 2H), 7.28-7.35 (m, 2H), 6.53 (d, J=2.8 Hz, 2H), 5.82 (dt, J=15.5, 5.3 Hz, 1H), 5.71 (dt, J=15.4, 5.6 Hz, 1H), 4.85-4.98 (m, 4H), 4.52 (quin, J=6.5 Hz, 4H), 3.96-4.04 (m, 2H), 3.70 (s, 3H), 3.00-3.09 (m, 2H), 2.66 (d, J=4.8 Hz, 6H), 2.11 (d, J=4.4 Hz, 6H), 1.85-2.03 (m, 2H), 1.20-1.32 (m, 6H); LCMS Method K: Rt=0.67 min, [M+H].sup.+=808.5

Example 40

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(methylamino)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2Hydrochloride

[1337] ##STR00259##

[1338] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, hydrochloride (100 mg, 0.122 mmol) was added TEA (0.102 mL, 0.734 mmol). The solution was cooled to 0° C. Methanesulfonyl chloride (28.0 mg, 0.245 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hr then another 1 eq of MsCl was then added, and the reaction was continued at 0° C. for 2 hrs. K.sub.2CO.sub.3 (85 mg, 0.612 mmol) was then added to reaction mixture followed by 1 mL methanamine (2 M in THF, 2.0 mmol). The reaction mixture was stirred at 80° C. in a sealed tube for 2h, then the reaction mixture was allowed to cool to RT and filtered. The crude filtrate was purified by mass directed HPLC. The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=10 mM Ammonium Bicarbonate in H.sub.2O adjusted to pH 10 with Ammonia, B=MeCN B %: 15-55. Collected desired MW peaks and removed the solvent. The material was dissolved in 2 mL of MeOH, and 1 mL 4N HCl in dioxane was added. The mixture was stirred at RT for 15 min then concentrated to afford the title compound (33 mg, 0.037 mmol, 30.2% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.90 (br, s, 1H), 8.79 (br. s., 2H) 8.03 (br. s., 2H) 7.66 (d, J=7.10 Hz, 2H) 7.26-7.48 (m, 4H) 6.52 (s, 2H) 5.68-5.90 (m, 2H) 4.92 (dd, J=17.24, 4.06 Hz, 4H) 4.52 (q, J=6.76 Hz, 4H) 4.09 (t, J=5.58 Hz, 2H) 3.73 (s, 3H) 2.90 (d, J=5.58 Hz, 2H) 2.46 (t, J=5.32 Hz, 3H) 2.11 (s, 6H) 1.88-2.01 (m, 2H) 1.27 (t, J=6.97 Hz, 6H); LCMS Method K: Rt=0.66 min, [M+H].sup.+=794.4.

Example 41

(E)-7-(3-aminopropoxy)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, 2Trifluoroacetic acid salt

[1339] ##STR00260##

[1340] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2Hydrochloride (100 mg, 0.117 mmol) was added TEA (0.049 mL, 0.351 mmol). The solution was cooled to 0° C. Methanesulfonyl chloride (0.014 mL, 0.176 mmol) was added and the reaction mixture was allowed to warm to RT and stirred at RT for 1h. Another 0.5 eq of MsCl was then added and stirred at RT for 2 hrs, then another 0.5 eq of MsCl was added and the reaction stirred for another 1 hr. K.sub.2CO.sub.3 (81 mg, 0.586 mmol) was then added to reaction mixture followed by 7M ammonia in MeOH (0.167 mL, 1.171 mmol). The reaction mixture was stirred at 50° C. in a sealed tube overnight. The reaction was then filtered and the crude filtrate was purified by mass directed HPLC to afford the title compound (15.6 mg, 13.2%). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=H.sub.2O (0.1% TFA), B=MeCN (0.1% TFA) B %: 15-55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.86 (br. s., 1 H), 7.99 (br. s., 2H), 7.76 (br. s., 2H), 7.65 (dd, J=6.21, 0.89 Hz, 2H), 7.40 (br. s., 2H), 7.28-7.36 (m, 2H), 6.51 (d, J=8.87 Hz, 2H), 5.72-5.88 (m, 4H), 4.91 (dd, J=9.50, 4.44 Hz, 4H), 4.43-4.59 (m, 4H), 4.10 (t, J=5.96 Hz, 2H), 3.72 (s, 3H), 2.83-2.97 (m, 2H), 2.11 (d, J=5.07 Hz, 6H), 1.90 (quin, J=6.40 Hz, 2H), 1.26 (td, J=7.10, 4.82 Hz, 6H); LCMS Method K: Rt=0.65 min, [M+H].sup.+=780.5

Example 42

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

[1341] ##STR00261##

[1342] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, 2Hydrochloride (100 mg, 0.117 mmol) in DMF (2 mL) was added TEA (71.1 mg, 0.703 mmol). The solution was cooled to 0° C. Methanesulfonyl chloride (26.8 mg, 0.234 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 45 min. Another 1 eq of MsCl (13.5 mg) was then added, continued to stir at 0° ° C. for 2 hrs. K.sub.2CO.sub.3 (97 mg, 0.703 mmol) was then added to reaction mixture followed by pyrrolidin-3-ol (102 mg, 1.17 mmol). The reaction mixture was stirred at 80° ° C. in a sealed tube for 1 hr, then the reaction mixture was allowed to cool to RT and the reaction mixture was filtered. The crude filtrate was purified by mass directed HPLC to provide the title compound (56.6 mg, 0.063 mmol, 54.0% yield). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=10 mM Ammonium Bicarbonate in H.sub.2O adjusted to pH 10 with Ammonia, B=MeCN B %: 15-55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.84 (br. s., 2H) 7.92-8.06 (m, 2H) 7.61-7.69 (m, 2H) 7.23-7.44 (m, 4H) 6.46-6.61 (m, 2H) 5.72-5.96 (m, 2H) 4.91 (dd, J=13.05, 4.18 Hz, 4H) 4.67 (br. s., 1H) 4.52 (q, J=7.18 Hz, 4H) 4.12 (br. s., 1H) 3.97 (t, J=5.96 Hz, 2H) 3.35 (br. s., 2 H) 2.54-2.65 (m, 1H) 2.33-2.47 (m, 4H) 2.26 (br. s., 2H) 2.12 (d, J=8.36 Hz, 6H) 1.81-1.96 (m, 1H) 1.60-1.76 (m, 2H) 1.46 (dd, J=8.24, 4.69 Hz, 1H) 1.19-1.37 (m, 6H); LCMS Method K: Rt=0.72 min, [M+H].sup.+=850.9

Example 43

(E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

[1343] ##STR00262##

[1344] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride (80 mg, 0.098 mmol) in DMF (2 mL) was added TEA (0.136 mL, 0.979 mmol) at RT. The solution was stirred at RT for 15 min. then methanesulfonic anhydride (51.1 mg, 0.294 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 45 min. K.sub.2CO.sub.3 (200 mg, 1.447 mmol) was then added to reaction mixture followed by 2-(piperazin-1-yl)ethan-1-ol (127 mg, 0.979 mmol). The reaction mixture was stirred at 80° C. in a sealed tube for 1h and at 50° C. overnight, then the reaction mixture was allowed to cool to RT and filtered. The crude filtrate was purified by mass directed HPLC. Collected desired MW peaks. Removed solvent to provide the title compound (45.1 mg, 0.051 mmol, 51.6% yield). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=10 mM Ammonium Bicarbonate in H.sub.2O adjusted to pH 10 with Ammonia, B=MeCN B %: 15-55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (br. s., 2H) 7.98 (br. s., 2 H) 7.61-7.71 (m, 2H) 7.21-7.45 (m, 4H) 6.47-6.65 (m, 2H) 5.75-5.92 (m, 2H) 4.85-5.01 (m, 4H) 4.48-4.65 (m, 4H) 4.34 (br. s., 1H) 3.91 (t, J=5.96 Hz, 2H) 3.70 (s, 3H) 3.44 (q, J=6.08 Hz, 2H) 2.18-2.39 (m, 10H) 2.14 (s, 3H) 2.11 (s, 3H) 1.57-1.70 (m, 2H) 1.29 (q, J=7.10 Hz, 6H); LCMS Method K: Rt=0.66 min, [M+H].sup.+=893.4

Example 44

(E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-(3-(hydroxymethyl)morpholino)propoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 2Trifluoroacetic acid salt

[1345] ##STR00263##

[1346] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride (100 mg, 0.122 mmol) in DMF (2 mL) was added TEA (0.20 mL, 1.435 mmol). The solution was cooled to 0° C. and methanesulfonyl chloride (28.0 mg, 0.245 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 1 hr. Another 1 eq of MsCl was then added, continued to stir at 0° C. for another 3 hrs. K.sub.2CO.sub.3 (85 mg, 0.612 mmol) was then added to reaction mixture followed by morpholin-3-ylmethanol (86 mg, 0.734 mmol). The reaction mixture was stirred at 50° C. in a sealed tube overnight then reaction mixture was allowed to cool to RT and filtered. The crude filtrate was purified by mass directed HPLC to provide the title compound (13.1 mg, 9.66%). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=H.sub.2O (0.1% TFA), B=MeCN (0.1% TFA) B %: 15-55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.49-13.47 (m, 1H) 9.64 (br. s., 1H) 7.99 (d, J=9.89 Hz, 2H) 7.67 (d, J=7.60 Hz, 2H) 7.40 (br. s., 2H) 7.31 (d, J=8.11 Hz, 2H) 6.54 (d, J=1.77 Hz, 2H) 5.70-5.85 (m, 2H) 4.80-5.01 (m, 6H) 4.54 (dd, J=6.72, 3.68 Hz, 4H) 3.84-4.13 (m, 5H) 3.73-3.81 (m, 1H) 3.54-3.66 (m, 2H) 3.43 (d, J=11.91 Hz, 2H) 2.91-3.32 (m, 5H) 2.12 (d, J=4.82 Hz, 6H) 1.89 (br. s., 2H) 1.21-1.33 (m, 6H); LCMS Method K: Rt=0.72 min, [M+H].sup.+=880.5.

Example 45

(E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-(ethyl(2-methoxyethyl)amino)propoxy)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

[1347] ##STR00264##

[1348] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, Hydrochloride (100 mg, 0.122 mmol) in DMF (2 mL) was added TEA (0.171 mL, 1.224 mmol) at RT. Methanesulfonic anhydride (42.6 mg, 0.245 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 1 hr. Another 1 eq of methanesulfonic anhydride was then added, continued to stir at RT for 30 min. K.sub.2CO.sub.3 (169 mg, 1.224 mmol) was then added to reaction mixture followed by N-ethyl-2-methoxyethan-1-amine (126 mg, 1.224 mmol). The reaction mixture was stirred at 80° C. in a sealed tube for 2 hrs then reaction mixture was allowed to cool to RT and filtered. The crude filtrate was purified by mass directed HPLC (2 injections). Collected desired MW peaks and removed solvent to provide the title compound (21.1 mg, 0.024 mmol, 19.52% yield). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=10 mM Ammonium Bicarbonate in H.sub.2O adjusted to pH 10 with Ammonia, B=MeCN B %: 15-55. .sup.1H NMR (400 MHz, DMSO-o) δ ppm 12.81 (br. s., 2H) 7.98 (br. s., 2H) 7.59-7.71 (m, 2H) 7.24-7.42 (m, 4H) 6.46-6.61 (m, 2H) 5.75-5.94 (m, 2H) 4.92 (dd, J=16.73, 4.06 Hz, 4H) 4.47-4.62 (m, 4H) 3.96 (t, J=5.83 Hz, 2H) 3.72 (s, 3H) 3.24 (t, J=6.08 Hz, 2H) 3.11 (s, 3H) 2.41 (t, J=5.96 Hz, 4H) 2.34 (q, J=7.10 Hz, 2H) 2.12 (d, J=10.39 Hz, 6H) 1.55-1.66 (m, 2H) 1.29 (q, J=7.10 Hz, 6H) 0.82 (t, J=6.97 Hz, 3H); LCMS Method K: Rt=0.69 min, [M+H].sup.+=866.4.

Example 46

(E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-methoxy-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3 trifluoroacetic acid salt

[1349] ##STR00265##

[1350] To a solution of (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, hydrochloride (100 mg, 0.122 mmol) in DMF (2 mL) was added TEA (0.171 mL, 1.224 mmol). The solution was cooled to 0° C. Methanesulfonic anhydride (42.6 mg, 0.245 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 1 hr. Another 1 eq. of MsCl was then added, continued to stir at 0° C. for 2 hrs. K.sub.2CO.sub.3 (85 mg, 0.612 mmol) was then added followed by 1-(2-methoxyethyl)piperazine (176 mg, 1.224 mmol) and the reaction mixture was stirred at 50° C. in a sealed tube for overnight. The reaction was then allowed to cool to RT and filtered. The crude filtrate was purified by mass directed HPLC. Collected desired MW peaks and removed solvent to provide the title compound (39.6 mg, 0.032 mmol, 25.9% yield). The HPLC analysis was conducted on an XSELECT SCH C18 column. Solvent condition: A=H.sub.2O (0.1% TFA), B=MeCN (0.1% TFA) B %: 15-55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.90 (br, s, 2H) 8.00 (d, J=9.89 Hz, 2H) 7.66 (s, 2H) 7.40 (d, J=4.06 Hz, 2H) 7.22-7.35 (m, 2H) 6.53 (d, J=4.06 Hz, 2H) 5.70-5.89 (m, 2H) 4.91 (dd, J=9.63, 4.56 Hz, 4H) 4.53 (dd, J=7.10, 3.55 Hz, 6H) 3.94-4.04 (m, 3H) 3.70 (s, 3H) 3.60 (d, J=4.06 Hz, 2H) 3.31 (s, 3H) 3.09-3.25 (m, 5H) 2.86 (br. s., 4H) 2.12 (d, J=5.07 Hz, 6 H) 1.74-1.88 (m, 2H) 1.28 (td, J=7.10, 3.30 Hz, 6H); LCMS Method K: Rt=0.66 min, [M+H].sup.+=907.4

Example 47

8-ethyl-23-((4-methoxybenzyl)(methyl)amino)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide

[1351] ##STR00266##

Step 1: 3-fluoro-N-(4-methoxybenzyl)-N-methyl-2-nitroaniline

[1352] ##STR00267##

[1353] A solution of 1-(4-methoxyphenyl)-N-methylmethanamine (5.23 g, 34.6 mmol) in CHCl.sub.3 (20 ml) was added to a stirring solution of 1,3-difluoro-2-nitrobenzene (5.5 g, 34.6 mmol) and TEA (5.78 mL, 41.5 mmol) in CHCl.sub.3 (250 mL) at RT under N.sub.2. The mixture was stirred at RT for 30 min and then heated to 50° C. overnight. Saturated NaHCO.sub.3 was added, the organic layer was separated, the aqueous layer was as extracted with DCM, and the combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 filtered and concentrated. The residue was purified by silica column chromatography (0-12% EtOAc in hexanes) to afford the title compound (8.5 g, 29.3 mmol, 85% yield) as an orange oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-7.34 (m, 1H) 7.20 (d, J=8.28 Hz, 2H) 6.86-6.93 (m, 3H) 6.78 (t, J=8.78 Hz, 1H) 4.29 (s, 2H) 3.82 (s, 3H) 2.80 (s, 3H); LCMS (LCMS Method D): Rt=1.28, [M+H].sup.+=120.5

Step 2: tert-butyl (4-((3-((4-methoxybenzyl)(methyl)amino)-2-nitrophenyl)amino)-butyl)carbamate

[1354] ##STR00268##

[1355] To a solution of 3-fluoro-N-(4-methoxybenzyl)-N-methyl-2-nitroaniline (8.5 g, 29.3 mmol) in N,N-Dimethylformamide (DMF) (60 mL) was added tert-butyl (4-aminobutyl)carbamate (8.27 g, 43.9 mmol) at RT and the mixture was stirred for 10 min; K2CO3 (8.09 g, 58.6 mmol) was then added and the mixture was stirred 80° C. overnight. The reaction was cooled to RT, diluted with EtOAc (200 mL) and washed successively with water (300 mL), 5% LiCl, and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated and the resulting residue was purified by silica column chromatography (0-30% EtOAc in hexane) to afford the title compound (10.68 g, 23.29 mmol, 80% yield) as a red oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.09-7.28 (m, 3H) 6.87 (d, J=7.53 Hz, 2H) 6.40 (br. s., 1H) 6.29 (d, J=7.03 Hz, 1H) 4.57 (br. s., 1H) 4.32 (br. s., 2H) 3.81 (s, 3H) 3.11-3.30 (m, 4H) 2.77 (br. s., 3H) 1.67-1.79 (m, 2H) 1.55-1.67 (m, 2H) 1.47 (s, 9H). LCMS (LCMS Method D): Rt=1.37, [M+H].sup.+=459.2.

Step 3: tert-butyl (4-((2-amino-3-((4-methoxybenzyl)(methyl)amino)phenyl)amino)butyl)carbamate

[1356] ##STR00269##

[1357] Zinc (4.66 g, 71.3 mmol) was added portionwise to a stirring solution of tert-butyl (4-((3-((4-methoxybenzyl)(methyl)amino)-2-nitrophenyl)amino)butyl)carbamate (10.9 g, 23.77 mmol) in acetic acid (200 mL). The mixture was stirred for 3h and another portion of zinc (4.66 g, 71.3 mmol) was added. The mixture was stirred for another 30 min. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DCM (200 mL), washed with 15% K.sub.2CO.sub.3 and brine. The organic layer were dried over Na.sub.2SO.sub.4, filtered and then concentrated in vacuo to give the title compound (9.95 g, 23.22 mmol, 98% yield) as brown foam which was used for the next step without purification. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.24 (d, J=8.53 Hz, 2H) 6.85 (d, J=8.28 Hz, 2H) 6.66-6.73 (m, 1H) 6.57-6.63 (m, 1H) 6.47 (d, J=7.78 Hz, 1H) 3.90 (s, 2H) 3.78 (s, 3H) 3.13 (dt, J=13.30, 6.65 Hz, 4H) 2.53 (s, 3H) 1.58-1.76 (m, 4H) 1.45 (s, 9H). LCMS (LCMS Method D): Rt=1.00, [M+H].sup.+=429.2

Step 4: tert-butyl (4-(2-amino-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-1-yl)butyl)carbamate, hydrobromide

[1358] ##STR00270##

[1359] Tert-butyl(4-((2-amino-3-((4-methoxybenzyl)(methyl)amino)phenyl)amino)butyl)carbamate (9.95 g, 23.22 mmol) was dissolved in methanol (80 mL), cyanogen bromide (4.64 mL, 23.22 mmol) was added. The mixture was stirred for 18 hours at RT, concentrated in vacuo to ˜¼ of the original volume and MeCN (50 mL) and toluene (50 mL) were added. The mixture was concentrated to dryness and dried in vacuo for 16 hr to afford the title compound (12.54 g, quantitative yield) as a dark brown solid. LCMS (LCMS Method D): Rt=1.04, [M+H].sup.+=454.2.

Step 5: ethyl4-(5-(5-((1-(4-((tert-butoxycarbonyl)amino)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1360] ##STR00271##

[1361] A mixture of 1-(5-(5-(ethoxycarbonyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl)pentyl)-3-methyl-1H-pyrazole-5-carboxylic acid (1 g, 2.66 mmol), tert-butyl (4-(2-amino-4-((4- methoxy-benzyl)(methyl)amino)-1H-benzo[d]imidazol-1-yl)butyl)carbamate, hydrobromide (1.704 g, 3.19 mmol), TEA (1.111 mL, 7.97 mmol), EDC (0.662 g, 3.45 mmol) and HOBt (0.610 g, 3.98 mmol) in NMP (25 mL) was stirred overnight at RT under nitrogen. The reaction was diluted with EtOAc (100 mL), washed with saturated NaHCO.sub.3, 5% LiCl, and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated, and the residue was purified by silica column chromatography (0-45% EtOAc in DCM) to afford ethyl the title compound (1.3 g, 1.601 mmol, 60.3% yield) as a pink solid. LCMS (LCMS Method E): Rt=1.56, [M+H].sup.+=812.6.

Step 6: ethyl 4-(5-(5-((1-(4-aminobutyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate, 2Hydrochloride

[1362] ##STR00272##

[1363] 4N HCl (2.232 mL, 8.93 mmol) was added to a stirring solution of ethyl 4-(5-(5-((1-(4-((tert-butoxycarbonyl)amino)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1.45 g, 1.786 mmol) in methanol (15 mL). The mixture was stirred overnight at room temperature under nitrogen. The reaction was concentrated in vacuo to ˜⅕ of the original volume and MeCN (10 mL) and toluene (10 mL) were added. The mixture was concentrated to dryness and dried in vacuo to afford the title compound (1.45 g, 1.792 mmol, 100% yield) as an orange-red solid which was used for the next step without purification. Assumed quantitative yield. LCMS (LCMS Method E): Rt=1.19, [M+H].sup.+=712.6

Step 7: ethyl 4-(5-(5-((1-(4-((4-carbamoyl-2-nitrophenyl)amino)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1364] ##STR00273##

[1365] To a solution of ethyl 4-(5-(5-((1-(4-aminobutyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate, 2Hydrochloride (100 mg, 0.124 mmol) in DMSO (1 mL) was added TEA (0.086 mL, 0.618 mmol) followed by 4-fluoro-3-nitrobenzamide (22.76 mg, 0.124 mmol) and the mixture was stirred at 70° C. overnight. The reaction was diluted with water, extracted three times with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica chromatography (EtOH/EtOAc 0-5%) to afford the title compound (74 mg, 0.084 mmol, 68.3% yield) as a yellow solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 8.69 (s, 1H) 7.91 (d, J=9.03 Hz, 1H) 7.18-7.31 (m, 3H) 7.09 (d, J=8.03 Hz, 1H) 6.96 (d, J=9.04 Hz, 1H) 6.82-6.92 (m, 3H) 6.66 (s, 1H) 4.65 (t, J=6.53 Hz, 2H) 4.20-4.43 (m, 8H) 3.76 (s, 3H) 3.48 (t, J=6.27 Hz, 2H) 2.88 (s, 3H) 2.59 (t, J=7.40 Hz, 2H) 2.21 (s, 3H) 2.11 (s, 3H) 2.03-2.08 (m, 2H) 1.72-1.90 (m, 4H) 1.41-1.55 (m, 2H) 1.22-1.35 (m, 9H). LCMS (LCMS Method E): Rt=1.41, [M+H].sup.+=877.5

Step 8: ethyl 4-(5-(5-((1-(4-((2-amino-4-carbamoylphenyl)amino)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1366] ##STR00274##

[1367] Zinc (0.240 g, 3.66 mmol) was added portionwise to a stirring solution of ethyl 4-(5-(5-((1-(4-((4-carbamoyl-2-nitrophenyl)amino)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1.07 g, 1.221 mmol) in acetic Acid (10 mL). The mixture was stirred for 30 min and another portion of zinc (0.240 g, 3.66 mmol) was added. The mixture was stirred for another 30 min, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DCM (50 mL) and washed with 15% K.sub.2CO.sub.3 and then brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and then concentrated in vacuo to give the title compound (1.16 g, 1.234 mmol) as brown foam which was used for the next step without purification. Assumed quantitative yield. LCMS (LCMS Method E): Rt=1.29, [M+H].sup.+=847.6

Step 9: ethyl 4-(5-(5-((1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

[1368] ##STR00275##

[1369] Ethyl-4-(5-(5-((1-(4-((2-amino-4-carbamoylphenyl)amino)butyl)-4-((4-methoxybenzyl)-(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1.03 g, 1.217 mmol) was dissolved in methanol (5 mL) and cyanogen bromide (0.243 mL, 1.217 mmol) was added. The mixture was stirred for 18 hours at RT. The reaction was concentrated, the residue was taken up in 10% MeOH in DCM (100 mL) and washed with 10% K.sub.2CO.sub.3 and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica chromatography (2M NH.sub.3 in MeOH/DCM 0-10%) to afford the title compound (870 mg, 0.999 mmol, 82% yield) as a light-purple foam. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.75 (s, 1H) 7.55 (d, J=8.28 Hz, 1H) 7.18-7.29 (m, 3H) 7.15 (d, J=8.28 Hz, 1H) 7.00 (d, J=8.28 Hz, 1H) 6.81-6.93 (m, 3H) 6.65 (s, 1H) 4.62 (t, J=6.65 Hz, 2H) 4.19-4.41 (m, 8H) 4.03-4.13 (m, 2H) 3.75 (s, 3H) 3.37 (s, 1H) 2.88 (s, 3H) 2.58 (t, J=7.40 Hz, 2H) 2.24 (s, 3H) 2.10 (s, 3H) 1.77-2.00 (m, 6H) 1.42-1.54 (m, 2H) 1.27 (t, J=7.03 Hz, 9H). LCMS (LCMS Method E): Rt=1.20, [M+H].sup.+=872.5

Step 10: 4-(5-(5-((1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid

[1370] ##STR00276##

[1371] To a suspension of ethyl 4-(5-(5-((1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (870 mg, 0.999 mmol) in methanol (8 mL) was added NaOH (4.99 mL, 4.99 mmol) and the resulting clear homogeneous solution was stirred overnight at rt. Methanol (8 mL) was added followed by dropwise addition of 1 M HCl (5 mL). The mixture was concentrated to remove most of the methanol, and water was added. The precipitates were filtered, washed with water, air dried, and then dried in vacuo to give the title compound (782 mg, 0.928 mmol, 93% yield) as a light pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.83 (br. s., 1H) 7.71 (s, 1H) 7.53 (d, J=8.07 Hz, 1H) 7.01-7.22 (m, 7H) 6.84 (d, J=8.31 Hz, 2H) 6.67 (br. s., 1H) 4.42 (br. s., 2H) 4.34 (q, J=7.09 Hz, 2H) 4.12 (br. s., 2H) 3.97-4.06 (m, 2H) 2.85 (s, 3H) 2.52-2.56 (m, 2H) 2.15 (s, 3H) 2.04 (s, 3H) 1.81 (br. s., 2H) 1.70 (d, J=6.36 Hz, 4H) 1.34-1.46 (m, 2H) 1.14-1.27 (m, 6 H). LCMS (LCMS Method E): Rt=1.02, [M+H].sup.+=843.5

Example 47

8-ethyl-23-((4-methoxybenzyl)(methyl)amino)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide

[1372] ##STR00277##

[1373] A solution of 4-(5-(5-((1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-4-((4-methoxybenzyl)(methyl)amino)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 0.237 mmol) in DMF (5 mL) was slowly added (8 hours) by a syringe pump to a mixture of 1Hbenzo[d][1,2,3]triazol-1-ol (64.1 mg, 0.475 mmol), DMAP (2.90 mg, 0.024 mmol) and EDC (68.2 mg, 0.356 mmol) in DMF (5 mL) at 60° C. under nitrogen. The reaction was stirred for an additional 24 hrs, concentrated under vacuum, and the residue was dissolved in 10% MeOH in DCM. Saturated aqueous NaHCO.sub.3 was added and the mixture was extracted with 10% MeOH in DCM. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated, and the residue was purified by flash silica chromatography (2M NH.sub.3 in MeOH/DCM 0-10%) to afford the title compound (40 mg, 0.048 mmol, 20.44% yield) as a off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.88 (s, 2H) 8.02 (d, J=1.47 Hz, 2H) 7.82 (d, J=8.56 Hz, 1H) 7.49-7.65 (m, 1H) 7.38 (br. s., 1H) 7.20 (br. s., 3H) 6.85 (br. s., 3H) 6.50-6.64 (m, 1H) 4.54-5.18 (m, 3H) 4.48 (d, J=7.09 Hz, 2H) 4.20 (br. s., 5H) 3.71 (s, 3H) 2.72-2.91 (m, 5H) 2.18 (br. s., 3H) 2.09 (s, 3H) 1.77-1.97 (m, 6H) 1.49 (br. s., 2H) 1.30 (t, J=7.09 Hz, 5H). LCMS (LCMS Method D): Rt=1.18, [M+H].sup.+=825.8.

Examples 48-50

[1374] ##STR00278##

Example 48

8-ethyl-10,18-dimethyl-23-(methylamino)-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31tetradeca-hydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[H,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide

[1375] ##STR00279##

[1376] Pd—C (0.258 g, 0.242 mmol) was added a solution of 8-ethyl-23-((4-methoxybenzyl)(methyl)amino)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo-[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]-pentaazacyclohenicosine-3-carboxamide (2.0 g, 2.424 mmol) in MeOH (20 mL) and DCM (20 mL). The flask was purged with nitrogen, then hydrogen and the mixture was stirred under H.sub.2. After 8 hrs Pd/C was filtered off and the filtrate was concentrated in vacuo to give a white solid which was washed with MeOH to afford the title compound (1.25 g, 1.773 mmol, 73.2% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.86 (br. s., 1H) 12.53 (br. s., 1H) 8.02 (br. s., 1H) 7.99 (br. s., 1H) 7.81 (d, J=8.07 Hz, 1H) 7.58 (d, J=8.07 Hz, 1H) 7.34 (br. s., 1H) 7.13 (t, J=7.70 Hz, 1H) 6.83 (d, J=7.82 Hz, 1H) 6.72 (d, J=4.16 Hz, 1H) 6.55 (s, 1H) 6.41 (d, J=7.83 Hz, 1H) 4.75 (br. s., 2H) 4.48 (d, J=6.85 Hz, 2H) 4.22 (br. s., 4H) 2.82 (d, J=3.91 Hz, 5H) 2.16 (br. s., 3H) 2.09 (br. s., 3H) 1.90 (br. s., 4H) 1.81 (br. s., 2H) 1.49 (br. s., 2H) 1.38 (br. s., 2H) 1.30 (t, J=6.85 Hz, 3H); LCMS (LCMS Method D): Rt=1.01, [M+H].sup.+=705.5

Example 49

2-((3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-23-yl)(methyl)amino)-2-oxoethyl acetate

[1377] ##STR00280##

[1378] 2-chloro-2-oxoethyl acetate (0.069 mL, 0.638 mmol) was added to a suspension of 8-ethyl-10,18-dimethyl-23-(methylamino)-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide (300 mg, 0.426 mmol) in pyridine (5 mL) at RT. The mixture was stirred overnight then concentrated, and the residue was taken up in 10% MeOH in DCM (100 mL) and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica chromatography (2M NH.sub.3 in MeOH/DCM 0-10%) to afford the title compound (198 mg, 0.246 mmol, 57.8% yield) as a light-pink solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.97 (s, 1H) 7.86 (d, J=8.28 Hz, 1H) 7.59 (d, J=6.78 Hz, 1H) 7.38-7.53 (m, 2H) 7.34 (d, J=7.78 Hz, 1H) 6.60-6.75 (m, 1H) 4.76 (br. s., 2 H) 4.48-4.60 (m, 3H) 4.31 (br. s., 5H) 3.54 (br. s., 1H) 3.36 (s, 2H) 2.89 (br. s., 2H) 2.26 (br. s., 3H) 2.18 (s, 3H) 2.04 (br. s., 6H) 1.96 (s, 1H) 1.88 (d, J=6.53 Hz, 2H) 1.60 (br. s., 2 H) 1.33-1.49 (m, 5H); LCMS (LCMS Method D): Rt=0.94, [M+H].sup.+=805.6

Example 50

8-ethyl-23-(2-hydroxy-N-methylacetamido)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide

[1379] ##STR00281##

[1380] To a solution of 2-((3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-23-yl)(methyl)amino)-2-oxoethyl acetate (132 mg, 0.164 mmol) in MeOH (4 mL) was added lithium hydroxide (1.640 mL, 1.640 mmol) and the mixture was stirred at RT. After 3 hours 1.64 mL of 1M HCl was added to the suspension to give a clear solution. Most of the MeOH was removed in vacuo, water was added, and the solid was isolated by filtration, washed with water, air dried, and then dried in vacuo to afford the title compound (119 mg, 0.156 mmol, 95% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.87 (s, 2H) 7.93-8.06 (m, 2H) 7.83 (d, J=7.58 Hz, 1H) 7.50-7.71 (m, 2H) 7.35 (br. s., 2H) 7.25 (d, J=7.09 Hz, 1H) 6.56 (br. s., 1H) 4.54-4.88 (m, 3H) 4.49 (q, J=7.01 Hz, 2H) 4.24 (br. s., 5H) 3.49-3.88 (m, 2H) 3.22 (br. s., 2H) 2.82 (br. s., 2H) 2.16 (br. s., 3H) 2.10 (s, 3H) 1.69-2.02 (m, 6H) 1.50 (br. s., 2H) 1.31 (t, J=7.09 Hz, 5H); LCMS Method D: Rt=0.88 min, [M+H].sup.+=763.6.

Example 51

(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H-enzo[d]imidazole-5-carboxamide

[1381] ##STR00282##

[1382] Example 51 can be prepared according to method 14 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: A mixture of 4-(2-bromoethyl)tetrahydro-2H-pyran (12.54 mg, 0.065 mmol), (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazole-5-arboxamide (45 mg, 0.065 mmol) and potassium carbonate (22.44 mg, 0.162 mmol) was heated for 3 hr at 85° C. in DMSO (650 μl) and NMP (650 μl), then cooled. The residue was purified via acidic reverse phase chromatography (5% to 50% in 0.1% TFA in MeCN to 0.1% TFA in water; 50×30 mm Phenomenex Eclipse, 5 M C18 column, 20 min gradient). The pure fractions were partitioned between EtOAc and aqueous saturated sodium bicarbonate, the organic layer was separated, dried over sodium sulfate and evaporated in vacuo to provide the title compound (8 mg, 15.3% yield) as a white solid. .sup.1H NMR (DMSO-d.sub.6, 600 MHz): δ (ppm) 12.83 (br s, 2H), 7.97-8.00 (m, 1H), 7.93 (br s, 2H), 7.69 (dd, J=8.4, 1.5 Hz, 1H), 7.63 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.33 (br d, J=11.4 Hz, 2H), 7.29 (s, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 5.96-6.02 (m, 1H), 5.70-5.79 (m, 1H), 4.93 (br d, J=5.0 Hz, 2H), 4.82 (br d, J=5.3 Hz, 2H), 4.49-4.58 (m, 4H), 3.96 (br t, J=6.7 Hz, 2H), 3.75 (br dd, =11.2, 2.9 Hz, 2H), 3.16-3.23 (m, 2H), 2.12 (d, J=12.7 Hz, 6H), 1.50-1.53 (m, 1H), 1.45-1.49 (m, 2H), 1.43 (br d, J=11.9 Hz, 2H), 1.28 (m, 6H), 1.08 (br dd, J=12.0, 3.6 Hz, 2H); LCMS (LCMS Method K): Rt=0.90 min, [M+H].sup.+=805.5.

Example 52

(E)-4-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)butanoic acid

[1383] ##STR00283##

[1384] Example 52 can be prepared according to a combination of method 14 and 16 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: Methyl (E)-4-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)butanoate (40 mg, 0.050 mmol) was dissolved in MeOH and THF (1 mL each) and sodium hydroxide (101 μl, 0.505 mmol, 5N) was added, and the mixture stirred at 25° C. for 18 hr. The reaction was then partitioned between EtOAc and 10% aqueous potassium hydrogen sulfate. The resulting gummy gel mixture was evaporated to near dryness, dissolved in 2 mL MeOH with aqueous sodium hydroxide (5N) to dissolve. The residue was purified via basic reverse phase chromatography (10% to 55% in 0.1% NH.sub.4OH in water to MeCN; 50×30 mm Phenomenex Gemini, 5 M C18 110A column, 10 min gradient). The pure fractions were collected and the product isolated by concentration in vacuo then dried under high vacuum to give the title compound as a white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ ppm 8.45-8.76 (m, 1H), 7.85-8.12 (m, 1H), 7.49-7.78 (m, 2H), 6.92-7.30 (m, 2H), 6.31-6.58 (m, 2H), 5.83-6.02 (m, 1H), 5.56-5.75 (m, 1H), 4.45-4.66 (m, 5H), 3.91-4.16 (m, 4H), 3.6 (q, J=6.3 Hz, 4H), 2.31 (m, 2H), 2.18 (s, 6H), 1.29 (q, J=6.1 Hz, 4H), 1.13 (t, J=6.1 Hz, 6H); LCMS Method K: Rt=0.75 min, [M+H].sup.+=779.4.

Example 53

3-(((Z)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl dihydrogen phosphate, 2Hydrochloride

[1385] ##STR00284##

Step 1: Di-tert-butyl (3-(((Z)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl) phosphate

[1386] ##STR00285##

[1387] (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]-imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxy-propoxy)-1H-benzo[d]imidazole-5-carboxamide (100 mg, 0.133 mmol) was suspended in DMF (1 mL), 2H-tetrazole in MeCN (1.480 mL, 0.666 mmol) was added, and the mixture was concentrated on rotovap to remove MeCN. The reaction mixture was cooled in an ice-water bath, and then a solution of di-tert-butyl diisopropylphosphoramidite (148 mg, 0.533 mmol) in DMF (1 mL) was added. The mixture was stirred for 1 hr, slowly warmed to RT and left over night for 16 hrs, then cooled with an ice-water bath, and an additional 2 eq of 2H-tetrazole in MeCN and 2 eq. of di-tert-butyl diisopropylphosphoramidite were added and the reaction stirred for 2 hrs. Additional 2 eq of 2H-tetrazole in MeCN and 2 eq of di-tert-butyl diisopropylphosphoramidite were then added and the reaction stirred for 2 hrs. The reaction was then cooled in an ice-water bath, H.sub.2O.sub.2 (0.272 mL, 2.66 mmol, 30%) was added, and stirring was continued for 30 min. The reaction mixture was poured into water (50 ml) containing a mixture of NaHCO.sub.3 and Na.sub.2S.sub.2O.sub.3 (1:1, 2M, 1 ml). The sticky paste was filtered, washed with water, and dried on the filter for 2 days. The residue was dissolved in THF, combined with the extracts from the filtrate using 3:1 CHCl.sub.3:EtOH, organics were dried with MgSO.sub.4, concentrated, dry-loaded on silica gel (12 g column), and purified by silica gel chromatography using 1-10% MeOH in DCM (+1% NH.sub.4OH) for 5 min then 10% for 15 min to the title compound (23 mg, 0.024 mmol, 18.31% yield) as a white solid. The compound was used for next step directly without purification. LCMS (LCMS Method I): Rt=1.03 min, [M+H].sup.+=943.3

Example 53

3-(((Z)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl dihydrogen phosphate, 2Hydrochloride

[1388] ##STR00286##

[1389] Di-tert-butyl (3-(((Z)-6-carbamoyl-3-((E)-4-((Z)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl) phosphate (22 mg, 0.023 mmol) was suspended in dioxane (1 mL), HCl 3M in CPME (0.156 mL, 0.467 mmol) was added at RT. After 2 hrs., diethyl ether (50 ml) was added, precipitate was filtered under N2, washed with ether, dried in vacuum oven at 40° C. for 2 hrs to give the title compound (18 mg, 0.020 mmol, 85% yield) as a white solid. .sup.1H NMR (700 MHz, DMSO-d.sub.6) δ (ppm) 12.83 (br s, 2H), 7.92-8.05 (m, 4H), 7.73 (dd, J=8.4, 1.4 Hz, 1H), 7.64-7.67 (m, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.30-7.39 (m, 4H), 6.55 (s, 1H), 6.49 (s, 1H), 6.02 (dt, J=15.4, 5.5 Hz, 1H), 5.62-5.77 (m, 1H), 4.95 (br d, J=4.8 Hz, 3H), 4.83 (br d, J=5.4 Hz, 3H), 4.44-4.59 (m, 9H), 4.15 (br t, J=6.1 Hz, 5H), 3.94-3.99 (m, 4H), 2.11 (s, 4H), 2.09 (s, 3H), 1.96 (quin, J=6.0 Hz, 3H), 1.25 (q, J=7.3 Hz, 8H); LCMS (LCMS Method I): Rt=0.64 min, [M+H].sup.+=831.2.

Example 54

3-Carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxylic acid

[1390] ##STR00287##

Step 1: Methyl 3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,-14,15,20,21,28,29,30,31-tetradecahydrobenzo-[4,5]imidazo[1,2a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxylate

[1391] ##STR00288##

[1392] Example 55 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last two steps step of the preparation are provided:

[1393] To a suspension of 24-cyano-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,-14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo-[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide (900 mg, 1.284 mmol) in MeOH (40 mL) was added boron trifluoride etherate (0.814 mL, 6.42 mmol). The reaction mixture was stirred at 80° C. for 48 hrs then concentrated under vacuum and poured into ice water. The precipitate was collected by filtration, washed with water and dried to afford the title compound (600 mg, 0.818 mmol, 63.7% yield) as a gray solid. LCMS (LCMS Method A): Rt=1.406 min, [M+H].sup.+=733.7

Example 54

3-Carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxylic acid

[1394] ##STR00289##

[1395] To a suspension of methyl 3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2a]benzo[4,5]imidazo [2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxylate (420 mg, 0.572 mmol) in MeOH (15 mL) and Water (15 mL) was added NaOH (229 mg, 5.72 mmol). The reaction mixture was stirred at 25° C. for 16 hrs. The mixture was diluted with water (20 mL), acidified to pH=3 with 2N HCl and the precipitate was collected by filtration to afford crude product. The crude product was purified by preparative HPLC (Gemini Prep C18 OBD column, 5p silica, 21.2 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (190 mg, 0.264 mmol, 46.1% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 12.89 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.71-7.52 (m, 3H), 7.45 (d, J=4.7 Hz, 1H), 6.55 (s, 1H), 4.51 (q, J=6.8 Hz, 2H), 4.36 (t, J=7.0 Hz, 2H), 4.17 (s, 2H), 4.10 (d, J=6.8 Hz, 2H), 2.65 (t, J=7.3 Hz, 2H), 2.10 (t, J=9.2 Hz, 6H), 1.87-1.61 (m, 6H), 1.46 (s, 2H), 1.28 (t, J=7.0 Hz, 3H), 1.19 (s, 2H); LCMS Method A: Rt=1.295 min, [M+H].sup.+=720.2

Example 55

Methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazole-5-carboxylate, 2Trifluoroacetic acid salt

[1396] ##STR00290##

[1397] Example 55 can be prepared according to method 11 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: In a 50 mL RB flask, methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (35 mg, 0.048 mmol) was stirred in DCM. Boron tribromide (58.0 μl, 0.058 mmol) was then added in portions. The reaction mixture was stirred at RT overnight (approximately 18 hrs), after which the reaction was quenched with MeOH and concentrated in vacuo. The crude containing both methoxy and phenol compounds purified on reverse phase HPLC (Gilson 115 liquid handler, Gilson 333 Aquious pump, Gilson 334 Organic pump, Gilson UV/VIS-155 detector, running Trilution v1.4 software. Lunar column: acetonitrile, 0.1% TFA/water eluent, 0-20% gradient. The desired fractions were combined and dried under vacuum to afford the title compound (5 mg, 5.07 umol, 10.47% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.62-13.04 (m, 2H) 10.69 (s, 1H) 7.99 (s, 2H) 7.72-7.82 (m, 1H) 7.65 (s, 1H) 7.54 (d, J=8.34 Hz, 1H) 7.34 (d, J=2.27 Hz, 2H) 6.59 (s, 2H) 4.57 (dd, J=6.82, 4.04 Hz, 5H) 4.44 (br. s., 3H) 3.80-3.90 (m, 3H) 2.10 (d, J=4.55 Hz, 6H) 1.89 (br. s., 4H) 1.31 (t, J=7.07 Hz, 6H); LCMS (LCMS Method C): Rt=0.87 min, [M+H].sup.+=710.6

Example 56

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide

[1398] ##STR00291##

[1399] Example 56 can be prepared according to method 20 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To a suspension of (E)-2-amino-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazole-5-carboxamide (50 mg, 0.073 mmol) in DMF (2 mL) was added a solution of 1-ethyl-3-fluoro-4-methyl-1H-pyrazole-5-carboxylic acid (31.5 mg, 0.183 mmol), HOBt (16.8 mg, 0.110 mmol), HATU (69.5 mg, 0.183 mmol) and triethylamine (0.04 mL, 0.3 mmol) in DMF (2 mL) at RT. The mixture was stirred overnight, then heated to 50° C. for 30 min. Water was added, and the cloudy solution was chilled in a refrigerator until a precipitate formed. The solid was collected by filtration and purified over silica gel (Isco 4 g silica column), eluting with 0-20% MeOH in DCM to afford the title compound (4 mg, 4.77 μmole, 6.5% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.81 (br. s., 2H), 7.99-8.03 (m, 2H), 7.92-7.97 (m, 1H), 7.67-7.73 (m, 1H), 7.64 (s, 1H), 7.30-7.44 (m, 4H), 6.53 (br. s., 1H), 5.93-6.04 (m, 1H), 5.68-5.82 (m, 1H), 4.90-4.97 (m, 2H), 4.76-4.84 (m, 2H), 4.45-4.57 (m, 4 H), 3.98 (br. s., 2H), 3.44-3.49 (m, 4H), 2.21-2.29 (m, 2H), 2.17-2.21 (m, 4H), 2.07-2.15 (m, 6H), 1.63-1.74 (m, 2H), 1.13-1.21 (m, 6H); LCMS (LCMS Method J): Rt=0.65 min, [M+H].sup.+=838.3

Example 57

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazole-5-carboxamide, trifluoroacetic acid salt

[1400] ##STR00292##

[1401] Example 57 can be prepared according to method 20 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide, bis trifluoroacetic acid salt (17 mg, 0.018 mmol) in DCM (2 mL) at −78° C. was added 1M BBr.sub.3 in DCM (50 μL, 0.050 mmol). After 1 hr, the reaction was warmed to RT, and LC/MS analysis showed no reaction progression. The reaction was cooled to 0° C., and another 100 μL 1M BBr.sub.3 in DCM was added. The reaction was allowed to slowly warm to RT over 72 hr, was returned to 0° C., and then another 100 μL 1M BBr.sub.3 in DCM was added. After an additional 24 hr, MeOH (˜2 mL) was added, and the reaction was concentrated. The residue was purified via reverse phase HPLC, eluting with 20-45% MeCN in H.sub.2O (with 0.1% TFA) to afford the title compound (8 mg, 0.01 mmol, 55% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.80 (br. s, 1H), 10.48 (s, 1H), 7.98 (d, J=1.27 Hz, 2H), 7.83 (br. s., 1H), 7.75 (dd, J=8.36, 1.52 Hz, 1H), 7.53 (d, J=8.36 Hz, 1H), 7.43 (d, J=1.27 Hz, 1H), 7.22 (s, 1H), 7.34 (br. s., 1H), 7.14 (d, J=1.52 Hz, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.58 (d, J=9.63 Hz, 2H), 4.49-4.65 (m, 4H), 4.43 (t, J=6.40 Hz, 2H), 4.27 (t, J=7.00 Hz, 2H), 2.10 (d, J=6.34 Hz, 6 H), 1.82-1.95 (m, 4H), 1.30 (td, J=7.03, 3.68 Hz, 6H); LCMS (LCMS Method D): Rt=0.78 min, [M+H].sup.+=695.4

Example 58

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazole-5-carboxamide

[1402] ##STR00293##

[1403] Example 58 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-methoxyethoxy)-1H-benzo[d]imidazole-5-carboxamide (300 mg, 0.400 mmol) in DCM (5 mL) at 0° C. was added BBr.sub.3 (501 mg, 2.00 mmol). After 3 hr, the reaction was quenched with water (5 mL), and the resulting solid was collected by filtration. This solid was purified via prep HPLC to afford the title compound (21 mg, 0.029 mmol, 7% yield) as a gray solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.83 (s, 2H), 7.97 (d, J=12.2 Hz, 3H), 7.62-7.78 (m, 2H), 7.29-7.50 (m, 4H), 6.54 (d, J=14.1 Hz, 2H), 5.99 (s, 1H), 5.86 (s, 1H), 4.99 (s, 3H), 4.82 (s, 2H), 4.53 (d, J=6.8 Hz, 4 H), 4.07 (s, 2H), 3.63 (s, 2H), 2.11 (s, 6H), 1.27 (s, 6H); LCMS (LCMS Method A): Rt=1.333 min, [M+H].sup.+=737.1

Example 59

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-ethoxy-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1404] ##STR00294##

[1405] Example 59 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (58 mg, 0.38 mmol) in NMP (3 ml) at RT was added HATU (171 mg, 0.450 mmol) and DIEA (0.14 mL, 0.77 mmol). After 15 min, (E)-2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-ethoxy-1H-benzo[d]imidazole-5-carboxamide (65 mg, 0.15 mmol) was added, and the mixture was heated to 60° C. After 16 hr, water was added, and the resulting solid was collected by filtration. This material was purified by prep HPLC to afford the title compound (35 mg, 0.047 mmol, 33% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (s, 2H), 7.97 (d, J=11.7 Hz, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.32 (d, J=12.3 Hz, 3H), 6.55 (s, 2H), 5.91-6.02 (m, 1H), 5.78 (dd, J=13.3, 7.7 Hz, 1H), 4.94 (d, J=4.7 Hz, 2H), 4.83 (d, J=4.9 Hz, 2H), 4.50-4.57 (m, 4H), 3.99-4.06 (s, 2H), 2.12 (d, J=3.8 Hz, 6H), 1.28 (dd, J=12.7, 6.9 Hz, 6H), 1.18 (t, J=6.9 Hz, 3H); LCMS (LCMS Method A): Rt=1.382 min, [M+H].sup.+=721.2

Example 60

(E)-7-Bromo-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1406] ##STR00295##

[1407] Example 60 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.12 g, 7.28 mmol), (E)-2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-bromo-1H-benzo[d]imidazole-5-carboxamide (1.6 g, 3.3 mmol), HATU (3.14 g, 8.28 mmol) and triethylamine (1.01 g, 9.93 mmol) were heated to 60° C. in DMF (30 mL). After 12 hr, water (5 mL) was added, and the resulting solid was collected by filtration. This material was purified by prep HPLC to afford the title compound (700 mg, 0.926 mmol, 28% yield) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.05 (br. s., 1H), 12.80 (s, 1H), 8.06 (s, 1H), 7.91-8.00 (m, 4H), 7.72 (d, J=8 Hz, 1H), 7.43-7.47 (m, 2H), 7.33 (s, 1H), 6.54 (d, J=4 Hz, 2H), 5.95-6.05 (m, 1H), 5.60-5.70 (m, 1H), 5.06-5.13 (m, 2H), 4.75-4.81 (m, 2H), 4.45-4.61 (m, 4H), 2.12 (d, J=4 Hz, 6H), 1.18-1.35 (m, 6H); LCMS (LCMS Method A): Rt=1.367 min, [M+H].sup.+=755.1

Example 61

(E)-7-(Aminomethyl)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide, trifluoroacetic acid salt

[1408] ##STR00296##

[1409] Example 61 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided:

[1410] To (E)-tert-butyl ((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)methyl)carbamate (410 mg, 0.509 mmol) in MeOH (10 mL) at RT was added 36.5% HCl (0.5 mL, 0.51 mmol). The reaction was heated to 40° C. and concentrated after 3 hr. The residue was purified by prep-HPLC to afford the title compound (9 mg, 11 μmol, 2% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.07-12.88 (m, 1H), 8.34 (s, 3H), 8.00 (d, J=7.3 Hz, 2H), 7.95 (s, 1H), 7.88 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.35 (s, 1H), 6.56 (d, J=15.5 Hz, 2H), 5.92 (d, J=15.9 Hz, 1H), 5.58 (d, J=16.0 Hz, 1H), 5.23-5.29 (m, 2H), 5.00 (s, 2H), 4.82 (s, 2H), 4.53 (dd, J=13.6, 6.6 Hz, 4 H), 4.15 (d, J=4.6 Hz, 2H), 2.12 (d, J=3.9 Hz, 6H), 1.28 (d, J=4.2 Hz, 6H); LCMS (LCMS Method A): Rt=1.183 min, [M+H].sup.+=706.3

Example 62

(E)-8-Ethyl-1,26-dimethoxy-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide, bis trifluoroacetic acid salt

[1411] ##STR00297##

[1412] Example 62 can be prepared according to methods 6 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To a solution of 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (37.5 mg, 0.108 mmol), HATU (101 mg, 0.267 mmol) and TEA (86 μL, 0.62 mmol) in DMF (4.1 ml) was added (E)-4,4′-(but-2-ene-1,4-diylbis(azanediyl))bis(3-amino-5-methoxybenzamide) dihydrochloride (50 mg, 0.10 mmol). The reaction was heated to 100° C., and after 3 hr, water was added. The resulting solid was collected by filtration and purified by HPLC to afford the title compound (1 mg, 1 μmol, 1% yield; low yield partially due to an injection port malfunction during HPLC purification). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.68 (s, 1H), 7.64 (s, 1H), 7.37 (d, J=4.56 Hz, 2H), 6.63 (s, 1H), 5.76 (d, J=12.67 Hz, 2H), 5.05 (d, J=12.93 Hz, 4H), 4.70 (br. s., 2H), 4.46-4.57 (m, 2H), 3.72 (d, J=8.36 Hz, 6H), 2.81 (d, J=6.59 Hz, 2H), 2.26 (s, 3H), 2.20 (s, 3H), 1.86 (br. s., 2H), 1.58 (br. s., 2H), 0.89-0.96 (m, 5H); LCMS (LCMS Method D): Rt=0.91 min, [M/2+H].sup.+=389.5

Example 63

8-Ethyl-1,26-bis(3-hydroxypropoxy)-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide dihydrochloride

[1413] ##STR00298##

[1414] Example 63 can be prepared according to method 6 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1,26-bis(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide (18 mg, 0.016 mmol) in THF (0.5 ml) at 0° C. was added 4 N HCl (0.025 mL, 0.099 mmol). After 60 min, the resulting precipitate was collected by filtration and washed with EtOAc to afford the title compound (15 mg, 0.016 mmol, 97% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.95-8.08 (m, 2H), 7.64-7.70 (m, 2H), 7.29-7.42 (m, 4H), 6.51-6.58 (m, 1H), 4.63-4.72 (m, 2H), 4.31-4.50 (m, 6H), 4.11-4.20 (m, 4H), 3.42-3.48 (m, 4 H), 2.74-2.85 (m, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.78-1.91 (m, 6H), 1.64-1.74 (m, 4 H), 1.48-1.58 (m, 2H), 1.37-1.47 (m, 2H), 1.26-1.32 (m, 3H); LCMS (LCMS Method D): Rt=0.82 min, [M+H].sup.+=867.5

Example 64

(29R,30R)-8-Ethyl-29,30-dihydroxy-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,-13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1415] ##STR00299##

[1416] Example 64 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: (28aR,31aR)-8-Ethyl-10,18,30,30-tetramethyl-7,20-dioxo-6,7,8,11,12,13,14,15,-20,21,28,28a,31a,32-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p][1,3]dioxolo[4,5-s]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]-pentaazacyclohenicosine-3,24-dicarboxamide (500 mg, 0.632 mmol), formic acid (15 mL, 391 mmol) and water (1.5 mL) were stirred at 25° C. After 48 hr, the mixture was concentrated and the residue was purified by prep HPLC (Gemini-C18 column, 5p silica, 21 mm diameter, 150 mm length), eluting with 10-30% water in MeCN (with 0.1% formic acid) to afford the title compound (7.5 mg, 9.5 μmol, 1.5% yield) as a white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.01 (d, J=13.1 Hz, 2H), 7.81-7.93 (m, 2 H), 7.63-7.76 (m, 2H), 6.66 (s, 1H), 4.83 (s, 1H), 4.62-4.74 (m, 1H), 4.42-4.63 (m, 6 H), 4.12-4.33 (m, 2H), 2.90-3.00 (m, 1H), 2.71-2.82 (m, 1H), 2.23 (d, J=18.2 Hz, 6H), 1.84-2.00 (m, 2H), 1.61-1.73 (m, 2H), 1.37-1.47 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); LCMS (LCMS Method A): Rt=1.295 min, [M+H].sup.+=751.2

Example 65

8-Ethyl-10,13,13,18-tetramethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1417] ##STR00300##

[1418] Example 65 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)-3,3-dimethylpentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (192 mg, 0.510 mmol) in NMP (10 mL) was added HATU (194 mg, 0.510 mmol). The reaction was heated to 40° C., and 1,1′-(propane-1,3-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (200 mg, 0.510 mmol) was added. After heating overnight, the reaction was purified by prep HPLC to afford the title compound (13 mg, 0.017 mmol, 3.4% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.01 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz), 7.51 (t, J=8.4 Hz, 2H), 6.65 (s, 1H), 4.73-4.77 (m, 2H), 4.45-4.53 (m, 2H), 4.28-4.33 (m, 4H), 2.78-2.87 (m, 2H), 2.29 (d, J=11.6 Hz, 6H), 1.98 (br. s., 4H), 1.88 (t, J=7.6 Hz, 2H), 1.45-1.54 (m, 2H), 1.27-1.39 (m, 5H), 1.07 (s, 6H); LCMS (LCMS Method A): Rt=1.397 min, [M+H].sup.+=747.3

Example 66

8-Ethyl-12,13-dihydroxy-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1419] ##STR00301##

[1420] Example 66 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,14,15,20,21,28,29,30,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]-pentaazacyclohenicosine-3,24-dicarboxamide (350 mg, 0.488 mmol) and NMO (114 mg, 0.977 mmol) in tert-BuOH (9 mL) and water (3 mL) was added osmium tetroxide (7.7 μL, 0.024 mmol). After 4 hr at 25° C., the reaction was quenched with Na.sub.2SO.sub.3 and diluted with DCM (50 mL). The mixture was washed with water (30 mL) and brine (30 mL), and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep HPLC (Gemini-C18 column, 5p silica, 21 mm diameter, 150 mm length), eluting with 20-40% MeCN in water (with 0.1% TFA) to afford the title compound (11 mg, 0.015 mmol, 3.0% yield) as a white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.14 (s, 1H), 8.04 (s, 1H), 7.94 (dd, J=27.0, 8.4 Hz, 2H), 7.68 (dd, J=37.9, 8.5 Hz, 2H), 6.68 (s, 1H), 5.29-5.41 (m, 1H), 4.38-4.61 (m, 6H), 4.20-4.29 (m, 1H), 3.74 (t, J=12.4 Hz, 2H), 3.16 (dd, J=14.1, 10.2 Hz, 1H), 2.95 (d, J=11.2 Hz, 1H), 2.38-2.49 (m, 1H), 2.29 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 2.04-2.15 (m, 3H), 1.92-1.99 (m, 1H), 1.45 (t, J=8 Hz, 3H); LCMS (LCMS Method A): Rt=1.270 min, [M+H].sup.+=750.9

Example 67

(1r,39r)-14-ethyl-16,25-dimethyl-12,28-dioxo-2,9,11,14,15,23,24,29,31,38-decaazaoctacyclo[37.2.2.0.SUP.2.,.SUP.1..SUP.0.0.SUP.3.,.SUP.8..0.SUP.13.,.SUP.1..SUP.7.0.SUP.23.,.SUP.2..SUP.7.0.SUP.3..SUP.0,.SUP.3..SUP.8.0.SUP.32.,.SUP.3..SUP.7]tritetraconta-3,5,7,9,13(17),15,24,26,30,32,34,36-dodecaene-6,34-Dicarboxamide

[1421] ##STR00302##

[1422] Example 67 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (483 mg, 1.39 mmol) in DMF (10 mL) at 25° C. was added HATU (1.10 g, 2.89 mmol) and DIEA (1.01 mL, 5.78 mmol). After 4 hr, 1,1′-((1R,4R)-cyclohexane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (500 mg, 1.16 mmol) was added, and the reaction was stirred at 80° C. for 16 hr. Water was added, a brown solid appeared and was collected. The solid was subjected to purification twice to give the product (3 mg, 4 μmol, 0.3% yield). .sup.1H NMR (400 MHz, DMSO-d) δ ppm 13.04 (s, 2H), 8.07 (d, J=8.2 Hz, 6H), 7.88 (d, J=8.2 Hz, 2H), 7.39 (s, 2H), 6.58 (s, 1H), 4.95 (br, s., 2H), 4.69 (br. s., 2H), 4.48 (br. s., 2H), 2.60-2.85 (m, 6H), 1.99-2.24 (m, 10H), 1.80-2.01 (m, 3H), 1.49-1.65 (m, 4H), 1.34 (br. s., 4H); LCMS (LCMS Method A): Rt=1.413 min, [M+H].sup.+=745.3

Example 68

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1Hbenzo[d]imidazole-5-carboxamide

[1423] ##STR00303##

[1424] Example 68 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.40 mmol) in DMF (5 mL) at 25° C. was added DIEA (0.489 mL, 2.80 mmol) and HATU (638 mg, 1.68 mmol). After 30 min, 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-7-isopropoxy-1H-benzo[d]imidazole-5-carboxamide (260 mg, 0.560 mmol) was added. After 16 hr, water was added, and the resulting precipitate was collected by filtration and washed with MeOH to afford the title compound (55 mg, 0.075 mmol, 13% yield) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.80 (d, J=12.5 Hz, 2H), 7.88-8.01 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 7.55-7.60 (m, 2H), 7.30 (br. s., 3H), 6.59 (s, 2H), 4.74-4.84 (m, 1H), 4.52-4.63 (m, 4H), 4.29-4.36 (m, 4H), 2.11 (d, J=6.5 Hz, 6H), 1.77-1.94 (m, 4H), 0.98-1.44 (m, 12H); LCMS (LCMS Method A): Rt=1.428 min, [M+H].sup.+=737.2

Example 69

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-7-ethoxy-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1425] ##STR00304##

[1426] Example 69 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (191 mg, 1.24 mmol) in DMF (10 mL) at 25° C. was added DIEA (0.550 mL, 3.15 mmol) and HATU (600 mg, 1.58 mmol). After 30 min, 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-7-ethoxy-1H-benzo[d]imidazole-5-carboxamide (270 mg, 0.599 mmol) was added. After 16 hr, water was added, and the resulting precipitate was collected by filtration and washed with MeOH to afford the title compound (28 mg, 0.039 mmol, 6% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.00 (s, 2 H), 7.94 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (s, 2H), 7.30 (s, 1H), 6.59 (s, 2H), 4.50-4.64 (m, 4H), 4.31 (d, J=36.9 Hz, 4H), 4.12 (d, J=7.0 Hz, 2H), 2.10 (d, J=1.7 Hz, 6H), 1.86 (s, 4H), 1.29 (dd, J=7.7, 6.6 Hz, 6H), 1.24 (d, J=7.0 Hz, 3H); LCMS (LCMS Method A): Rt=1.426 min, [M+H].sup.+=723.2

Example 70

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide

[1427] ##STR00305##

[1428] Example 70 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (331 mg, 2.15 mmol) in NMP (10 mL) at RT was added DIEA (0.900 mL, 5.15 mmol) and HATU (979 mg, 2.58 mmol). After 30 min, 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide dihydrobromide (500 mg, 0.859 mmol) was added, and the reaction was heated to 60° C. overnight. Water was added, and the resulting precipitate was collected by filtration and purified by prep HPLC to afford the title compound (45 mg, 0.065 mmol, 7.6% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (s, 2H), 7.98 (s, 2H), 7.91 (s, 1H), 7.85 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.54-7.64 (m, 2H), 7.32 (d, J=9.9 Hz, 2H), 6.60 (d, J=15.5 Hz, 2H), 4.56 (dd, J=10.8, 7.1 Hz, 4H), 4.39 (s, 2H), 4.29 (s, 2H), 2.62 (s, 3H), 2.09 (d, J=13.4 Hz, 6H), 1.89 (d, J=22.1 Hz, 4H), 1.30 (q, J=7.3 Hz, 6H); LCMS (LCMS Method A): Rt=1.341 min, [M+H].sup.+=693.3

Example 71

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(morpholinomethyl)-1H-benzo[d]imidazole-5-carboxamide

[1429] ##STR00306##

[1430] Example 71 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (302 mg, 1.96 mmol) in NMP (3 mL) at RT was added DIEA (0.777 mL, 4.45 mmol) and HATU (846 mg, 2.23 mmol). After 1 hr, 2-amino-1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-7-(morpholinomethyl)-1H-benzo[d]-imidazole-5-carboxamide (450 mg, 0.890 mmol) was added, and the reaction was heated to 60° C. overnight. Water was added, and the resulting precipitate was collected by filtration to afford the title compound (70 mg, 0.090 mmol, 10% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.99 (br. s., 2H), 9.89 (br. s., 2H), 7.99-8.11 (m, 5H), 7.87 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.35 (s, 1H), 6.66 (s, 1H), 6.62 (s, 1H), 4.53-4.61 (m, 5H), 4.47 (s, 2H), 4.26 (s, 2H), 3.92 (br. s., 2H), 3.60 (br. s., 2H), 3.36 (br. s., 2H), 2.10 (s, 3H), 2.07 (s, 3H), 1.83 (d, J=22.7 Hz, 4H), 1.23-1.45 (m, 6H); LCMS (LCMS Method A): Rt=1.255 min, [M+H].sup.+=778.3

Example 72

4-(2-(Dimethylamino)acetamido)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide

[1431] ##STR00307##

[1432] Example 72 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-amino-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l]-[1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide (200 mg, 0.290 mmol), 2-(dimethylamino)acetic acid (119 mg, 1.158 mmol), HOBt (44.3 mg, 0.290 mmol), DIEA (0.405 mL, 2.32 mmol) and DMAP (17.7 mg, 0.145 mmol) in DMF (5 mL) at 60° C. was added HATU (661 mg, 1.74 mmol) in 10 portions at 30 min intervals. The reaction was cooled to RT, diluted with water, and the resulting solid was collected by filtration, washed with water and air dried. The solid was then purified over silica gel (Combiflash R.sup.f 120 g column, 85 mL/min), eluting with 0-20% MeOH in DCM to afford the title compound (205 mg, 0.251 mmol, 87% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.90 (br. s., 1H), 12.55 (br. s., 1H), 10.37 (br. s., 1H), 8.02 (s, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=8.6, 1.5 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.22-7.29 (m, 1H), 6.57 (s, 1H), 4.69-4.80 (m, 2H), 4.47 (d, J=7.1 Hz, 2H), 4.14-4.34 (m, 4H), 3.25 (s, 2 H), 2.81 (br. s., 2H), 2.33 (s, 6H), 2.16 (s, 3H), 2.08 (s, 3H), 1.91 (br. s., 4H), 1.76-1.86 (m, 2H), 1.48 (d, J=5.9 Hz, 2H), 1.38 (d, J=5.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.82 min, [M+H].sup.+=776.7

Example 73

7-(Aminomethyl)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

[1433] ##STR00308##

[1434] Example 73 can be prepared according to method 9 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To tert-butyl ((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)methyl)carbamate (200 mg, 0.248 mmol) in MeOH (10 mL) at RT was added 12 M HCl (0.5 ml, 16.5 mmol). After stirring overnight, the mixture was concentrated and purified by prep-HPLC to afford the title compound (50 mg, 0.071 mmol, 29% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.21 (s, 1H), 7.89-8.01 (m, 5H), 7.76 (d, J=6.5 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.33 (s, 2H), 6.59 (d, J=12.7 Hz, 2H), 4.47-4.62 (m, 6H), 4.28 (s, 2H), 4.07 (s, 2H), 2.08 (d, J=10.8 Hz, 6H), 1.89 (d, J=17.6 Hz, 4 H), 1.29 (q, J=6.9 Hz, 6H); LCMS (LCMS Method A): Rt=1.176 min, [M+H].sup.+=708.3

Example 74

(E)-1,26-Dibromo-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1435] ##STR00309##

[1436] Example 74 can be prepared according to method 6 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To (E)-1,1′-(but-2-ene-1,4-diyl)bis(2-amino-7-bromo-1H-benzo[d]imidazole-5-carboxamide) (500 mg, 0.889 mmol), 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (310 mg, 0.889 mmol) and HATU (1.01 g, 2.67 mmol) in DMF (15 mL) was added DIEA (0.466 mL, 2.67 mmol), and the reaction was heated to 90° C. After 1.5 hr, the mixture was poured into water, and the resulting solid was collected by filtration. The crude material was purified over silica gel, eluting with 5:1 DCM:MeOH with 0.1% aq NH.sub.3 to afford the title compound (250 mg, 0.215 mmol, 24% yield) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.04 (br. s., 2H), 8.02-8.10 (m, 4H), 7.92 (s, 2H), 7.47 (s, 2H), 6.51 (s, 1H), 5.72-5.78 (m, 2H), 5.01-5.25 (m, 4H), 4.52-4.66 (m, 2H), 4.39-4.50 (m, 2H), 2.71-2.76 (m, 2 H), 2.17 (s, 3H), 2.10 (s, 3H), 1.62-1.76 (m, 2H), 1.45-1.54 (m, 2H), 1.24-1.40 (m, 5 H); LCMS (LCMS Method A): Rt=1.448 min, [M+H].sup.+=873.2

Example 75

Example 75 is Mixture of Two Isomers 28-ethyl-17,26-dimethyl-14,30-dioxo-4,11,13,18,19,27,28,31,33,40-decaazaoctacyclo[42.3.1.0.SUP.4.,.SUP.12..0.SUP.5.,.SUP.1..SUP.0.0.SUP.1..SUP.5,.SUP.1..SUP.9.0.SUP.2..SUP.5,.SUP.2..SUP.9.0.SUP.32.,.SUP.40..0.SUP.3..SUP.4,.SUP.3..SUP.9]octatetraconta-1(48),5,7,9,11,15,17,25(29),26,32,34,36,38,44,46-pentadecaene-8,36-dicarboxamide and 16-ethyl-18,27-dimethyl-14,30-dioxo-4,11,13,16,17,25,26,31,33,40-decaazaoctacyclo[42.3.1.0.SUP.4.,.SUP.12..0.SUP.5.,.SUP.1..SUP.0.0.SUP.1..SUP.5,.SUP.1..SUP.9.0.SUP.2..SUP.5,.SUP.2..SUP.9.0.SUP.32.,.SUP.40..0.SUP.3..SUP.4,.SUP.3..SUP.9]octatetraconta-1(48),5,7,9,11,15(19),17,26,28,32,34,36,38,44,46-pentadecaene-8,36-dicarboxamide

[1437] ##STR00310##

[1438] Example 75 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (140 mg, 0.403 mmol) in NMP (10 mL) at 40° was added HATU (153 mg, 0.403 mmol) and 2-amino-1-(3-(3-(2-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)-propyl)-1H-benzo[d]imidazole-5-carboxamide (200 mg, 0.403 mmol). After stirring overnight, the reaction was purified by prep HPLC to afford the title compounds as a mixture (2 mg, 2 μmol, 0.6% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.97 (s, 1H), 7.84-7.91 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.93-6.98 (m, 2H), 6.81-6.89 (m, 2H), 6.64 (s, 1H), 4.66-4.72 (m, 2H), 4.49-4.57 (m, 2H), 4.40-4.47 (m, 2H), 4.25-4.31 (m, 2H), 2.96-3.02 (m, 2H), 2.78-2.84 (m, 2H), 2.60-2.66 (m, 2H), 2.28 (s, 3 H), 2.18 (s, 3H), 1.83-1.92 (m, 2H), 1.56-1.64 (m, 2H), 1.29-1.39 (m, 7H); LCMS (LCMS Method A): Rt=1.428 min, [M+H].sup.+=809.3

Example 76

4-Amino-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide

[1439] ##STR00311##

[1440] Example 76 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To neat tert-butyl (24-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-4-yl)carbamate (2.85 g, 3.60 mmol) was slowly added TFA (10 mL, 130 mmol). After 30 min, the reaction was concentrated. The residue was suspended in water, treated with NaHCO.sub.3 until basic, filtered and washed with water. This material was purified over silica gel (120 g column), eluting with 0-20% MeOH in DCM to afford the title compound (2.35 g, 3.23 mmol, 90% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.90 (s, 1H), 12.36 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.99 (br. s., 1 H), 7.83 (dd, J=8.4, 1.3 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.34 (br. s., 1H), 6.91-7.03 (m, 1 H), 6.70 (d, J=7.8 Hz, 1H), 6.57 (s, 1H), 6.48 (d, J=7.8 Hz, 1H), 5.92 (s, 2H), 4.74 (t, J=7.1 Hz, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.26 (br. s., 2H), 4.14 (br. s., 2H), 2.74-2.88 (m, 2 H), 2.16 (s, 3H), 2.08 (s, 3H), 1.72-1.96 (m, 6H), 1.48 (d, J=5.4 Hz, 2H), 1.38 (d, J=5.6 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.91 min, [M+H].sup.+=691.5

Example 77

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazole-5-carboxamide

[1441] ##STR00312##

[1442] Example 77 can be prepared according to method 4 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To a suspension of 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-methoxyethoxy)-1H-benzo[d]imidazole-5-carboxamide (100 mg, 0.133 mmol) in DCM (5 mL) at RT was added, dropwise, BBr.sub.3 (0.126 mL, 1.33 mmol). After 2 hr the reaction was quenched with MeOH, concentrated, and the residue was purified by prep HPLC to afford the title compound (15 mg, 0.020 mmol, 15% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.81 (br. s., 2H), 7.93-8.01 (m, 3H), 7.75 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.38 (m, 3H), 6.59 (d, J=11.6 Hz, 2H), 4.94 (br. s., 1H), 4.54-4.61 (m, 4H), 4.40-4.49 (m, 2H), 4.21-4.32 (m, 2H), 4.12-4.20 (m, 2H), 3.70-3.76 (m, 2 H), 2.08 (d, J=5.6 Hz, 6H), 1.77-1.91 (m, 4H), 1.22-1.35 (m, 6H); LCMS (LCMS Method A): Rt=1.290 min, [M+H].sup.+=739.2

Example 78

(E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide bis trifluoroacetic acid salt

[1443] ##STR00313##

[1444] Example 78 can be prepared according to method 11 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To (E)-2-amino-1-(4-(2-amino-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (250 mg, 0.178 mmol), HATU (203 mg, 0.534 mmol), HOBt (40.9 mg, 0.267 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (82 mg, 0.53 mmol) in DMF (3 mL) was added TEA (0.149 mL, 1.07 mmol). After stirring over the weekend, the reaction was passed through a syringe filter and purified via reverse phase HPLC (Gilson, Sunfire Prep C18 OBD 5 μm 30×100 mm column), eluting with 20-90% MeCN in water (0.1% TFA) to afford the title compound (18 mg, 0.020 mmol, 11% yield). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 7.60 (d, J=1.27 Hz, 1H), 7.33 (d, J=1.27 Hz, 1H), 7.26 (s, 1H), 7.13 (d, J=8.11 Hz, 1H), 6.87 (d, J=8.11 Hz, 1H), 6.58 (s, 1H), 6.54-6.57 (m, 1H), 5.85-5.93 (m, 2H), 5.14 (br. s., 2H), 5.06 (d, J=3.80 Hz, 2H), 4.59 (dd, J=13.81, 6.97 Hz, 4H), 3.79 (s, 6H), 2.20 (d, J=1.77 Hz, 6H), 1.36 (td, J=7.16, 2.91 Hz, 6H); LCMS (LCMS Method D): Rt=1.02 min, [M+H].sup.+=694.5

Example 79

8-4-(2-Aminoacetamido)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide

[1445] ##STR00314##

[1446] Example 79 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To tert-butyl (2-((24-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-4-yl)amino)-2-oxoethyl)carbamate (350 mg, 0.413 mmol) was slowly added TFA (3.00 mL, 38.9 mmol). After 30 min the reaction was concentrated. The resulting residue was suspended in water and treated with NaHCO.sub.3 until basic. The solid was collected by filtration and washed with water. This material was purified over silica gel (80 g column), eluting with 0-20% (2N NH.sub.3 in MeOH) in DCM to afford the title compound (270 mg, 0.343 mmol, 83% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.03 (d, J=1.2 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=8.3, 1.5 Hz, 1H), 7.58-7.69 (m, 2H), 7.34 (d, J=7.3 Hz, 2H), 7.20-7.31 (m, 1H), 6.57 (s, 1H), 4.74 (t, J=7.1 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.14-4.34 (m, 4H), 3.54 (s, 2H), 2.76-2.85 (m, 2 H), 2.16 (s, 3H), 2.09 (s, 3H), 1.91 (br. s., 4H), 1.82 (d, J=6.6 Hz, 2H), 1.48 (d, J=5.6 Hz, 2 H), 1.38 (d, J=4.9 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.78 min, [M+H].sup.+=748.6

Example 80

8-Ethyl-10,17-dimethyl-7,19-dioxo-7,8,11,12,13,14,19,20,27,28,29,30-dodecahydro-6H-benzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-o]dipyrazolo[5,1-e:4′,3′-k][1,3,6,14,16]pentaazacycloicosine-3,23-dicarboxamide

[1447] ##STR00315##

[1448] Example 80 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: A mixture of 4-(4-(5-carboxy-3-methyl-1H-pyrazol-1-yl)butyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (165 mg, 0.492 mmol), 1,1′-(butane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (200 mg, 0.492 mmol), HATU (561 mg, 1.48 mmol) and DIEA (382 mg, 2.95 mmol) in NMP (8 mL) was stirred at 120° C. for 18 hr. The mixture was concentrated, and the residue was purified over silica gel, eluting with 80:20:1 DCM:MeOH:NH.sub.4OH(aq). The partially pure product was further purified prep-HPLC to afford the title compound (7 mg, 10 μmol, 2% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.83 (br. s., 2H), 7.90-8.01 (m, 4H), 7.79 (t, J=6 Hz, 2H), 7.52-7.62 (m, 2H), 7.35 (br. s., 2H), 6.56 (s, 1H), 4.80 (br. s., 2H), 4.46-4.54 (m, 2H), 4.25 (br. s., 4H), 2.90-3.01 (m, 2H), 2.17 (s, 3H), 2.08 (s, 3H), 1.78-1.89 (br. m., 6H), 1.53-1.57 (m, 2H), 1.30 (t, J=6 Hz, 3H); LCMS (LCMS Method A): Rt=1.316 min, [M+H].sup.+=704.7

Example 81

8-Ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,14,15,20,21,28,29,30,31-dodecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3,24-dicarboxamide

[1449] ##STR00316##

[1450] Example 81 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-(5-(5-carboxy-3-methyl-1H-pyrazol-1-yl)pent-2-en-1-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (320 mg, 0.924 mmol), 1,1′-(butane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (488 mg, 1.20 mmol) and DIEA (0.484 mL, 2.77 mmol) in NMP (10 mL) was added HATU (878 mg, 2.31 mmol). The reaction was stirred at 80° C. for 16 hr, then poured into Et.sub.20 (50 mL). The resulting precipitate was collected by filtration and washed with Et.sub.2O and water. The crude product was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), eluting with 20-40% MeCN in water (containing 0.1% TFA) to afford the title compound (11 mg, 15 μmol, 1.7% yield) as a white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 8.00 (s, 1H), 7.93 (s, 1H), 7.81 (t, J=9.7 Hz, 2H), 7.56-7.40 (m, 2H), 6.66 (s, 1H), 5.77 (d, J=15.2 Hz, 1H), 5.42 (d, J=15.5 Hz, 1H), 4.78-4.85 (m, 1H), 4.68-4.52 (m, 2H), 4.37-4.22 (m, 4H), 3.62 (d, J=5.8 Hz, 2H), 2.82-2.49 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 2.09-1.93 (m, 5H), 1.41 (t, J=8.0 Hz, 3H); LCMS (LCMS Method A): Rt=1.376 min, [M+H].sup.+=716.9

Example 82

35-ethyl-5,37-dimethyl-8,33-dioxo-3,4,9,11,18,23,30,32,35,36-decaazaoctacyclo[38.1.1.0.SUP.3.,.SUP.7..0.SUP.1..SUP.0,.SUP.1..SUP.8.0.SUP.12.,.SUP.1..SUP.7.0.SUP.23.,.SUP.31..0.SUP.2..SUP.4,2.SUP.9..0.SUP.3..SUP.4,.SUP.3..SUP.8]dotetraconta-4,6,10,12,14,16,24,26,28,30,34(38),36-dodecaene-14,27-dicarboxamide

[1451] ##STR00317##

[1452] Example 82 can be prepared according to method 19 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-((3-((5-carboxy-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutyl)methyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (175 mg, 0.486 mmol), 1,1′-(butane-1,4-diyl)bis(2-amino-1H-benzo[d]imidazole-5-carboxamide) (220 mg, 0.541 mmol), and HATU (559 mg, 1.47 mmol) in NMP (2 mL) at RT was slowly added DIEA (0.514 mL, 2.94 mmol). The mixture was heated to 70° C. for 4 hr and poured into water. The crude product was collected by filtration, and the filtrate was concentrated to yield a second batch of crude product, which was washed with water. The combined crude product was purified by prep-HPLC (Gemini-C18 column, 5p silica, 21 mm diameter, 150 mm length), eluting with 30-60% MeCN in water (containing 0.1% TFA) to afford the title compound as a white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 12.87 (s, 2H), 8.02 (t, J=9.0 Hz, 4H), 7.83 (dd, =19.9, 8.4 Hz, 2H), 7.65 (dd, J=23.0, 8.2 Hz, 2H), 7.37 (d, J=2.1 Hz, 2H), 6.52 (s, 1H), 4.64 (d, J=5.3 Hz, 2H), 4.44 (m, 2H), 4.28 (s, 4H), 2.91 (d, J=7.3 Hz, 2H), 2.47 (m, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1.96 (s, 6H), 1.53 (m, 2H), 1.28 (t, J=7.1 Hz, 3H); LCMS (LCMS Method A): Rt=1.351 min, [M+H].sup.+=731.3

Example 83

(E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid

[1453] ##STR00318##

[1454] Example 83 can be prepared according to method 11 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To (E)-methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylate (1.26 g, 1.82 mmol) in MeOH (10 mL), DMF (10 mL) and water (10 mL) at RT was added NaOH (0.729 g, 18.2 mmol). After 3 hr, another portion of NaOH (0.729 g, 18.2 mmol) was added, and the reaction was stirred overnight. The mixture was concentrated, and the residue diluted with water (100 mL) and acidified with 3N HCl to pH=3. The resulting precipitate was collected by filtration to afford the title compound (1.06 g, 1.56 mmol, 86% yield) as a yellow-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.80-12.87 (m, 2H), 7.93-7.98 (m, 3H), 7.85 (d, J=8.3 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.4 Hz, 1 H), 7.33 (s, 1H), 6.54 (d, J=6.6 Hz, 2H), 5.90-5.98 (m, 2H), 4.86 (d, J=20.0 Hz, 4H), 4.52 (d, J=6.7 Hz, 4H), 2.12 (s, 6H), 1.27 (m, J=6.8, 4.6 Hz, 6H); LCMS (LCMS Method A): Rt=1.376 min, [M+H].sup.+=677.9

Example 84

23-(Aminomethyl)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-3-carboxamide

[1455] ##STR00319##

[1456] Example 84 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To tert-butyl ((3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,-28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-23-yl)methyl)carbamate (410 mg, 0.509 mmol) was slowly added TFA (3 mL, 38.9 mmol). After 30 min the reaction was concentrated. The resulting residue was suspended in water and treated with NaHCO.sub.3 until basic. The solid was collected by filtration and washed with water. This material was purified over silica gel (80 g column), eluting with 0-20% (2N NH.sub.3 in MeOH) in DCM to afford the title compound (340 mg, 0.458 mmol, 90% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.02 (d, J=1.2 Hz, 1H), 7.98 (br. s., 1H), 7.82 (dd, J=8.3, 1.5 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.34 (br. s., 1H), 7.24 (t, J=7.8 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.55 (s, 1H), 4.74 (t, J=7.1 Hz, 2H), 4.47 (q, J=7.0 Hz, 2H), 4.18-4.32 (m, 4H), 4.12 (s, 2 H), 2.77-2.88 (m, 2H), 2.15 (s, 3H), 2.05-2.11 (m, 3H), 1.91 (br. s., 4H), 1.77-1.86 (m, 2H), 1.43-1.56 (m, 2H), 1.38 (m, 2H), 1.30 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=0.77 min, [M+H].sup.+=705.6

Example 85

(E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-4-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide

[1457] ##STR00320##

[1458] Example 85 can be prepared according to method 11 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (208 mg, 1.35 mmol) in NMP (8 mL) was added HATU (616 mg, 1.62 mmol) and DIEA (0.57 mL, 3.2 mmol). After 30 min, (E)-2-amino-1-(4-(2-amino-4-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide dihydrobromide (290 mg, 0.540 mmol) was added, and the reaction was heated to 60° C. After stirring overnight, water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated and purified by prep-HPLC to afford the title compound (45 mg, 0.069 mmol, 13% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.79 (br. s., 1H), 12.19 (br. s., 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.72-7.75 (m, 1H), 7.44-7.47 (m, 1H), 7.37 (s, 1H), 7.24-7.27 (m, 1H), 7.00-7.12 (m, 2H), 6.56 (s, 2H), 5.78-5.89 (m, 2H), 4.75-4.85 (m, 4H), 4.49-4.56 (m, 4H), 2.48-2.52 (m, 3H), 2.13 (s, 6H), 1.21-1.29 (m, 6H); LCMS (LCMS Method A): Rt=1.507 min, [M+H].sup.+=648.2

Example 86

(E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide

[1459] ##STR00321##

[1460] Example 86 can be prepared according to method 11 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (295 mg, 1.92 mmol) in NMP (8 mL) at RT was added HATU (874 mg, 2.30 mmol) and DIPEA (0.803 mL, 4.60 mmol). After 30 min (E)-2-amino-1-(4-(2-amino-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide (300 mg, 0.766 mmol) was added, and the reaction was heated to 60° C. overnight. Water was added, and the resulting solid was collected by filtration and purified by prep-HPLC to afford the title compound (78 mg, 0.12 mmol, 15% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.75 (s, 2H), 7.95 (d, J=12.1 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.17-7.09 (m, 2H), 6.80 (dd, J=6.8, 2.4 Hz, 1H), 6.53 (d, J=17.1 Hz, 2H), 5.92-5.96 (m, 1H), 5.71-5.75 (m, 1H), 4.91 (d, J=4.9 Hz, 2H), 4.81 (d, J=5.4 Hz, 2H), 4.52 (q, J=7.1 Hz, 4H), 3.69 (s, 3H), 2.11 (d, J=4.0 Hz, 6H), 1.26 (td, J=7.1, 2.0 Hz, 6H); LCMS (LCMS Method A): Rt=1.494 min, [M+H].sup.+=664.2

Example 87

4-((Dimethylamino)methyl)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide

[1461] ##STR00322##

[1462] Example 87 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: A mixture of 4-(aminomethyl)-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,-15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo-[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosine-24-carboxamide (100 mg, 0.142 mmol) and formaldehyde (37% in water) (0.106 mL, 1.42 mmol) in acetic acid (5 mL) was stirred at RT for 20 min and then cooled to 0° C. Sodium triacetoxyborohydride (301 mg, 1.42 mmol) was added, the reaction was stirred at 0° C. for 1 hr and then at RT overnight. The solvent was removed, and the residue was suspended in water and treated with NaHCO.sub.3 until basic. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with brine (2×), dried over Na.sub.2SO.sub.4, filtered and concentrated The residue was purified over silica gel (40 g column), eluting with 0-20% MeOH in DCM to afford the title compound (30 mg, 0.039 mmol, 27% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.89 (br. s., 1H), 12.24 (br. s., 1H), 7.96-8.09 (m, 2H), 7.84 (dd, J=8.44, 1.59 Hz, 1H), 7.65 (d, J=8.31 Hz, 1H), 7.51 (d, J=7.82 Hz, 1H), 7.35 (br. s., 1H), 7.26 (t, J=7.83 Hz, 1H), 7.14 (d, J=7.58 Hz, 1H), 6.58 (s, 1H), 4.74 (t, J=7.09 Hz, 2H), 4.47 (q, J=7.01 Hz, 2H), 4.13-4.34 (m, 4H), 3.73 (s, 2H), 2.74-2.88 (m, 2H), 2.23 (s, 6H), 2.16 (s, 3H), 2.09 (s, 3H), 1.92 (br. s., 4H), 1.81 (m, 2H), 1.49 (m, 2H), 1.39 (m, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (LCMS Method D): Rt=0.80 min, [M+H].sup.+=733.6

Example 88

tert-Butyl ((3-carbamoyl-8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,29,30,31-tetradecahydrobenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[2,1-p]dipyrazolo[5,1-e:4′,3′-l][1,3,6,15,17]pentaazacyclohenicosin-23-yl)methyl)carbamate

[1463] ##STR00323##

[1464] Example 88 can be prepared according to method 13 with modifications known to one of ordinary skill in the art. The last step of the preparation is provided: To 4-(5-(5-((1-(4-(2-amino-5-carbamoyl-1H-benzo[d]imidazol-1-yl)butyl)-4-(((tert-butoxycarbonyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)-3-methyl-1H-pyrazol-1-yl)pentyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.50 g, 1.82 mmol), HOBt (0.335 g, 2.19 mmol) and EDC (0.524 g, 2.73 mmol) in DMF (100 mL) was added DIEA (1.27 mL, 7.29 mmol) and DMAP (22 mg, 0.18 mmol). The reaction was heated to 60° C. After 6 hr, the mixture was cooled to RT, diluted with water and extracted with EtOAc (3×). The combined organics were washed with saturated NH.sub.4Cl (2×) and brine (2×), dried over Na.sub.2SO.sub.4, filtered and concentrated. This residue was purified over silica gel (120 g column), eluting with 0-20% MeOH in DCM to afford the title compound (860 mg, 1.0 mmol, 56% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.85 (s, 1H), 12.41 (s, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.98 (br. s., 1 H), 7.82 (dd, J=8.6, 1.5 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.57 (br. s., 1H), 7.54 (d, J=8.1 Hz, 1H), 7.34 (br. s., 1H), 7.27 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.55 (s, 1H), 4.74 (t, J=7.1 Hz, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.37 (d, J=5.9 Hz, 2H), 4.25 (m, 4H), 2.75-2.87 (m, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 1.91 (br. s., 4H), 1.75-1.86 (m, 2H), 1.49 (br. s., 2H), 1.39 (m, 11H), 1.30 (t, J=7.1 Hz, 3H); LCMS (LCMS Method D): Rt=1.11 min, [M+H].sup.+=805.7

Table 1 provides Example 89 to Example 197. The compounds can be prepared by using synthetic methods described above.

TABLE-US-00016 Synthetic Example Structure / Name Method NMR LCMS Example l-(((4R,5R)-5-((5-carbamoyl-2- Method 9 .sup.1H NMR (400 LCMS 89 (1-ethyl-3-methyl-1H-pyrazole- MHz, Methanol- Method A: 5-carboxamido)-1H- d4) δ 7.58 (s, Rt = benzo[d]imidazol-1-yl)methyl)- 1H), 7.48 (d, J = 1.338 2,2-dimethyl-1,3-dioxolan-4- 8.4 Hz, 1H), 7.33 min, yl)methyl)-2-(1-ethyl-3-methyl- (s, 1H), 7.17 (d, [M + H].sup.+ = 1H-pyrazole-5-carboxamido)-7- J = 8.4 Hz, 1H), 824.8 (3-hydroxypropoxy)-1H- 6.89 (s, 1H), 6.58 benzo[d]imidazole-5- (s, 2H), 5.11- carboxamide   [00324] 4.99 (m, 1H), 4.93 (s, 1H), 4.61 (m, 5H), 4.46- 4.36 (m, 1H), 4.31 (dd, J = 13.4, 3.2 Hz, 1H), 4.19 (dd, J = 14.0, 3.4 Hz, 1H), 4.03 (dd, J = 15.1, 6.4 Hz, 1H), 3.88 (dd, J = 14.9, 6.4 Hz, 1H), 3.83-3.72 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 2.05 (dd, J = 11.5, 5.9 Hz, 2H), 1.64 (d, J = 10.3 Hz, 6H), 1.50-1.28 (m, 6H) Example 1-(4-(4- Method .sup.1H NMR (400 LCMS 90 ((dimethylamino)methyl)-2-(1- 11 MHz, DMSO-d.sub.6) δ Method A: ethyl-3-methyl-1H-pyrazole-5- ppm 12.86 (s, Rt = carboxamido)- 2H), 9.55 (s, 1H), 1.275 min, 1Hbenzo[d]imidazol-1-yl)butyl)- 7.99 (s, 2H), 7.78 [M + H].sup.+ = 2-(1-ethyl-3-methyl-1H- (s, 1H), 7.65 (dd, 693.3 pyrazole-5-carboxamido)- J = 6.7, 2.2 Hz, 1Hbenzo[d]imidazole-5- 1H), 7.55 (d, J = carboxamide, trifluoroacetic acid 8.4 Hz, 1H), 7.33 salt   [00325] (t, J = 7.9 Hz, 3H), 6.61 (d, J = 9.9 Hz, 2H), 4.68 (d, J = 4.9 Hz, 2H), 4.56 (dd, J = 13.9, 6.8 Hz, 4H), 4.28 (s, 4H), 2.77 (d, J = 4.5 Hz, 6H), 2.11 (s, 6H), 1.87 (s, 4H), 1.30 (t, J = 7.0 Hz, 6H) Example (E)-1,1′-(but-2-ene-1,4- Method 2 .sup.1H NMR (400 LCMS 91 diyl)bis(2-(1-ethyl-3-methyl-1H- MHz, Methanol- Method F: pyrazole-5-carboxamido)-7-(3- d.sub.4) δ ppm 7.52- Rt = methoxypropoxy)-1H- 7.65 (m, 2 H), 0.87 min, benzo[d]imidazole-5- 7.23-7.37 (m, 2 [M + H].sup.+ = carboxamide)   [00326] H), 6.55-6.69 (m, 2 H), 5.78- 5.93 (m, 2 H), 5.03-5.10 (m, 4 H), 4.49-4.70 (m, 4 H), 3.98- 4.10 (m, 4 H), 3.36-3.46 (m, 6 H), 2.24 (s, 6 H), 1.71-1.90 (m, 4 H), 1.35-1.47 (m, 6 H). 853.7 Example 1,1′-(cyclopentane-1,3- 15 .sup.1H NMR (400 LCMS 92 diyl)bis(2-(1-ethyl-3-methyl-1H- MHz, Methanol- Method F: pyrazole-5-carboxamido)-7-(3- d.sub.4) δ ppm 7.59- Rt = hydroxypropoxy)-1H- 7.78 (m, 2 H), 0.80 min, benzo[d]imidazole-5- 7.46-7.55 (m, 2 [M + H].sup.+ = carboxamide)   [00327] H), 6.57-6.72 (m, 2 H), 5.78- 6.04 (m, 2 H), 4.48-4.71 (m, 4 H), 4.32-4.45 (m, 4 H), 3.74- 3.89 (m, 4 H), 2.92-3.02 (m, 2 H), 2.29-2.44 (m, 2 H), 2.15- 2.26 (m, 4 H), 2.09 (s, 6 H), 1.32 (m, 6 H), 0.84-0.99 (m, 2 H) 839.7 Example ethyl (E)-3-(5-carbamoyl-1-(4- Method .sup.1H NMR (400 LCMS 93 (5-carbamoyl-2-(1-ethyl-3- 10 MHz, DMSO-d.sub.6) δ Method F: methyl-1H-pyrazole-5- ppm 12.66- Rt = carboxamido)-1H- 13.00 (m, 2 H), 0.86 min, benzo[d]imidazol-1-yl)but-2-en- 7.89-8.05 (m, 2 [M + H].sup.+ = 1-yl)-2-(1-ethyl-3-methyl-1H- H), 7.88 (s, 1 H), 777.5 pyrazole-5-carboxamido)-1H- 7.71 (d, J = 8.11 benzo[d]imidazol-7- Hz, 1 H), 7.53 (s, yl)propanoate   [00328] 1 H), 7.42 (d, J = 8.36 Hz, 1 H), 7.34 (d, J = 9.38 Hz, 2 H), 6.53 (d, J = 3.55 Hz, 2 H), 5.95-6.07 (m, 1 H), 5.49-5.65 (m, 1 H), 4.96- 5.08 (m, 2 H), 4.79-4.88 (m, 2 H), 4.37-4.63 (m, 4 H), 3.97 (q, J = 7.10 Hz, 2 H), 3.03-3.15 (m, 2 H), 2.63 (t, J = 7.73 Hz, 3 H), 2.12 (d, J = 6.08 Hz, 6 H), 1.28 (d, J = 3.80 Hz, 6 H), 1.09 (t, J = 7.10 Hz, 3 H) Example methyl (E)-4-((5-carbamoyl-1- Method .sup.1H NMR (400 LCMS 94 (4-(5-carbamoyl-2-(1-ethyl-3- 10 MHz, DMSO-d.sub.6) δ Method K: methyl-1H-pyrazole-5- ppm 12.71- Rt = 0.85 carboxamido)-1H- 12.97 (m, 2 H), min, benzo[d]imidazol-1-yl)but-2-en- 7.98 (d, J = 1.27 [M + H].sup.+ = 1-yl)-2-(1-ethyl-3-methyl-1H- Hz, 2 H), 7.91- 793.5 pyrazole-5-carboxamido)-1H- 7.96 (m, 1 H), benzo[d]imidazol-7- 7.67-7.76 (m, 1 yl)oxy)butanoate   [00329] H), 7.59-7.66 (m, 1 H), 7.42 (d, J = 7.60 Hz, 1 H), 7.33-7.39 (m, 2 H), 7.28-7.32 (m, 1 H), 6.47- 6.58 (m, 2 H), 5.92-6.05 (m, 1 H), 5.67-5.80 (m, 1 H), 4.91- 4.99 (m, 2 H), 4.78-4.87 (m, 2 H), 4.46-4.58 (m, 4 H), 4.03 (s, 2 H), 3.55 (s, 3 H), 2.29-2.39 (m, 2 H), 2.12 (d, J = 3.80 Hz, 6 H), 1.71-1.93 (m, 2 H), 1.22-1.32 (m, 6 H) Example (E)-1-((E)-4-((E)-5-carbamoyl-2- Method .sup.1H NMR (400 LCMS 95 ((1-ethyl-3-methyl-1H-pyrazole- 14 MHz, DMSO-d.sub.6) δ Method K: 5-carbonyl)imino)-2,3-dihydro- ppm 12.62- Rt = 0.81 1H-benzo[d]imidazol-1-yl)but-2- 12.93 (m, 1 H), min, en-1-yl)-2-((1-ethyl-3-methyl- 7.91-8.05 (m, 3 [M + H].sup.+ = 1H-pyrazole-5-carbonyl)imino)- H), 7.71 (d, 765.5 7-(3-hydroxy-2-methylpropoxy)- J = 8.11 Hz, 1 H), 2,3-dihydro-1H- 7.58-7.68 (m, 1 benzo[d]imidazole-5- H), 7.41 (d, carboxamide   [00330] J = 7.86 Hz, 1 H), 7.28-7.37 (m, 3 H), 6.47-6.55 (m, 2 H), 5.93- 6.08 (m, 1 H), 5.70-5.84 (m, 1 H), 4.90-5.00 (m, 2 H), 4.77- 4.87 (m, 2 H), 4.62 (t, J = 5.80 Hz, 1 H), 4.45- 4.58 (m, 4 H), 3.99-4.08 (m, 2 H), 3.84-3.93 (m, 1 H), 2.11 (s, 6 H), 1.87 (m, 1H), 1.27 (d, J = 6.84 Hz, 6 H), 0.80-0.89 (m, 3 H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method .sup.1H NMR (400 LCMS 96 ethyl-3-methyl-1H-pyrazole-5- 14 MHz, DMSO-d.sub.6) δ Method K: carboxamido)-1H- 12.64-13.10 (m, Rt = 0.85 benzo[d]imidazol-1-yl)but-2-en- 2 H), 7.97-8.13 min, 1-yl)-2-(1-ethyl-3-methyl-1H- (m, 1 H), 7.86- [M + H].sup.+ = pyrazole-5-carboxamido)-7-(3- 7.97 (m, 1 H), 779.5 hydroxy-3-methylbutoxy)-1H- 7.66-7.76 (m, 1 benzo[d]imidazole-5- H), 7.58-7.66 carboxamide   [00331] (m, 1 H), 7.37- 7.47 (m, 1 H), 7.21-7.37 (m, 3 H), 6.53 (s, 2 H), 5.87-6.09 (m, 1 H), 5.60-5.87 (m, 1 H), 4.98 (d, J = 4.82 Hz, 2 H), 4.81 (d, J = 4.80 Hz, 2 H), 4.44- 4.67 (m, 5 H), 4.40 (s, 1 H), 3.98-4.19 (m, 2 H), 2.11 (s, 6 H), 1.70 (t, J = 7.10 Hz, 2 H), 1.28 (m, 6 H), 1.07 (s, 6 H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method 9 .sup.1H NMR (400 LCMS 97 ethyl-3-methyl-1H-pyrazole-5- MHz, DMSO-d.sub.6) δ Method F: carboxamido)-7-(3- ppm 12.91 (br, Rt = 2.33 methoxypropoxy)-1H- 1H), 7.89-8.16 min, benzo[d]imidazol-1-yl)but-2-en- (m, 4 H) 7.64 (s, [M + H].sup.+ = 1-yl)-2-(1-ethyl-3-methyl-1H- 1 H) 7.47 (br. s., 822.1 pyrazole-5-carboxamido)-7- 1 H) 7.25-7.40 isobutyl-1H-benzo[d]imidazole- (m, 2 H) 6.47- 5-carboxamide, trifluoroacetic 6.60 (m, 2 H) acid salt   [00332] 5.82 (d, J = 15.72 Hz, 1 H) 5.54 (d, J = 15.72 Hz, 1 H), 4.91 (br. s., 4 H) 4.41-4.65 (m, 4 H) 4.03 (t, J = 6.46 Hz, 2 H) 3.29 (t, J = 6.08 Hz, 2 H) 3.14 (s, 3 H), 2.55 (br, 2H), 2.11 (d, J = 12.17 Hz, 6 H) 1.69-1.84 (m, 2 H), 1.36 (m, 1H), 1.27 (q, J = 7.10 Hz, 6 H), 0.69 (s, J = 6.3 Hz, 6 H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method 9 .sup.1H NMR (400 LCMS 98 ethyl-3-methyl-1H-pyrazole-5- MHz, DMSO) δ Method A: carboxamido)-1H- 12.98 (s, 1H), Rt = 1.30 benzo[d]imidazol-1-yl)but-2-en- 7.98 (m, 4H), min, 1-yl)-2-(1-ethyl-3-methyl- 7.77-7.65 (m, [M + H].sup.+ = 1Hpyrazole-5-carboxamido)-7- 2H), 7.44 (d, J = 721.4 (methoxymethyl)-1H- 8.4 Hz, 2H), 7.35 benzo[d]imidazole-5- (s, 2H), 6.53 (d, carboxamide   [00333] J = 6.8 Hz, 2H), 5.95 (d, J = 15.8 Hz, 1H), 5.52 (d, J = 15.8 Hz, 1H), 4.95 (s, 2H), 4.81 (s, 2H), 4.52 (d, J = 7.0 Hz, 6H), 3.15 (s, 3H), 2.11 (s, 6H), 1.26 (td, J = 7.1, 3.7 Hz, 6H) Example (E)-2-(5-carbamoyl-1-(4-(5- Method 9 .sup.1H NMR (400 Method A: 99 carbamoyl-2-(1-ethyl-3-methyl- MHz, DMSO) δ Rt = 1.30 1H-pyrazole-5-carboxamido)- 12.87 (s, 3H), min, 1H-benzo[d]imidazol-1-yl)but-2- 8.02-7.87 (m, [M + H].sup.+ = en-1-yl)-2-(1-ethyl-3-methyl-1H- 4H), 7.71 (d, J = 735.4 pyrazole-5-carboxamido)-1H- 8.4 Hz, 1H), 7.57 benzo[d]imidazol-7-yl)acetic (s, 1H), 7.41 (d, acid   [00334] J = 8.4 Hz, 1H), 7.32 (s, 2H), 6.52 (d, J = 14.4 Hz, 2H), 5.95 (d, J = 15.0 Hz, 1H), 5.48 (d, J = 15.5 Hz, 1H), 4.97 (s, 2H), 4.79 (s, 2H), 4.59-4.46 (m, 4H), 3.71 (s, 2H), 2.08 (t, J = 12.1 Hz, 6H), 1.25 (td, J = 7.1, 2.6 Hz, 6H) Example l-(4-(5-carbamoyl-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 100 methyl-1H-pyrazole-5- 16 MHz, DMSO-d6 + Method A: carboxamido)-1H- D.sub.2O) δ ppm 7.76 Rt = benzo[d]imidazol-1-yl)-2,3- (d, J = 9.6 Hz, 1.335 & dimethylbutyl)-2-(1-ethyl-3- 1H), 7.55-7.47 1.362 min, methyl-1H-pyrazole-5- (m, 2H), 7.14 (s, [M].sup.+ = carboxamido)-7-(3- 1H), 7.03 (d, J = 780.7 hydroxypropoxy)-1H- 9.7 Hz, 2H), 6.62 benzo[d]imidazole-5- (s, 1H), 6.56 (s, carboxamide   [00335] 1H), 4.62-4.50 (m, 4H), 4.35- 4.17 (m, 3H), 4.05-3.97 (m, 1H), 3.78-3.70 (m, 2H), 3.38- 3.32 (m, 2H), 2.68 (s, 1H), 2.34 (s, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.08-1.96 (m, 2H), 1.66-1.48 (m, 2H), 1.38- 1.28 (m, 4H), 1.22 (s, 2H), 1.04 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.91- 0.80 (m, 2H) (NMR analysis is based on the major peaks from the major diastereomer) Example (E)-7-(2-aminoethyl)-1-(4-(5- Similar to .sup.1H NMR (400 LCMS 101 carbamoyl-2-(1-ethyl-3-methyl- Method MHz, DMSO- Method A: 1H-pyrazole-5-carboxamido)- 15 d.sub.6) δ ppm 8.41 Rt = 1H-benzo[d]imidazol-1-yl)but-2- (br s, 3H), 8.00 1.168 en-1-yl)-2-(1-ethyl-3-methyl-1H- (br d, J = 14.1 min, pyrazole-5-carboxamido)-1H- Hz, 3H), 7.90 (s, [M].sup.+ = benzo[d]imidazole-5- 1H), 7.73 (d, J = 719.9 carboxamide, Formic acid salt   [00336] 7.5 Hz, 2H), 7.56 (s, 1H), 7.41- 7.34 (m, 3H), 6.53 (br s, 2H), 5.98 (d, J = 16.4 Hz, 1H), 5.56 (s, 1H), 4.99 (br s, 2H), 4.81 (br s, 2H), 4.51 (d, J = 5.7 Hz, 4H), 3.03 (br s, 4H), 2.11 (s, 6H), 2.05 (br t, 2H), 1.32- 1.13 (m, 6H) Example 8-ethyl-10,18-dimethyl-7,20- Method .sup.1H NMR (400 LCMS 102 dioxo-7,8,11,12,13,- 13 MHz, Methanol- Method A: 14,15,20,21,28,29,30,31,32- d.sub.4) δ ppm 8.02 Rt = tetradecahydro-6H- (d, J = 1.2 Hz, 1.274 benzo[4,5]imidazo[2,1- 1H), 7.97-7.93 min, b]benzo[4,5]imidazo[1,2- (m, 1H), 7.68 (d, [M + H].sup.+ = i]dipyrazolo[5,1-m:4′,3′-t] J = 8.5 Hz, 1H), 691.3 [1,3,6,9,11,14]hexaazacyclodo 7.56 (td, J = 6.6, cosine-3-carboxamide   [00337] 3.4 Hz, 2H), 7.42- 7.34 (m, 2H), 6.84 (s, 1H), 4.73 (t, J = 5.8 Hz, 4H), 4.52 (q, J = 7.1 Hz, 2H), 4.34 (t, J = 6.9 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.68- 3.63 (m, 2H), 2.84-2.78 (m, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 1.89- 1.82 (m, 2H), 1.42 (dd, J = 13.9, 6.4 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.27- 1.19 (m, 2H) Example 8-ethyl-10,18-dimethyl-7,20- Method .sup.1H NMR (400 LCMS 103 dioxo-7,8,11,12,13,- 13 MHz, Methanol- Method A: 14,15,20,21,28,29,30,31,32- d.sub.4) 8.08-8.06 Rt = tetradecahydro-6H- (m, 1H), 7.94- 1.297 benzo[4,5]imidazo[2,1- 7.90 (m, 1H), min, b]benzo[4,5]imidazo[1,2- 7.63-7.59 (m, [M + H].sup.+ = i]dipyrazolo[5,1-m:4′,3′- 2H), 7.55-7.51 691.3 t][1,3,6,9,11,14]hexaazacyclodo (m, 1H), 7.42- cosine-24-carboxamide   [00338] 7.34 (m, 2H), 6.85-6.82 (m, 1H), 4.75-4.69 (m, 4H), 4.53- 4.46 (m, 3H), 4.36-4.30 (m, 2H), 3.82-3.77 (m, 2H), 3.69- 3.65 (m, 2H), 2.83-2.76 (m, 2H), 2.25-2.21 (m, 3H), 2.19- 2.17 (m, 3H), 1.87 (s, 2H), 1.46- 1.41 (m, 2H), 1.33-1.32 (m, 3H), 1.25-1.19 (m, 2H) Example 8-ethyl-10,18,30-trimethyl-7,20- Method .sup.1H NMR (400 LCMS 104 dioxo-7,8,11,12,13,- 19 MHz, Methanol- Method A: 14,15,20,21,28,29,30,31,32- d4) δ 8.00 (s, Rt = tetradecahydro-6H- 1H), 7.93 (d, J = 1.32 min, benzo[4,5]imidazo[2,1- 8.4 Hz, 1H), 7.56 [M + H].sup.+ = b]benzo[4,5]imidazo[1,2- (dd, J = 15.9, 7.1 705.3 i]dipyrazolo[5,1-m:4,3′- Hz, 3H), 7.39- t][1,3,6,9,11,14]hexaazacyclodo 7.35 (m, 2H), cosine-3-carboxamide   [00339] 6.75 (s, 1H), 4.78 (s, 2H), 4.68 (s, 2H), 4.53 (dd, J = 14.3, 7.2 Hz, 4H), 4.00 (s, 2H), 3.78 (s, 2H), 3.15 (s, 3H), 2.83 (s, 3H), 2.35 (d, J = 7.8 Hz, 2H), 2.17 (s, 6H), 1.77 (s, 2H), 1.36 (dd, J = 15.7, 8.6 Hz, 6H), 1.14 (s, 2H) Example 35-ethyl-5,37-dimethyl-8,33- Method .sup.1H NMR (400 LCMS 105 dioxo-3,4,9,11,18,23,- 19 MHz, DMSO-d.sub.6) δ Method A: 30,32,35,36-Decaaza- ppm 12.86 (br. Rt = octacyclo[38.3.1.0.sup.3,.sup.7.0.sup.10,1.sup.8.0.sup.12, s., 2H) 8.00-8.01 1.386 .sup.17.0.sup.23,.sup.31.0.sup.24,.sup.29.0.sup.34,.sup.38] (m, 4H) 7.77- min, tetratetraconta-1(44),4,6,10,- 7.81 (m, 2H) [M + H].sup.+ = 12(17),13,15,24(29),25,27,30,3 7.52-7.58 (m, 753.2 4(38),36,40,42-pentadecaene- 2H) 7.36 (s, 2H) 14,27-dicarboxamide   [00340] 7.14 (t, J = 8.0 Hz, 2H) 6.98- 7.00 (m, 1H) 6.61-6.65 (m, 2H) 5.99 (s, 2H) 4.56 (q, J = 6.7 Hz, 2H) 4.28 (s, 2H) 3.85-3.96 (m, 4H) 2.15 (s, 3H) 1.93 (m, 3H) 1.40-1.56 (m, 4H) 1.35 (t, J = 6.0 Hz, 3H) Example 1,1′-((2R,3R)-2,3- Method .sup.11H NMR (400 LCMS 106 diethoxybutane-1,4-diyl)bis(2- 15 MHz, DMSO-d.sub.6) δ Method A: (1-ethyl-3-methyl-1H-pyrazole- ppm 12.93 (br. Rt = 5-carboxamido)-1H- s., 2H) 8.02 (s, 1.372 benzo[d]imidazole-5- 4H) 7.81 (dd, J = min, carboxamide)   [00341] 8.0, 1.2 Hz, 2H) 7.56 (d, J = 8.4 Hz, 2H) 7.35 (s, 2H) 6.68 (s, 2H) 4.55-4.69 (m, 6H) 4.43-4.48 (m, 2 H) 4.05- 4.07 (m, 2H) 3.49-3.57 (m, 2H) 3.13-3.20 (m, 2H) 2.11 (s, 6H) 1.36 (t, J = 7.2 Hz, 6H) 0.77 (t, J = 7.0 Hz, 6H) [M + H].sup.+ = 766.8 Example 1,1′-(butane-1,4-diyl)bis(2-(1- Method 2 .sup.1H NMR (400 LCMS 107 ethyl-3-methyl-1H-pyrazole-5- MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 12.85 (br. Rt = 0.76 benzo[d]imidazole-5- s., 2 H) 7.99 (s, 4 min., carboxamide), 2Trifluoroacetic acid salt   [00342] H) 7.77 (d, J = 8.34 Hz, 2 H) 7.56 (d, J = 8.34 Hz, 2 H) 7.36 (br. s., 2 H) 6.61 (s, 2 H) 4.51-4.69 (m, 4 H) 4.28 (br. s., 4 H) 2.04- 2.21 (m, 6 H) 1.88 (br. s., 4 H) 1.31 (t, J = 7.07 Hz, 6 H) [M + H].sup.+ = 679.6 Example 1-(4-(5-carbamoyl-2-(1,3- Method .sup.1H NMR (400 LCMS 108 dimethyl-1H-pyrazole-5- 20 MHz, DMSO-d.sub.6) δ Method carboxamido)-1H- ppm 12.82 (br. D: Rt = benzo[d]imidazol-1-yl)butyl)-2- s., 2 H) 7.98 (s, 4 0.77 min., (1-ethyl-3-methyl-1H-pyrazole- H) 7.76 (dd, [M + H].sup.+ = 5-carboxamido)-1H- J = 8.31, 1.47 Hz, 665.6 benzo[d]imidazole-5- 2 H) 7.55 (d, carboxamide, 2Trifluoroacetic J = 8.31 Hz, 2 H) acid salt   [00343] 7.35 (br. s., 2 H) 6.60 (s, 2 H) 4.57 (q, J = 7.01 Hz, 2 H) 4.28 (d, J = 5.87 Hz, 4 H) 4.09 (s, 3 H) 2.10 (d, J = 4.65 Hz, 6 H) 1.87 (br. s., 4 H) 1.30 (t, J = 7.09 Hz, 3 H) Example 1-(4-(5-carbamoyl-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 109 methyl-1H-pyrazole-5- 20 MHz, DMSO-d.sub.6) δ Method carboxamido)-1H- ppm 12.84 (br. D: Rt = benzo[d]imidazol-1-yl)butyl)-2- s., 2 H) 7.99 (s, 4 0.84 min., (3-cyclopropyl-1-methyl-1H- H) 7.76 (dd, [M + H].sup.+ = pyrazole-5-carboxamido)-1H- J = 8.56, 1.47 Hz, 691.6 benzo[d]imidazole-5- 2 H) 7.54 (d, carboxamide, 2Trifluoroacetic J = 8.31 Hz, 2 H) acid salt   [00344] 7.35 (br. s., 2 H) 6.66 (s, 1 H) 6.60 (s, 1 H) 4.57 (q, J = 7.01 Hz, 2 H) 4.26- 4.39 (m, 4 H) 4.09 (s, 3 H) 2.09 (s, 3 H) 1.70-1.90 (m, 5 H) 1.31 (t, J = 7.09 Hz, 3 H) 0.72-0.83 (m, 2 H) 0.46-0.57 (m, 2 H) Example (11Z,29E)-8-ethyl-1,26-bis(3- Method .sup.1H NMR (400 LCMS 110 hydroxypropoxy)-10,18- 19 MHz, Method L: dimethyl-7,20-dioxo- METHANOL-d.sub.4) δ Rt = 0.75 6,7,8,13,14,15,20,21,28,31- ppm 7.71 (dd, min, decahydrobenzo[4,5]imidazo[1, J = 5.32, 1.01 Hz, [M + H].sup.+ = 2-a]benzo[4,5]imidazo[2,1- 2 H), 7.44 (dd, 863.7 p]dipyrazolo[5,1- J = 8.74, 1.14 Hz, e:4′,3′l][1,3,6,15,17] 2 H), 6.82 (s, 1 pentaazacyclohenicosine-3,24- H), 6.46 (d, dicarboxamide, 2Hydrochloride   [00345] J = 11.15 Hz, 1 H), 5.84-5.96 2 H), 5.09 (br. s., 4 H), 4.62-4.75 (m, 1 H), 5.58 (s, (m, 2 H), 4.07- 4.23 (m, 4 H), 3.72-3.79 (m, 4 H), 3.53-3.58 (m, 2 H), 2.33 (s, 3 H), 2.26 (s, 3 H), 1.93-2.11 (m, 4 H), 1.54- 1.71 (m, 4 H), 1.49 (t, J = 7.10 Hz, 3 H); Example (E)-1,1′-(but-2-ene-1,4- Method 2 .sup.1H NMR (400 LCMS 111 diyl)bis(2-(1-ethyl-4-fluoro-3- MHz, DMSO-d.sub.6) δ Method methyl-1H-pyrazole-5- ppm 12,90 (s, D: Rt = carboxamido)-7-(3- 2H), 7.99 (br. s., 0.89 min, hydroxypropoxy)-1H- 2 H), 7.64 (d, [M + 2].sup.+/2= benzo[d]imidazole-5- J = 1.27 Hz, 2 H), 431.5 carboxamide),   [00346] 7.29-7.38 (m, 4 H), 5.87 (br. s., 2 H), 4.91 (br. s., 4 H), 4.40-4.62 (m, 6 H), 4.04 (t, J = 6.08 Hz, 4 H), 3.43 (d, J = 5.07 Hz, 4 H), 2.10 (s, 6H), 1.67 (t, J = 6.08 Hz, 4 H), 1.24 (t, J = 7.10 Hz, 6H); Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 112 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Method A: (2-(1-ethyl-3-methyl-1H- ppm 12.80 (s, Rt = pyrazole-5-carboxamido)-4- 1H), 12.57 (s, 1.275 (morpholinomethyl)-1H- 1H), 7.98 (s, 2H), min, benzo[d]imidazol-1-yl)butyl)- 7.77 (d, J = 8.2 [M + H].sup.+ = 1H-benzo[d]imidazole-5- Hz, 1H), 7.54 (d, 735.3 carboxamide   [00347] J = 8.4 Hz, 1H), 7.30-7.48 (m, 2H), 7.14 (d, J = 27.8 Hz, 2H), 6.59 (s, 2H), 4.48- 4.67 (m, 4H), 4.27 (s, 4H), 3.81 (s, 2H), 3.70 (s, 4H), 2.42 (s, 4H), 2.11 (s, 6H), 1.88 (s, 4H), 1.30 (td, J = 7.0, 3.4 Hz, 6H) Example tert-butyl ((1-(4-(5-carbamoyl- Method .sup.1H NMR (400 LCMS 113 2-(1-ethyl-3-methyl-1H- 16 MHz, DMSO-d.sub.6) δ Method A: pyrazole-5-carboxamido)-1H- ppm 12.81 (s, Rt = benzo[d]imidazol-1-yl)butyl)-2- 2H), 7.99 (t, J = 1.646 (1-ethyl-3-methyl-1Hpyrazole-5- 5.1 Hz, 2H), 7.78 min, carboxamido)-1H- (d, J = 8.4 Hz, [M + H].sup.+ = benzo[d]imidazol-4-yl)methyl)- 1H), 7.55 (d, J = 779.3 (methyl )carbamate   [00348] 8.4 Hz, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.21 (d, J = 7.7 Hz, 2H), 6.60 (d, J = 12.2 Hz, 2H), 4.48-4.77 (m, 6H), 4.27 (d, J = 5.9 Hz, 4H), 2.72 (s, 3H), 2.09 (t, J = 4.3 Hz, 6H), 1.87 (s, 4H), 1.44 (s, 9H), 1.28 (td, J = 7.0, 2.4 Hz, 6H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 114 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Method A: (2-(1-ethyl-3-methyl-1H- ppm 12.83 (s, Rt = pyrazole-5-carboxamido)-4- 1H), 12.21 (s, 1.601 isopropyl-1H-benzo[d]imidazol- 1H), 7.98 (d, J = min, 1-yl)butyl)-1H- 8.2 Hz, 2H), 7.77 [M + H].sup.+ = benzo[d]imidazole-5- (d, J = 8.3 Hz, 678.5 carboxamide   [00349] 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30- 7.41 (m, 2H), 7.07-7.28 (m, 2H), 6.60 (d, J = 10.0 Hz, 2H), 4.57 (d, J = 6.8 Hz, 4H), 4.28 (s, 4H), 3.40-3.54 (m, 1H), 2.11 (s, 6H), 1.87 (s, 4H), 1.05-1.47 (m, 12H) Example 1,1′-((2R,3R)-2,3- Method .sup.1H NMR (400 LCMS 115 dimethoxybutane-1,4-diyl)bis(2- 15 MHz, DMSO-d.sub.6) δ Method A: (1-ethyl-3-methyl-1H-pyrazole- (ppm) 12.99 (br. Rt = 1.29 5-carboxamido)-1H- s. 2 H) 8.01 (s, 4 min, benzo[d]imidazole-5- H), 7.81 (d, [M + H].sup.+ = carboxamide)   [00350] J = 8.56 Hz, 2 H), 7.55 (d, J = 8.80 Hz, 2 H), 7.36 (br. s., 2 H), 6.64 (s, 2 H), 4.53- 4.70 (m, 6 H), 4.46 (dd, J = 14.06, 8.68 Hz, 2 H), 4.04 (br. s., 2 H), 3.21 (s, 6 H), 2.11 (s, 6 H), 1.35 (t, J = 7.09 Hz, 6H). 739.8 Example (E)-1-(4-(6-carbamoyl-2-(1,3- Method .sup.1H NMR (400 Method A: 116 diethyl-1H-pyrazole-5- 16 MHz, DMSO-d.sub.6) δ Rt = carboxamido)-1H- ppm 12.56- 1.339 benzo[d]imidazol-1-yl)but-2-en- 13.10 (m, 1 H), min, 1-yl)-2-(1,3-diethyl-1H-pyrazole- 7.99 (s, 2 H), [M + H].sup.+ = 5-carboxamido)-7-(3- 7.94 (br. s., 1 H), 779.8 hydroxypropoxy)-1H- 7.71 (d, J = 8.56 benzo[d]imidazole-5- Hz, 1 H), 7.64 (s, carboxamide   [00351] 1 H), 7.41 (d, J = 8.31 Hz, 1 H), 7.34 (br. s., 3 H), 6.57 (d, J = 13.20 Hz, 2 H), 5.98 (s, 1 H), 5.71-5.82 (m, 1 H), 4.95 (d, J = 4.65 Hz, 2 H), 4.84 (d, J = 4.89 Hz, 2 H), 4.49- 4.62 (m, 5 H), 4.11 (t, J = 6.36 Hz, 2 H), 3.48 (q, J = 5.71 Hz, 2 H), 2.43-2.49 (m, 2 H), 1.75 (t, J = 6.24 Hz, 2 H), 1.28 (t, J = 7.09 Hz, 6 H), 1.13 (td, J = 7.64, 3.06 Hz, 6 H) Example 2-(1-Ethyl-3-methyl-1Hpyrazole- Method .sup.1H NMR (400 Method A: 117 5-carboxamido)-1-(4-(2-(1- 16 MHz, DMSO-d.sub.6) δ Rt = ethyl-3-methyl-1Hpyrazole-5- ppm 12.82 (s, 1.468 carboxamido)-7-methoxy- 2H), 7.98 (t, J = min, 1Hbenzo[d]imidazol-1-yl)butyl)- 4.5 Hz, 2H), 7.73- [M + H].sup.+ = 1H-benzo[d]imidazole-5- 7.81 (m, 1H), 666.3 carboxamide   [00352] 7.54 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.11-7.18 (m, 2H), 6.86 (dd, J = 6.0, 3.2 Hz, 1H), 6.59 (d, J = 14.3 Hz, 2H), 4.57 (dt, J = 13.6, 6.8 Hz, 4H), 4.38 (s, 2H), 4.28 (s, 2H), 3.81 (s, 3H), 2.11 (d, J = 5.9 Hz, 6H), 1.85 (s, 4H), 1.30 (q, J = 7.0 Hz, 6H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 Method A: 118 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Rt = (2-(1-ethyl-3-methyl-1H- ppm 12.84 (s, 1.259 pyrazole-5-carboxamido)-4- 2H), 8.67 (s, 2H), min, ((methylamino)methyl)- 7.98 (d, J = 1.2 [M + H].sup.+ = 1Hbenzo[d]imidazol-1yl)butyl)- Hz, 2H), 7.77 679.3 1Hbenzo[d]imidazole-5- (dd, J = 8.4, 1.4 carboxamide   [00353] Hz, 1H), 7.60 (d, J = 6.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.31 (dt, J = 15.2, 6.7 Hz, 3H), 6.62 (d, J = 2.8 Hz, 2H), 4.54 (ddd, J = 30.5, 10.8, 6.4 Hz, 6H), 4.28 (s, 4H), 2.62 (t, J = 5.3 Hz, 3H), 2.11 (s, 6H), 1.86 (s, 4H), 1.30 (td, J = 7.1, 3.6 Hz, 6H). Example l,1′-(2,2-Difluorobutane-1,4- Method .sup.1H NMR (400 Method A: 119 diyl)bis(2-(1-ethyl-3-methyl-1H- 15 MHz, DMSO-d.sub.6) δ Rt = pyrazole-5-carboxamido)-1H- ppm 12.91 (d, J = 1.298 benzo[d]imidazole-5- 31.5 Hz, 2H), min, carboxamide)   [00354] 7.99 (s, 3H), 7.77 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 14.0, 8.4 Hz, 2H), 7.35 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.67 (d, J = 17.3 Hz, 2H), 4.89 (t, J = 14.3 Hz, 2H), 4.35- 4.68 (m, 6H), 2.61-2.82 (m, 2H), 1.92-2.14 (m, 6H), 1.16- 1.39 (m, 6H) [M + H].sup.+ = 715.7 Example 1-(4-(4-(benzyloxy)-2-(1-ethyl- Method .sup.1H NMR (DMSO- LCMS 120 3-methyl-1H-pyrazole-5- 11 d.sub.6) δ 12.80 (s, Method carboxamido)-1H- 1H), 12.07 (s, D: Rt = benzo[d]imidazol-1-yl)butyl)-2- 1H), 7.98 (d, 1.18 min, (1-ethyl-3-methyl-1H-pyrazole- J = 1.5 Hz, 1H), [M + H].sup.+ = 5-carboxamido)-1H- 7.94 (br s, 1H), 742.5 benzo[d]imidazole-5- 7.75 (dd, J = 8.4, carboxamide   [00355] 1.3 Hz, 1H), 7.47-7.59 (m, 3H), 7.39-7.45 (m, 2H), 7.33- 7.39 (m, 1H), 7.26-7.32 (m, 1H), 7.14 (br s, 2H), 6.92-7.02 (m, 1H), 6.59 (s, 2H), 5.30 (s, 2H), 4.43-4.62 (m, 4H), 4.15-4.31 (m, 4H), 2.11 (s, 3H), 2.10 (s, 3H), 1.85 (br s, 4H), 1.28 (dt, J = 14.5, 7.2 Hz, 6H) Example tert-butyl ((24-carbamoyl-8- 13 .sup.1H NMR (DMSO- LCMS 121 ethyl-10,18-dimethyl-7,20- d.sub.6) δ 12.90 (br. Method dioxo- s., 1H), 12.36 D: 6,7,8,11,12,13,14,15,20,21,28, (br. s., 1H), 8.02 Rt = 1.10 29,30,31-tetradeca- (br. s., 2H), 7.84 min, hydrobenzo[4,5]imidazo[1,2- (dd, J = 8.3,1.3 [M + H].sup.+ = a]benzo[4,5]imidazo[2,1- Hz, 1H), 7.66 (d, 805.6 p]dipyrazolo[5,1- J = 8.5 Hz, 1H), e:4′,3′l][1,3,6,15,17] 7.62 (t, J = 6.3 Hz, pentaazacyclohenicosin-4- 1H), 7.50 (d, yl)methyl)carbamate   [00356] J = 8.0 Hz, 1H), 7.36 (br. s., 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 4.74 (t, J = 6.8 Hz, 2H), 4.47 (q, J = 7.0 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.15-4.33 (m, 4H), 2.74-2.87 (m, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 1.90 (br. s., 4H), 1.80 (br. s., 2H), 1.32-1.54 (m, 2H), 1.40 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (DMSO- LCMS 122 pyrazole-5-carboxamido)-1-(4- 11 d.sub.6) δ 12.73 (br. Method (2-(1-ethyl-3-methyl-1H- s, 1H), 7.99 (d, D: Rt = pyrazole-5-carboxamido)-4- J = 1.5 Hz, 1H), 0.91 min, hydroxy-1H-benzo[d]imidazol-1- 7.81-7.92 (m, [M + H].sup.+ = yl)butyl)-1H-benzo[d]imidazole- 1H), 7.61-7.74 652.2 5-carboxamide   [00357] (m, 1H), 7.36- 7.50 (m, 1H), 7.14-7.28 (m, 1H), 6.95-7.06 6.90 (m, 1H), 6.58-6.64 (m, (m, 1H), 6.79- 1H), 6.49-6.58 (m, 2H), 4.49- 4.64 (m, 4H), 4.13-4.30 (m, 4H), 2.10 (s, 3H), 2.09 (s, 3H), 1.84 (br s, 4H), 1.18-1.37 (m, 6H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 123 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.81 (br. C: Rt = pyrazole-5-carboxamido)-4- s., 1 H), 11.96 1.05 min, isopropoxy-1H- (br. s., 1 H), 7.98 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- (d, J = 1.0 Hz, 1 694.7 1H-benzo[d]imidazole-5- H), 7.96 (br. s., 1 carboxamide   [00358] H), 7.76 (dd, J = 8.6, 1.5 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.33 (br. s., 1 H), 7.08-7.21 (m, 2 H), 6.91 (d, J = 7.1 Hz, 1 H), 6.51-6.63 (m, 2 H), 4.81 (br. s., 1 H), 4.45-4.62 (m, 4 H), 4.24 (m, 4 H), 2.11 (s, 6 H), 1.85 (br. s., 4 H), 1.20-1.41 (m, 12H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 124 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (s, 1 C: Rt = pyrazole-5-carboxamido)-4- H), 12.38 (s, 1 0.92 min, (methylamino)-1H- H), 7.97 (s, 1 H), [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- 7.96 (br. s., 1 H), 665.6 1H-benzo[d]imidazole-5- 7.75 (d, J = 8.6 carboxamide   [00359] Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.33 (br. s., 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 2 H), 6.60 (s, 1 H), 6.55 (s, 1 H), 6.35 (d, J = 8.1 Hz, 1 H), 4.57 (q, J = 6.9 Hz, 4 H), 4.27 (br. s., 2 H), 4.19 (br. s., 2 H), 2.79 (d, J = 4.5 Hz, 3 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 1.84 (br. s., 4 H), 1.29 (q, J = 6.8 Hz, 6 H) Example l-(4-(4-Amino-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 125 methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method carboxamido)-1H- ppm 12.90 (br s, D: Rt = benzo[d]imidazol-1-yl)butyl)-2- 1H), 12.30 (br s, 0.88 min, (1-ethyl-3-methyl-1Hpyrazole-5- 1H), 7.98 (d, [M + H].sup.+ = carboxamido)-1H- J = 1.5 Hz, 1 H), 651.6 benzo[d]imidazole-5- 7.96 (br. s., 1 H), carboxamide, tris trifluoroacetic 7.76 (dd, J = 8.4, acid salt   [00360] 1.6 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.33 (br. s., 1 H), 6.95 (t, J = 8.0 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 6.61 (s, 1 H), 6.56 (s, 1 H), 6.49 (d, J = 8.0 Hz, 1 H), 4.56 (q, J = 7.2 Hz, 4 H), 4.27 (br. s., 2 H), 4.14-4.23 (m, 2 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 1.84 (br. s., 4 H), 1.22-1.36 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 126 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (br. D: Rt = pyrazole-5-carboxamido)-4-(N- s., 1 H), 12.05 0.98 min, methylmethylsulfonamido)-1H- (br. s., 1 H), 7.98 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- (s, 1 H), 7.96 (br. 743.7 1H-benzo[d]imidazole-5- s., 1 H), 7.76 (d, carboxamide, bis trifluoroacetic J = 8.5 Hz, 1 H), acid salt   [00361] 7.55 (d, J = 7.5 Hz, 2 H), 7.41 (br. s., 1 H), 7.27- 7.37 (m, 2 H), 6.62 (s, 2 H), 4.46-4.62 (m, 4 H), 4.27 (br. s., 4 H), 3.31 (s, 3 H), 3.05 (s, 3 H), 2.11 (s, 6 H), 1.86 (br. s., 4 H), 1.20-1.34 (m, 6 H) Example 1-(4-(4-(2-Aminoethyl)-2-(1- Method .sup.1H NMR (400 LCMS 127 ethyl-3-methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method carboxamido)-1H- ppm 7.98 (d, D: Rt = benzo[d]imidazol-1-yl)butyl)-2- J =1.3 Hz, 2 H), 0.78 min, (1-ethyl-3-methyl-1H-pyrazole- 7.73-7.85 (m, 4 [M + H].sup.+ = 5-carboxamido)-1H- H), 7.54 (d, 679.6 benzo[d]imidazole-5- J = 8.3 Hz, 1 H), carboxamide, tris trifluoroacetic 7.44 (d, J = 7.8 acid salt   [00362] Hz, 1 H), 7.35 (br. s., 1 H), 7.17- 7.24 (m, 1 H), 7.09-7.15 (m, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 4.48-4.61 (m, 4 H), 4.20-4.31 (m, 4 H), 3.05- 3.19 (m, 4 H), 2.11 (s, 6 H), 1.86 (br. s., 4 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 128 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.81 (br. s, N: Rt = pyrazole-5-carboxamido)-4-(N- 1H), 7.98 (s, 1 6.584 methylacetamido)-1H- H), 7.97 (br. s., 1 min, benzo[d]imidazol-1-yl)butyl)- H), 7.76 (dd, [M + H].sup.+ = 1H-benzo[d]imidazole-5- J = 8.3, 1.5 Hz, 1 707.2 carboxamide   [00363] H), 7.52 (d, J = 8.3 Hz, 2 H), 7.34 (br. s., 1 H), 7.24 (t, J = 7.9 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 6.59 (s, 2 H), 4.43-4.59 (m, 4 H), 4.24 (br. s., 4 H), 3.14 (s, 3 H), 2.11 (br. s., 3 H), 2.10 (s, 3 H), 1.85 (br. s., 4 H), 1.66 (s, 3 H), 1.27 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 129 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (s, 1 D: Rt = pyrazole-5-carboxamido)-4-(1- H), 12.23 (s, 1 0.95 min, hydroxyethyl)-1H- H), 7.92-8.02 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- (m, 2 H), 7.76 680.6 1H-benzo[d]imidazole-5- (dd, J = 8.3, 1.3 carboxamide   [00364] Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.34 (br. s., 1 H), 7.17 (t, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 1 H), 6.61 (s, 1 H), 6.58 (s, 1 H), 5.88 (d, J = 3.3 Hz, 1 H), 5.11 (d, J = 4.3 Hz, 1 H), 4.56 (m, 4 H), 4.27 (m, 4 H), 2.10 (d, J = 1.3 Hz, 6 H), 1.86 (br. s., 4 H), 1.42 (d, J = 6.5 Hz, 3 H), 1.29 (q, J = 7.3 Hz, 6 H) Example 1-(4-(4-(2-Amino-N- Method .sup.1H NMR (400 LCMS 130 methylacetamido)-2-(1-ethyl-3- 11 MHz, DMSO-d.sub.6) δ Method methyl-1H-pyrazole-5- ppm 12.81 (br. s, D: Rt = carboxamido)-1H- 1H), 8.16 (br. s., 0.78 min, benzo[d]imidazol-1-yl)butyl)-2- 1 H), 7.99 (s, 2 [M + H].sup.+ = (1-ethyl-3-methyl-1H-pyrazole- H), 7.92 (br. s., 2 722.6 5-carboxamido)-1H- H), 7.77 (dd, benzo[d]imidazole-5- J = 8.4, 1.4 Hz, 1 carboxamide, tris trifluoroacetic H), 7.64 (d, acid salt   [00365] J = 7.8 Hz, 1 H), 7.48-7.59 (m, 1 H), 7.35 (m, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.23-7.29 (m, 1 H), 6.68 (br. s., 1 H), 6.61 (s, 1 H), 4.56 (q, J = 6.9 Hz, 4 H), 4.46 (br. s., 2 H), 4.26 (br. s., 4 H), 3.24 (s, 3 H), 2.08- 2.15 (m, 6 H), 1.86 (br. s., 4 H), 1.19-1.35 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 131 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 10.37 (s, 1 D: Rt = pyrazole-5-carboxamido)-4- H), 7.98 (d, 0.90 min, (methylsulfonamido)-1H- J = 1.3 Hz, 1 H), [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- 7.96 (br. s., 1 H), 729.6 1H-benzo[d]imidazole-5- 7.76 (dd, J = 8.5, carboxamide, bis trifluoroacetic 1.5 Hz, 1 H), acid salt   [00366] 7.55 (d, J = 8.5 Hz, 1 H), 7.34 (br. s., 1 H), 7.31 (dd, J = 7.3, 1.5 Hz, 1 H), 7.17- 7.27 (m, 2 H), 6.61 (s, 1 H), 6.59 (s, 1 H), 4.51-4.61 (m, 4 H), 4.16-4.34 (m, 4 H), 3.04 (s, 3 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 1.86 (br. s., 4 H), 1.30 (td, J = 7.2, 2.8 Hz, 6 H) Example 1-(4-(4-(2-(Dimethylamino)-N- Method .sup.1H NMR (400 LCMS 132 methylacetamido)-2-(1-ethyl-3- 11 MHz, DMSO-d.sub.6) δ Method methyl-1H-pyrazole-5- ppm 12.8 (br. s, D: Rt = carboxamido)-1H- 1H), 9.50 (br. s., 0.79 min, benzo[d]imidazol-1-yl)butyl)-2- 1 H), 7.99 (s, 2 [M + H].sup.+ = (1-ethyl-3-methyl-1H-pyrazole- H), 7.78 (dd, 750.7 5-carboxamido)-1H- J = 8.4, 1.4 Hz, 1 benzo[d]imidazole-5- H), 7.62 (d, carboxamide, tris trifluoroacetic J = 7.8 Hz, 1 H), acid salt   [00367] 7.55 (d, J = 8.5 Hz, 1 H), 7.35 (br. s., 1 H), 7.21- 7.33 (m, 2 H), 6.62 (s, 2 H), 4.52-4.63 (m, 6 H), 4.28 (m, 4 H), 3.23 (s, 3 H), 2.70 (d, J = 4.0 Hz, 6 H), 2.11 (d, J = 1.5 Hz, 6 H), 1.87 (br. s., 4 H), 1.28 (dt, J = 14.1, 7.0 Hz, 6 H) Example 1-(4-(4-(2- Method .sup.1H NMR (400 LCMS 133 (Dimethylamino)acetamido)-2- 11 MHz, DMSO-d.sub.6) δ Method (1-ethyl-3-methyl-1H-pyrazole- ppm 12.82 (br. s, D: Rt = 5-carboxamido)-1H- 1H), 12.7 (br. s, 0.80 min, benzo[d]imidazol-1-yl)butyl)-2- 1H), 10.91 (s, 1 [M + 2H].sup.+/ (1-ethyl-3-methyl-1H-pyrazole- H), 9.94 (br. s., 1 2 = 369.0 5-carboxamido)-1H- H), 7.97 (s, 2 H), benzo[d]imidazole-5- 7.76 (d, J = 8.3 carboxamide, tris trifluoroacetic Hz, 1 H), 7.72 (d, acid salt   [00368] J = 8.0 Hz, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.18-7.28 (m, 1 H), 6.60 (s, 1 H), 6.59 (s, 1 H), 4.55 (q, J = 6.8 Hz, 4 H), 4.27 (br. s., 6 H), 2.92 (s, 6 H), 2.10 (s, 6 H), 1.87 (br. s., 4 H), 1.29 (t, J = 7.0 Hz, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 134 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (br. D: Rt = pyrazole-5-carboxamido)-4-(2- s., 1 H), 12.52 0.86 min, hydroxyacetamido)-1H- (br. s., 1 H), [M + 2H].sup.+/ benzo[d]imidazol-1-yl)butyl)- 10.32 (br. s., 1 2 = 355.4 1H-benzo[d]imidazole-5- H), 7.99 (s, 1 H), carboxamide, bis trifluoroacetic 7.97 (br. s., 1 H), acid salt   [00369] 7.76 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.34 (br. s., 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.16- 7.23 (m, 1 H), 6.61 (s, 2 H), 4.50-4.62 (m, 4 H), 4.27 (br. s., 4 H), 4.14 (s, 2H), 2.68 (br. s., 1 H), 2.11 (s, 6 H), 1.87 (br. s., 4 H), 1.30 (q, J = 7.0 Hz, 6H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 135 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (br. D: Rt = pyrazole-5-carboxamido)-4-(N- s., 1 H), 8.61 (br. 0.79 min, methyl-2- s., 1 H), 7.91- [M + 2H].sup.+/ (methylamino)acetamido)-1H- 8.04 (m, 2 H), 2 = 369.0 benzo[d]imidazol-1-yl)butyl)- 7.77 (d, J = 8.5 1H-benzo[d]imidazole-5- Hz, 1 H), 7.63 carboxamide, tris trifluoroacetic (br. s., 1 H), 7.44- acid salt   [00370] 7.59 (m, 2 H), 7.19-7.40 (m, 3 H), 6.55-6.64 (m, 2 H), 4.48- 4.63 (m, 4 H), 4.26 (br. s., 6 H), 3.33 (s, 1 H), 3.24 (s, 2 H), 2.63-2.71 (m, 1 H), 2.44 (t, J = 5.1 Hz, 2 H), 2.05- 2.19 (m, 6 H), 1.76-1.95 (m, 4 H), 1.28 (q, J = 6.7 Hz, 6 H) Example 1-(4-(4-(Aminomethyl)-2-(1- Method .sup.1H NMR (400 LCMS 136 ethyl-3-methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method carboxamido)-1H- ppm 12.82 (br. D: Rt = benzo[d]imidazol-1-yl)butyl)-2- s., 1 H), 12.53 0.76 min, (1-ethyl-3-methyl-1H-pyrazole- (br. s., 1 H), 8.05 [M + 2H].sup.+/ 5-carboxamido)-1H- (br. s., 3 H), 7.97 2 = 333.4 benzo[d]imidazole-5- (s, 2 H), 7.76 (d, carboxamide, tris trifluoroacetic J = 8.3 Hz, 1 H), acid salt   [00371] 7.55 (t, J = 8.5 Hz, 2 H), 7.25-7.39 (m, 3 H), 6.61 (s, 2 H), 4.56 (d, J = 7.0 Hz, 4 H), 4.38 (m, 2 H), 4.27 (br. s., 4 H), 2.10 (s, 6H), 1.84 (br. s., 4 H), 1.21-1.36 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 137 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.80 (br. D: Rt = pyrazole-5-carboxamido)-4-(2- s., 1 H), 12.54 0.79 min, (methylamino)acetamido)-1H- (br. s., 1 H), [M + 2H].sup.+/ benzo[d]imidazol-1-yl)butyl)- 10.86 (br. s., 1 2 = 362.0 1H-benzo[d]imidazole-5- H), 8.88 (br. s., 2 carboxamide, tris trifluoroacetic H), 7.97 (s, 2 H), acid salt   [00372] 7.76 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.19-7.27 (m, 1 H), 6.59 (s, 2 H), 4.55 (q, J = 7.0 Hz, 4 H), 4.26 (m, 4 H), 4.08 (t, J = 5.5 Hz, 2 H), 2.63-2.72 (m, 3 H), 2.10 (s, 6 H), 1.87 (br. s., 4 H), 1.29 (t, J = 7.0 Hz, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 138 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.83 (br. D: Rt = pyrazole-5-carboxamido)-4-(2- s., 2 H), 7.99 (d, 0.86 min, hydroxy-N-methylacetamido)- J = 1.3 Hz, 1 H), [M + 2H].sup.+/ 1H-benzo[d]imidazol-1- 7.96 (br. s., 1 H), 2 = 362.4 yl)butyl)-1H-benzo[d]imidazole- 7.76 (dd, J = 8.3, 5-carboxamide, bis 1.5 Hz, 1 H), trifluoroacetic acid salt   [00373] 7.54 (br. s., 2 H), 7.33 (br. s., 1 H), 7.26 (t, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 6.61 (br. s., 2 H), 4.45-4.63 (m, 4 H), 4.25 (br. s., 4 H), 3.44-3.86 (br. s., 2 H), 3.29 (br. s., 1 H), 3.18 (br. s., 3 H), 2.11 (br. s., 3 H), 2.10 (br. s., 3 H), 1.86 (br. s., 4 H), 1.21- 1.35 (m, 6 H) Example 1-(4-(4-(2-Aminoacetamido)-2- Method .sup.1H NMR (400 LCMS 139 (1-ethyl-3-methyl-1H-pyrazole- 11 MHz, DMSO-d.sub.6) δ Method 5-carboxamido)-1H- ppm 12.82 (br. s, D: Rt = benzo[d]imidazol-1-yl)butyl)-2- 1H), 12.6 (br. s, 0.79 min, (1-ethyl-3-methyl-1H-pyrazole- 1H), 10.81 (s, 1 [M + H].sup.+ = 5-carboxamido)-1H- H), 8.20 (br. s., 3 708.6 benzo[d]imidazole-5- H), 7.97 (d, carboxamide   [00374] J = 1.3 Hz, 2 H), 7.76 (dd, J = 8.5, 1.5 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.19- 7.28 (m, 1 H), 6.59 (s, 2 H), 4.55 (q, J = 7.0 Hz, 4 H), 4.26 (d, J = 6.3 Hz, 4 H), 3.85-4.02 (m, 2 H), 2.10 (s, 6 H), 1.87 (br. s., 4 H), 1.29 (t, J = 7.2 Hz, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 140 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method E: (2-(1-ethyl-3-methyl-1H- ppm 12.7 (br. s, Rt = 0.73 pyrazole-5-carboxamido)-4-(5- 1H), 12.4 (br. s, min, oxoimidazolidin-1-yl)-1H- 1H), 7.96 (s, 2 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- H), 7.74 (dd, 720.9 1H-benzo[d]imidazole-5- J = 8.4, 1.3 Hz, 1 carboxamide   [00375] H), 7.51 (d, J = 8.6 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.35 (br. s., 1 H), 7.23 (t, J = 8.1 Hz, 1 H), 6.98 (d, J = 7.8 Hz, 1 H), 6.61 (s, 1 H), 6.59 (s, 1 H), 4.86 (br. s., 2 H), 4.46-4.64 (m, 4 H), 4.26 (br. s., 4 H), 3.73 (br. s., 1 H), 3.55 (br. s., 2 H), 2.10 (s, 6 H), 1.87 (br. s., 4 H), 1.21-1.38 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 141 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.81 (br. D: Rt = pyrazole-5-carboxamido)-4-(3- s., 1 H), 12.24 0.82 min, methyl-5-oxoimidazolidin-1-yl)- (br. s., 1 H), 7.97 [M + H].sup.+ = 1H-benzo[d]imidazol-1- (s, 2 H), 7.75 734.6 yl)butyl)-1H-benzo[d]imidazole- (dd, J = 8.4, 1.3 5-carboxamide   [00376] Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.34 (br. s., 1 H), 7.25 (t, J = 8.1 Hz, 1 H), 7.00 (d, J = 7.8 Hz, 1 H), 6.61 (s, 1 H), 6.59 (br. s., 1 H), 4.66 (br. s., 2 H), 4.48-4.61 (m, 4 H), 4.27 (br. s., 4 H), 3.51 (br. s., 2 H), 2.46 (s, 3 H), 2.10 (s, 6 H), 1.80-1.93 (m, 4 H), 1.22-1.36 (m, 6 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 142 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.82 (br. E: Rt = pyrazole-5-carboxamido)-4-(3- s., 1 H), 12.53 (s, 0.99 min, methylbutanamido)-1H- 1 H), 10.36 (s, 1 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- H), 7.91-8.01 736.1 1H-benzo[d]imidazole-5- (m, 2 H), 7.76 carboxamide   [00377] (dd, J = 8.4, 1.3 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.34 (br. s., 1 H), 7.22- 7.30 (m, 1 H), 7.12-7.21 (m, 1 H), 6.59 (s, 1 H), 6.58 (s, 1 H), 4.56 (q, J = 7.0 Hz, 4 H), 4.18- 4.32 (m, 4 H), 2.33 (d, J = 7.1 Hz, 2 H), 2.15 (m, 1 H), 2.09 (s, 6 H), 1.86 (br. s., 4 H), 1.29 (td, J = 7.0, 4.6 Hz, 6 H), 0.98 (d, J = 6.6 Hz, 6 H) Example 8-Ethyl-10,18-dimethyl-7,20- Method .sup.1H NMR (400 LCMS 143 dioxo-23-(5-oxoimidazolidin-1- 13. MHz, DMSO-d.sub.6) δ Method yl)- ppm 8.02 (s, 1 C: Rt = 6,7,8,11,12,13,14,15,20,21,28, H), 7.98 (br. s., 1 0.83 min, 29,30,31- H), 7.82 (d, [M + H].sup.+ = tetradecahydrobenzo[4,5]- J = 8.5 Hz, 1 H), 760.4 imidazo[1,2- 7.60 (d, J = 7.8 a]benzo[4,5]imidazo-[2,1- Hz, 1 H), 7.52 (d, p]dipyrazolo[5,1-e:4′,3′- J = 8.0 Hz, 1 H), l][1,3,6,15,17]pentaaza- 7.28-7.40 (m, 2 cyclohenicosine-3-carboxamide   [00378] H), 7.06 (br. s., 1 H), 6.55 (br. s., 1 H), 4.87 (br. s., 2 H), 4.74 (br. s., 2 H), 4.47 (q, J = 7.3 Hz, 2 H), 4.24 (br. s., 4 H), 3.55 (br. s., 2 H), 2.82 (br. s., 2 H), 2.16 (s, 3H), 2.09 (s, 3 H), 1.92 (br. s., 4 H), 1.81 (br. s., 2 H), 1.49 (br. s., 2 H), 1.38 (br. s., 2 H), 1.30 (t, J = 6.9 Hz, 3 H) Example 2-(1-Ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 144 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 12.81 (br. C: Rt = pyrazole-5-carboxamido)-4-(2- s., 1 H), 11.98 0.79 min, (methylamino)ethoxy)-1H- (br. s., 1 H), 8.90 [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- (br. s., 2 H), 7.97 709.4 1H-benzo[d]imidazole-6- (s, 2 H), 7.76 carboxamide   [00379] (dd, J = 8.3, 1.5 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.35 (br. s., 1 H), 7.14-7.22 (m, 2 H), 6.91 (dd, J = 6.1, 2.9 Hz, 1 H), 6.59 (s, 2 H), 4.55 (q, J = 6.7 Hz, 4 H), 4.37 (t, J = 4.4 Hz, 2 H), 4.25 (d, J = 7.6 Hz, 4 H), 3.39 (s, 3 H), 2.71 (t, J = 5.1 Hz, 3 H), 2.10 (s, 6H), 1.85 (br. s., 4 H), 1.28 (td, J = 7.1, 5.1 Hz, 6 H) Example 8-ethyl-10,18-dimethyl-4- Method .sup.1H NMR (400 LCMS 145 (methylamino)-7,20-dioxo- 13 MHz, DMSO-d.sub.6) δ Method 6,7,8,11,12,13,14,15,20,21,28, ppm 12.92 (br. D: Rt = 29,30,31- s., 1 H) 12.45 (s, 1.01 01 tetradecahydrobenzo[4,5]imidazo 1 H) 8.02 (br. s., min, [1,2-a]benzo-[4,5]imidazo[2,1- 2 H) 7.84 (d, [M + H].sup.+ = p]dipyrazolo[5,l-e:4′,3′- J = 8.56 Hz, 1 H) 705.4 l][1,3,6,15,17] 7.66 (d, J = 8.31 pentaazacyclohenicosine-24-carboxamide   [00380] Hz, 1 H) 7.39 (br. s., 1 H) 7.12 (t, J = 8.07 Hz, 1 H) 6.72-6.86 (m, 2 H) 6.58 (s, 1 H) 6.39 (d, J = 8.07 Hz, 1 H) 4.75 (br. s., 2 H) 4.48 (q, J = 7.01 Hz, 2 H) 4.27 (br. s., 2 H) 4.16 (br. s., 2 H) 2.82 (d, J = 4.65 Hz, 4 H) 2.74- 2.79 (m, 1 H) 2.16 (s, 3H) 2.08 (s, 3 H) 1.89 (br. s., 4 H) 1.80 (br. s., 2 H) 1.48 (br. s., 2 H) 1.37 (br. s., 2 H) 1.30 (t, J = 6.97 Hz, 3 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 146 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method C: (2-(1-ethyl-3-methyl-1H- ppm 1.29 (m, 6 Rt = 0.98 pyrazole-5-carboxamido)-4- H) 1.85 (br. s., 4 min, methyl-1H-benzo[d]imidazol-1- H) 2.07-2.19 [M + H].sup.+ = yl)butyl)-1H-benzo[d]imidazole- (m, 6 H) 4.25 (d, 650.5 5-carboxamide, 2Trifluoroacetic J = 7.83 Hz, 4 H) acid salt   [00381] 4.55 (quin, J = 6.69 Hz, 4 H) 6.59 (s, 2 H) 7.01-7.19 (m, 2 H) 7.30-7.41 (m, 2 H) 7.53 (d, J = 8.34 Hz, 1 H) 7.75 (dd, J = 8.46, 1.39 Hz, 1 H) 7.92-8.05 (m, 2 H) 12.83 (br. s., 2 H) Example methyl 2-((1-(4-(5-carbamoyl-2- Method .sup.1H NMR (400 LCMS 147 (1-ethyl-3-methyl-1H-pyrazole- 11 MHz, DMSO-d.sub.6) δ Method 5-carboxamido)-1H- ppm 1.22-1.34 D: Rt = benzo[d]imidazol-1-yl)butyl)-2- (m, 6 H) 1.85 1.03 min, (1-ethyl-3-methyl-1H-pyrazole- (br. s., 4 H) 2.11 [M + H].sup.+ = 5-carboxamido)-1H- (d, J = 1.00 Hz, 6 666.5 benzo[d]imidazol-4- H) 3.94 (s, 3 H) yl)oxy)acetate, 2Trifluoroacetic 4.24 (d, J = 9.29 acid salt   [00382] Hz, 4 H) 4.45- 4.60 (m, 4 H) 6.56-6.64 (m, 2 H) 6.90 (d, J = 7.78 Hz, 1 H) 7.12-7.23 (m, 2 H) 7.33 (br. s., 1 H) 7.51 (d, J = 8.53 Hz, 1 H) 7.75 (dd, J = 8.53, 1.51 Hz, 1 H) 7.97 (d, J = 1.51 Hz, 2 H) 12.80 (br. s., 2 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 148 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 1.29 (m, 6 D: Rt = pyrazole-5-carboxamido)-4- H) 1.86 (br. s., 4 0.97 min, methoxy-1H-benzo[d]imidazol- H) 2.11 (s, 6 H) [M + H].sup.+ = 1-yl)butyl)-1H- 3.71 (s, 3 H) 724.5 benzo[d]imidazole-5- 4.25 (br. s., 4 H) carboxamide, 2Trifluoroacetic 4.56 (q, J = 7.01 acid salt   [00383] Hz, 4 H) 6.58- 6.65 (m, 2 H) 5.00 (s, 2 H) 6.88 (br. s., 1 H) 7.12-7.22 (m, 2 H) 7.30 (br. s., 1 H) 7.51 (d, J = 8.31 Hz, 1 H) 7.75 (dd, J = 8.44, 1.59 Hz, 1 H) 7.90-8.00 (m, 2 H) 12.79 (br. s., 2 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 149 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 1.20-1.39 D: Rt = pyrazole-5-carboxamido)-4-(2- (m, 6 H) 1.85 0.90 min, hydroxyethoxy)-l (br. s., 4 H) 2.10 [M + H].sup.+ = H-benzo[d]imidazol-1-yl)butyl)- (d, J = 1.96 Hz, 6 696.4 1H-benzo[d]imidazole-5- H) 3.74-3.82 carboxamide, 2Trifluoroacetic (m, 3 H) 4.13 (t, acid salt   [00384] J = 4.52 Hz, 2 H) 4.20-4.31 (m, 4 H) 4.48-4.61 (m, 4 H) 6.60 (s, 2 H) 6.87 (d, J = 7.58 Hz, 1 H) 7.10-7.20 (m, 2 H) 7.34 (br. s., 1 H) 7.53 (d, J = 8.31 Hz, 1 H) 7.75 (dd, J = 8.56, 1.47 Hz, 1 H) 7.97 (d, J = 1.47 Hz, 2 H) 12.11 (br. s., 1 H) 12.83 (br. s., 2 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 150 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 1.24-1.35 D: Rt = pyrazole-5-carboxamido)-4- (m, 6 H) 1.87 0.89 min, (hydroxymethyl)-1H- (br. s., 4 H) 2.00- [M + H].sup.+ = benzo[d]imidazol-1-yl)butyl)- 2.14 (m, 6H) 666.5 1H-benzo[d]imidazole-5- 4.27 (d, J = 4.65 carboxamide, 2Trifluoroacetic Hz, 4 H) 4.56 acid salt   [00385] (quin, J = 7.21 Hz, 4 H) 4.83 (s, 2 H) 6.60 (d, J = 8.56 Hz, 2 H) 7.06- 7.12 (m, 1 H) 7.14-7.23 (m, 1 H) 7.31 (br. s., 1 H) 7.41 (d, J = 7.83 Hz, 1 H) 7.53 (d, J = 8.31 Hz, 1 H) 7.75 (dd, J = 8.56, 1.47 Hz, 1 H) 7.89- 8.01 (m, 2 H) 12.17 (br. s., 1 H) 12.80 (br. s., 2 H) Example l-(4-(4-(2-(dimethylamino)-2- Method .sup.1H NMR (400 LCMS 151 oxoethoxy)-2-(1-ethyl-3-methyl- 16 MHz, DMSO-d.sub.6) δ Method E: 1H-pyrazole-5-carboxamido)- ppm 1.18-1.38 Rt = 0.88 1H-benzo[d]imidazol-1- (m, 6 H)) 1.80- min, yl)butyl)-2-(1-ethyl-3-methyl- 1.94 (m, 4 H) [M + H].sup.+ = 1H-pyrazole-5-carboxamido)- 2.11 (s, 6 H) 737.5 1H-benzo[d]imidazole-5- 2.85 (s, 3 H) carboxamide   [00386] 3.00 (s, 3 H) 4.26 (d, J = 10.27 Hz, 4 H) 4.49- 4.64 (m, 4 H) 5.02 (s, 2 H) 6.60 (d, J = 9.29 Hz, 2 H) 6.81- 6.92 (m, 1 H) 7.10-7.20 (m, 2 H) 7.30 (br. s., 1 H) 7.52 (d, J = 8.31 Hz, 1 H) 7.75 (dd, J = 8.44, 1.35 Hz, 1 H) 7.87-8.03 (m, 2 H) 12.09 (br. s., 1 H) 12.80 (s, 1 H) Example 1-(4-(4-(2-amino-2-oxoethoxy)- Method .sup.1H NMR (400 LCMS 152 2-(1-ethyl-3-methyl-1H- 16 MHz, DMSO-d.sub.6) d Method pyrazole-5-carboxamido)-1H- ppm 1.26-1.33 D: Rt = benzo[d]imidazol-1-yl)butyl)-2- (m, 6 H) 1.86 0.86 min, (1-ethyl-3-methyl-1H-pyrazole- (br. s., 4 H) 2.07- [M + H].sup.+ = 5-carboxamido)-1H- 2.14 (m, 6H) 709.4 benzo[d]imidazole-5- 4.25 (d, J9.54 carboxamide, 2Trifluoroacetic Hz, 6 H) 4.51- acid salt   [00387] 4.60 (m, 4 H) 6.59 (d, J = 7.09 Hz, 1 H) 6.86 (dd, J = 5.62, 3.42 Hz, 1 H) 7.13- 7.16 (m, 2 H) 7.30 (br. s., 1 H) 7.50-7.59 (m, 2 H) 7.76 (dd, J = 8.31, 1.47 Hz, 1 H) 7.89-8.01 (m, 2 H) 8.44 (br. s., 1 H) 12.77 (br. s., 2 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 153 pyrazole-5-carboxamido)-1-(4- 16 MHz, DMSO-d.sub.6) δ Method (2-(1-ethyl-3-methyl-1H- ppm 1.25-1.35 D: Rt = pyrazole-5-carboxamido)-4-(2- (m, 6 H) 1.86 0.89 min, (methylamino)-2-oxoethoxy)- (br. s., 4 H) 2.04- [M + H].sup.+ = 1H-benzo[d]imidazol-1- 2.18 (m, 6H) 723.5 yl)butyl)-1H-benzo[d]imidazole- 2.75 (d, J = 4.40 5-carboxamide   [00388] Hz, 3 H) 4.25 (br. s., 4 H) 4.52- 4.63 (m, 7 H) 6.54-6.63 (m, 2 H) 6.84-6.90 (m, 1 H) 7.16 (d, J = 4.65 Hz, 2 H) 7.31 (br. s., 1 H) 7.53 (d, J = 8.31 Hz, 1 H) 7.76 (d, J = 8.31 Hz, 1 H) 7.90-8.01 (m, 2 H) 8.64 (d, J = 4.40 Hz, 1 H) 12.31 (br. s., 1 H) 12.80 (br. s., 1H) Example 1-(4-(5-carbamoyl-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 154 methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 9.66 (br. s., Rt = 0.75 benzo[d]imidazol-1-yl)butyl)-2- 1 H) 8.70-8.77 min, (1-ethyl-3-methyl-1H-pyrazole- (m, 1 H) 7.98 (s, [M + H].sup.+ = 5-carboxamido)-N-(2- 3 H) 7.68-7.81 792.7 morpholinoethyl)-1H- (m, 2 H) 7.57 benzo[d]imidazole-5- (dd, J = 19.20, carboxamide, 3Trifluoroacetic 8.34 Hz, 2 H) acid salt   [00389] 7.38 (br. s., 1 H) 6.61 (d, J = 9.60 Hz, 2 H) 4.51- 4.66 (m, 4 H) 4.29 (br. s., 4 H) 4.03 (d, J = 11.87 Hz, 2 H) 3.54- 3.75 (m, 6 H) 3.35 (br. s., 2 H) 3.16 (d, J = 9.60 Hz, 2 H) 2.07- 2.13 (m, 1 H) 2.11 (s, 6 H) 1.88 (br. s., 4 H) 1.31 (m, J = 7.07 Hz, 6 H). Example 1-(4-(5-carbamoyl-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 155 methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 12.73- Rt = 0.86 benzo[d]imidazol-1-yl)butyl)-2- 12.87 (m, 2 H) min, (1-ethyl-3-methyl-1H-pyrazole- 7.97 (s, 1 H) [M + H].sup.+ = 5-carboxamido)-N,N-dimethyl- 7.75 (d, J = 8.34 707.7 1H-benzo[d]imidazole-5- Hz, 1 H) 7.48- carboxamide   [00390] 7.58 (m, 3 H) 7.34 (br. s., 1 H) 7.24 (dd, J = 8.34, 1.26 Hz, 1 H) 6.60 (d, J = 9.60 Hz, 2 H) 4.56 (d, J = 7.07 Hz, 4 H) 4.27 (d, J = 6.32 Hz, 4 H) 2.95 (br. s., J = 15.66 Hz, 6 H) 2.09 (d, J =1.77 Hz, 6 H) 1.87 (br. s., 4 H) 1.30 (m, J7.07 Hz, 6 H) 1.23 (s, 1H) Example 1-(4-(5-carbamoyl-2-(1-ethyl-3- Method .sup.1H NMR (400 LCMS 156 methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 12.84 (br. Rt = 0.80 benzo[d]imidazol-1-yl)butyl)-2- s., 2 H) 8.41 (d, min, (1-ethyl-3-methyl-1H-pyrazole- J = 4.55 Hz, 1 H) [M + H].sup.+ = 5-carboxamido)-N-methyl-1H- 7.95 (d, J = 14.15 693.6 benzo[d]imidazole-5- Hz, 3 H) 7.75 (d, carboxamide, 2Trifluoroacetic J = 8.34 Hz, 1 H) acid salt   [00391] 7.69 (d, J = 8.34 Hz, 1 H) 7.54 (dd, J = 8.46, 2.65 Hz, 2 H) 7.34 (br. s., 1 H) 6.59 (s, 2 H) 4.56 (q, J = 6.99 Hz, 4 H) 4.27 (br. s., 4 H) 2.79 (d, J = 4.29 Hz, 3 H) 2.09 (s, 6 H) 1.86 (br. s., 4 H) 1.29 (t, J = 6.95 Hz, 6 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 157 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method A: (2-(1-ethyl-3-methyl-1H- 12.78 (br s, 2H), Rt = pyrazole-5-carboxamido)-7- 8.02-7.92 (m, 1.518 isopropoxy-1Hbenzo[d]imidazol- 2H), 7.75 (dd, J = min, 1-yl)butyl)-1H- 8.4, 1.3 Hz, [M + H].sup.+ = benzo[d]imidazole-5- 1H), 7.53 (d, 7 = 694.5 carboxamide   [00392] 8.4 Hz, 1H), 7.32 (br s, 1H), 7.14- 7.03 (m, 2H), 6.85-6.75 (m, 1H), 6.59 (s, 2H), 4.74-4.63 (m, 1H), 4.62-4.51 (m, 4H), 4.43- 4.22 (m, 4H), 2.11 (s, 3H), 2.10 (s, 3H), 1.97- 1.69 (m, 4H), 1.35-1.23 (m, 6H), 1.15 (d, J = 6.0 Hz, 6H) Example 23-(2-(dimethylamino)-N- Method .sup.1H NMR LCMS 158 methylacetamido)-8-ethyl- 13 (METHANOL-d.sub.4) Method A: 10,18-dimethyl-7,20-dioxo- δ 8.35 (s, 1H), Rt = 0.82 6,7,8,11,12,13,14,15,20,21,28, 7.99 (s, 2H), 7.88 min, 29,30,31- (s, 1H), 7.72 (d, [M + H].sup.+ = tetradecahydrobenzo[4,5]imidazo 1H), 7.46 (br. s., 790.6 [1,2-a]benzo[4,5]imidazo[2,1- 2H), 7.35 (d, p]dipyrazolo[5,1-e:4′,3′- 1H), 6.75 (s, 1H), l][1,3,6,15,17]- 4.47-4.62 (m, pentaazacyclohenicosine-3- 3H), 4.35 (br. s., carboxamide, Trifluoroacetic 6H), 3.71 (br. s., acid salt   [00393] 2H), 3.43 (s, 2H), 3.12 (s, 1H), 2.79-2.92 (m, 6H), 2.29 (d, J = 6.3 Hz, 2H), 2.20 (br. s., 4H), 2.05 (br. s., 4H), 1.90 (br. s., 6H), 1.62 (br. s., 2H), 1.32-1.45 (m, 6H) Example 23-(2-amino-N- Method .sup.1H NMR (DMSO- LCMS 159 methylacetamido)-8-ethyl- 13 d.sub.6) δ 7.95-8.07 Method A: 10,18-dimethyl-7,20-dioxo- (m, 2H), 7.88- Rt = 0.81 6,7,8,11,12,13,14,15,20,21,28, 7.15 (m, 5H), min, 29,30,31- 6.75 (br s, 1H), [M + H].sup.+ = tetradecahydrobenzo[4,5]imidazo 4.69 (br. s, 2H), 762.7 [1,2-a]benzo[4,5]imidazo[2,1- 4.35 (br. s, 6H), p]dipyrazolo[5,1-e:4′,3′- 4.49 (d, J = 7.1 l][1,3,6,15,17]- Hz, 2H), 4.22 (br. pentaazacyclohenicosine-3- s, 6H), 3.34 (s, carboxamide   [00394] 3H), 2.75-2.89 (m, 2H), 2.21 (s, 2H), 2.17 (s, 2H), 1.91 (br. s, 3H), 1.72-1.85 (m, 3H), 1.50 (br. s, 2H), 1.24-1.41 (m, 6H) Example 8-ethyl-10,18-dimethyl-23-(N- Method .sup.1H NMR LCMS 160 methyl-2- 13 (METHANOL-d.sub.4) Method A: (methylamino)acetamido)-7,20- δ 7.99 (s, 2H), Rt = 0.80 dioxo- 7.88 (s, 1H), 7.72 min, 6,7,8,11,12,13,14,15,20,21,28, (d, 1H), 7.46 (br. [M + H].sup.+ = 29,30,31- s., 2H), 7.35 (d, 776.6 tetradecahydrobenzo[4,5]imidazo 1H), 6.75 (s, 1H), [1,2-a]benzo[4,5]imidazo[2,1- 4.47-4.62 (m, p]dipyrazolo[5,1-e:4′,3′- 3H), 4.35 (br. s., l][1,3,6,15,17]- 6H), 3.71 (br. s., pentaazacyclohenicosine-3- 2H), 3.43 (s, 2H), carboxamide Trifluoroacetic acid 3.12 (s, 1H), salt   [00395] 2.79-2.92 (m, 3H), 2.29 (d, J = 6.3 Hz, 2H), 2.20 (br. s., 4H), 2.05 (br. s., 6H), 1.90 (br. s., 6H), 1.62 (br. s., 2H), 1.32-1.45 (m, 6H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method 9 .sup.1H NMR (400 LCMS 161 ethyl-3-methyl-1H-pyrazole-5- MHz, DMSO-d.sub.6) δ Method A: carboxamido)-1H- 12.90 (br s, 2H), Rt = 1.29 benzo[d]imidazol-1-yl)but-2-en- 8.12-7.80 (m, min, 1-yl)-7-(cyanomethyl)-2-(1- 4H), 7.73 (d, J = [M + H].sup.+ = ethyl-3-methyl-1H-pyrazole-5- 6.5 Hz, 2H), 7.48- 716.4 carboxamido)-1H- 7.30 (m, 3H), benzo[d]imidazole-5- 6.55 (s, 2H), 6.01- carboxamide   [00396] 5.94 (m, 1H), 5.62-5.54 (m, 1H), 5.01 (s, 2H), 4.82 (s, 2H), 4.56- 4.46 (m, 4H), 4.34 (s, 2H), 2.11 (s, 3H), 2.08 (s, 3H), 1.29-1.23 (m, 6H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method 9 .sup.1HNMR (400 LCMS 162 ethyl-3-methyl-1H-pyrazole-5- MHz, DMSO-d.sub.6) δ Method A: carboxamido)-1H- 12.92 (br s, 2H), Rt = benzo[d]imidazol-1-yl)but-2-en- 8.02-7.91 (m, 1.234 1-yl)-2-(1-ethyl-3-methyl- 4H), 7.72 (d, J = min, 1Hpyrazole-5-carboxamido)-7- 10.1 Hz, 2H), [M + H].sup.+ = (hydroxymethyl)-1H- 7.71 (s, 1H) 7.43 707.9 benzo[d]imidazole-5- (d, J = 8.4 Hz, carboxamide   [00397] 1H), 7.34 (br s, 2H), 6.52 (d, J = 6.7 Hz, 2H), 5.98 (d, J = 15.5 Hz, 1H), 5.51 (dd, J = 13.2, 8.0 Hz, 1H), 5.09 (s, 2H), 4.81 (d, J = 4.2 Hz, 2H), 4.61 (s, 2H), 4.55-4.48 (m, 4H), 2.12 (s, 3H), 2.11 (s, 3H), 1.29-1.25 (m, 6H) Example (E)-2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 163 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d.sub.6) δ Method A: (2-(1-ethyl-3-methyl-1H- 12.90 (br s, 2H), Rt = pyrazole-5-carboxamido)-4- 9.81 (s, 1H), 7.97 1.308 (morpholinomethyl)-1H- (s, 2H), 7.72- min, benzo[d]imidazol-1-yl)but-2-en- 7.23 (m, 6H), [M + H].sup.+ = 1-yl)-1H-benzo[d]imidazole-5- 6.56 (d, J = 15.7 733 carboxamide   [00398] Hz, 2H), 5.93- 5.85 (m, 2H), 4.85 (br s, 4H), 4.72 (br s, 2H), 4.54-4.50 (m, 4H), 3.8 (brs, 2H), 3.5 (br s, 2H), 3.26 (br s, 4H), 2.13 (s, 6H), 1.30-1.22 (m, 6H) Example 2-(1-ethyl-3-methyl-1Hpyrazole- Method .sup.1H NMR (400 LCMS 164 5-carboxamido)-1-(4-(2-(1- 11 MHz, DMSO-d.sub.6) δ Method A: ethyl-3-methyl-1H-pyrazole-5- ppm 12.84 (s, 2), Rt = carboxamido)-7- 10.03 (s, 1), 7.97 1.329 (morpholinomethyl)- (t, J = 4.4 Hz, 2), min, 1Hbenzo[d]imidazol-1-yl)butyl)- 7.75 (dd, J = 8.4, [M + H].sup.+ = 1Hbenzo[d]imidazole-5- 1.3 Hz, 1), 7.66 735.3 carboxamide, Trifluoroacetic acid (d, J = 7.6 Hz, salt   [00399] 1), 7.51 (d, J = 8.4 Hz, 1), 7.32 (d, J = 12.3 Hz, 3), 6.60 (t, J = 11.2 Hz, 2), 4.52 (dd, J = 18.6, 13.6 Hz, 8H), 4.25 (d, J = 6.2 Hz, 2H), 3.89 (s, 2), 3.61 (s, 2H, 3.25 (s, 4H, 2.08 (d, J = 15.6 Hz, 6H), 1.81 (d, J = 22.1 Hz, 4H), 1.30 (t, J = 7.0 Hz, 6H) Example 2-(1-ethyl-3-methyl-1Hpyrazole- Method .sup.1H NMR (400 LCMS 165 5-carboxamido)-1-(4-(2-(1- 11 MHz, DMSO-d.sub.6) δ Method A: ethyl-3-methyl-1Hpyrazole-5- ppm 12.77 (s, Rt = carboxamido)-7-methyl-1H- 2H), 7.97 (t, J = 1.470 benzo[d]imidazol-1-yl)butyl)- 4.1 Hz, 2H), 7.76 min, 1Hbenzo[d]imidazole-5- (dd, J = 8.4, 1.4 [M + H].sup.+ = carboxamide   [00400] Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.37 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 21.8 Hz, 2H), 4.56 (dq, J = 14.2,7.0 Hz, 4H), 4.39 (t, J = 6.8 Hz, 2H), 4.28 (d, J = 6.9 Hz, 2H), 2.61 (d, J = 8.6 Hz, 3H), 2.09 (d, J = 14.8 Hz, 6H), 1.88 (dd, J = 29.7, 5.6 Hz, 4H), 1.29 (dt, J = 9.8, 7.1 Hz, 6H) 650.3 Example (E)-2-(1-ethyl-3-methyl- Method .sup.1H NMR (400 LCMS 166 1Hpyrazole-5-carboxamido)-1- 11 MHz, DMSO-d.sub.6) Method A: (4-(2-(1-ethyl-3-methyl- δ ppm 7.97 (m, 2 Rt = 1Hpyrazole-5-carboxamido)-4- H), 7.72 (d, 1.496 methoxy-1Hbenzo[d]imidazol-1- J = 8.3 Hz, 1 H), min, yl)but-2-en-1-yl)- 7.43 (d, J = 8.3 [M + H].sup.+ = 1Hbenzo[d]imidazole-5- Hz, 1 H), 7.35 (s, 664.2 carboxamide   [00401] 1 H), 7.14 (t, J = 8.1 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.89 (s, 1 H), 6.58 (m, 2 H), 5.90 ( s, 2 H), 4.82 (m, 4H), 4.52 (m, 4 H), 3.94 (s, 3 H), 2.14 (s, 6 H), 1.30-1.24 (m, 6 H) Example (E)-2-(1-ethyl-3-methyl- Method .sup.1HNMR (400 LCMS 167 1Hpyrazole-5-carboxamido)-1- 11 MHz, DMSO-d6) Method A: (4-(2-(1-ethyl-3-methyl- δ ppm 12.76 (br. Rt =1.447 1Hpyrazole-5-carboxamido)-1H- m., 2 H), 7.96 min, benzo[d]imidazol-1-yl)but-2-en- (m, 2 H), 7.71 (d, [M + H].sup.+ = 1-yl)-1Hbenzo[d]imidazole-5- J = 8.5 Hz, 1 H), 634.2 carboxamide   [00402] 7.50 (s, 1 H), 7.43 (d, J = 8.4 Hz, 1H), 7.38 (s, 1 H), 7.33 (s, 1 H), 7.16 (m, 2H), 6.55 (d, J = 7.4 Hz, 2 H), 5.91 (s, 2 H), 4.83 (s, 4 H), 4.53 (q, J = 7.1 Hz, 4 H), 2.13 (s, 6H), 1.28 (m, 6 H) Example (E)-1-(4-(5-carbamoyl-2-(1- Method .sup.1H NMR (400 LCMS 168 ethyl-3-methyl-1H-pyrazole-5- 16 MHz, DMSO-d.sub.6) Method A: carboxamido)-1H- δ ppm 13.10 (br. Rt =1.255 benzo[d]imidazol-1-yl)but-2-en- s., 2 H), 8.01 (m, min, 1-yl)-2-(1-ethyl-3-methyl- 4 H), 7.75 (m, 2 [M + H].sup.+ = 1Hpyrazole-5-carboxamido)-7- H), 7.43 (m, 2 776.8 (morpholinomethyl)-1H- H), 7.36 (s, 1 H), benzo[d]imidazole-5- 6.58 (s, 2 H), carboxamide   [00403] 5.92 (d, J = 16.3 Hz, 1 H), 5.46 (d, J = 15.6 Hz, 1 H), 5.11 (s, 2 H), 4.80 (s, 2 H), 4.54 (br. s., 6 H), 2.14 (s, 6 H), 1.31-1.26 (m, 6 H) Example Structure not determined Method .sup.1H NMR (400 LCMS 169 One of two possible structures 13 MHz, MeOD-d.sub.4) Method A: 8-ethyl-10,18-dimethyl-7,20- δ ppm 8.07 (d, Rt =1.270 dioxo- J = 1.3 Hz, 1 H), min, 6,7,8,11,12,13,14,15,20,21,28, 7.89 (dd, J = 8.6, [M + H].sup.+ = 29,30,31- 1.4 Hz, 1 H), 677.3 tetradecahydrobenzo[4,5]imidazo 7.60 (d, J = 8.4 [1,2-a]benzo[4,5]imidazo[2,1- Hz, 1 H), 7.52 (d, p]dipyrazolo[5,1-e:4′,3′- J = 7.4 Hz, 1 H), l][l,3,6,9,15,17]- 7.31-7.44 (m, 3 hexaazacyclohenicosine-24- H), 6.06 (s, 1 H), carboxamide   [00404] 4.87 (br. s., 2 H), 4.26 (br. s., 2 H), 4.20 (br. s., 2 H), 4.08-4.16 (m, 2 H), 3.59 (t, J = 4.9 Hz, 2 H), 3.36- 3.42 (m, 2 H), 3.08-3.14 (m, 2 H), 2.29 (s, 3 H), 2.21 (s, 3 H), 2.04 (br. s., 4 H), 1.09 (t, J = 7.1 Hz, 3 H) 8-ethyl-10,18-dimethyl-7,20- dioxo- 6,7,8,11,12,13,14,15,20,21,28, 29,30,31- tetradecahydrobenzo[4,5]imidazo [1,2-a]benzo[4,5]imidazo[2,1- p]dipyrazolo[5,1-e:4′,3′- l][l,3,6,9,15,17]- hexaazacyclohenicosine-3- carboxamide Example Structure not determined Method .sup.1H NMR (MeOD- LCMS 170 One of two possible structures 13 d4) δ ppm 7.89- Method A: 8-ethyl-10,18-dimethyl-7,20- 7.96 (m, 2 H), Rt =1.289 dioxo- 7.52-7.61 (m, min, 6,7,8,11,12,13,14,15,20,21,28, 3H), 7.34-7.43 [M + H].sup.+ = 29,30,31- (m, 2H), 6.07 (s, 677.2 tetradecahydrobenzo[4,5]imidazo 1H), 4.85-4.94 [1,2-a]benzo[4,5]imidazo[2,1- (br. m., 2H), p]dipyrazolo[5,1-e:4′,3′- 4.19-4.26 (m, l][1,3,6,9,15,17]- 1H), 4.13 (d, hexaazacyclohenicosine-24- J = 7.3 Hz, 1H), carboxamide   [00405] 3.57 (t, J = 4.9 Hz, 2H), 3.39 (t, J = 6.3 Hz, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.05 (br. s., 4H), 1.08 (t, J = 7.1 Hz, 3H) 8-ethyl-10,18-dimethyl-7,20- dioxo- 6,7,8,11,12,13,14,15,20,21,28, 29,30,31- tetradecahydrobenzo[4,5]imidazo [1,2-a]benzo[4,5]imidazo[2,1- p]dipyrazolo[5,1-e:4,3′- l][1,3,6,9,15,17]- hexaazacyclohenicosine-3- carboxamide Example 1,1′-(2,3-difluorobutane-1,4- Method 1H NMR (DMSO- LCMS 171 diyl)bis(2-(1-ethyl-3-methyl-1H- 15 d6) δ ppm 12.95 Method A: pyrazole-5-carboxamido)-1H- (s, 2 H), 8.03 (s, Rt =1.268 benzo[d]imidazole-5- 2 H), 8.00 (br. s., min, carboxamide)   [00406] 2 H), 7.82 (d, J = 8.4 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.36 (br. s., 2 H), 6.67 (s, 2 H), 4.80- 4.92 (m, 2 H), 4.59 (q, J = 7.2 Hz, 4 H), 2.06 (s, 6 H), 1.33 (t, J = 7.1 Hz, 6 H) [M + H].sup.+ = 715.2 Example N,N′-(4-carbamoyl- Method .sup.1H NMR (400 LCMS 172 8,9,16,17,18,19- 21 MHz, DMSO-d.sub.6) δ Method hexahydro-7H-6,10-dioxa- ppm 12.62- D: Rt = 2,14,15a,19a-tetraaza- 13.07 (m, 1 H), 1.05 min, cyclopentadeca[1,2,3- 8.02 (br. s., 1 H), [M + H].sup.+ = cd:11,10,9-c′d′]diindene-1,15- 7.67 (s, 1 H), 708.9 diyl)bis(1-ethyl-3-methyl-1H 7.45 (s, 1 H), pyrazole-5-carboxamide), 7.38 (br. s., 1 H), 2Trifluoroacetic acid salt   [00407] 7.13-7.21 (m, 2 H), 6.96 (dd, J = 6.24, 3.06 Hz, 1 H), 6.59 (d, J = 10.51 Hz, 2 H), 4.54-4.67 (m, 6 H), 4.32- 4.53 (m, 10 H), 2.30-2.36 (m, 1 H), 2.14-2.25 (m, 1 H), 2.08- 2.14 (m, 6 H), 2.05 (br. s., 3 H), 1.26-1.39 (m, 6 H) Example 1-(4-(5-carbamoyl-2-(1-ethyl-3- Method 9 1H-NMR (400 LCMS 173 methyl-1H-pyrazole-5- MHz, CD.sub.3OD) δ Method A: carboxamido)-1H- ppm 7.88 (d, J = Rt = benzo[d]imidazol-1-yl)butyl)-2- 1.2 Hz, 1H), 7.77 1.362 (1-ethyl-3-methyl-1H-pyrazole- (dd, J = 8.4, 1.2 min, 5-carboxamido)-4-hydroxy-1H- Hz, 1H), 7.65 (d, [M + H].sup.+ = benzo[d]imidazole-5- J = 8.8 Hz, 1H), 695.6 carboxamide 2,2,2- 7.41 (d, J = 8.4 trifluoroacetate   [00408] Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), Hz, 2H), 4.68- 4.59 (m, 4H), 6.59 (d, J = 3.2 4.29-4.26 (m, 4H), 2.22 (s, 3H), 2.21 (s, 3H), 2.05 (s, 4H), 1.42- 1.38 (m, 6H) Example 1,1′-(Ethane-1,2-diyl)bis(2-(1- Method 1H-NMR (400 LCMS 174 ethyl-3-methyl-1H-pyrazole-5- 15 MHz, DMSO-d.sub.6) δ Method A: carboxamido)-1H- ppm 12.53 (s, Rt = 1.25 benzo[d]imidazole-5- 2H), 8.01 (s, 2H), min, carboxamide)   [00409] 7.9 (s, 2H), 7.89 (s, 2H), 7.59 (s, 2H), 7.35 (s, 2H), 7.25 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 5.34 (s, 2H), 4.43 (q, J = 6.7 Hz, 4H), 1.95 (s, 6H), 1.24 (t, J = 8.0 Hz, 6H) [M + H].sup.+ = 651.2 Example 1-(2-(N-(2-(5-Carbamoyl-2-(1- Method .sup.1H NMR (400 LCMS 175 ethyl-3-methyl-1H-pyrazole-5- 16 MHz, DMSO-d.sub.6) δ Method A: carboxamido)-1H- ppm 12.86 (s, Rt = 1.23 benzo[dimidazol-1-yl)ethyl)-2- 1H), 12.77 (s, min, hydroxyacetamido)ethyl)-2-(1- 1H), 7.98 (d, J = [M + H].sup.+ = ethyl-3-methyl-1Hpyrazole-5- 8.0 Hz, 3H), 7.76 751.9 carboxamido)-1H (d, J = 8.0 Hz, benzo[d]imidazole-5- 2H), 7.517.54- carboxamide   [00410] 7.48 (m, 2H), 7.35-7.32 (s, 2H), 6.64 (s, 1H), 6.59 (s, 1H), 4.59-4.51 (m, 4H), 4.41-4.38 (m, 4H), 3.85- 4.82 (m, 2H), 3.70-3.64 (m, 4H), 2.09-2.08 (m, 5H), 1.33- 1.30 (m, 5H) Example 1-(2-(2-Amino-N-(2-(5- Method 1H NMR (400 LCMS 176 carbamoyl-2-(1-ethyl-3-methyl- 15 MHz, DMSO-d.sub.6) δ Method A: 1H-pyrazole-5-carboxamido)- ppm 12.91 (s, Rt = 1.16 1H-benzo[d]imidazol-1- 2H), 8.03-7.99 min, yl)ethyl)acetamido)ethyl)-2-(1- (m, 6H), 7.81- [M + H].sup.+ = ethyl-3-methyl-1H-pyrazole-5- 7.78 (m, 2H), 750.7 carboxamido)-1H 7.63 (d, J = 8.0 benzo[d]imidazole-5- Hz, 1H), 7.55 (d, carboxamide   [00411] J = 8.0 Hz, 1H), 7.37 (d, J = 4.0 Hz, 2H), 6.67 (s, 1H), 6.58 (s, 1H), 4.60-4.50 (m, 6H), 4.42 (d, J = 6.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.56 (d, J = 4.0 Hz, 2H), 2.06 (d, J = 8.0 Hz, 5H), 1.34-1.30 (m, 5H) Example 8-Ethyl-10,18-dimethyl-7,20- Method 1H-NMR (400 LCMS 177 dioxo- 19 MHz, DMSO-d.sub.6) δ Method A: 6,7,8,11,12,13,14,15,20,21,28, ppm 12.74 (s, Rt = 29- 2H), 8.06-7.90 1.299 dodecahydrobenzo[4,5]imidazo (m, 4H), 7.61 (s, min, [2,1-b]benzo[4,5]imidazo[1,2- 2H), 7.34 (s, 2H), [M + H].sup.+ = f]dipyrazolo[5,1-j:4′,3′- 6.90 (s, 2H), 6.28 691.2 q][1,3,6,8,11] (s, 1H), 4.69 (s, pentaazacyclononadecine-3,24-dicarboxamide   [00412] 4H), 4.56 (s, 2H), 4.27 (s, 2H), 2.69 (d, J = 12.7 Hz, 2H), 2.11 (d, J = 22.2 Hz, 6H), 1.87 (s, 2H), 1.58 (s, 2H), 1.34 (s, 2H), 1.21 (dd, J = 15.2, 8.2 Hz, 3H) Example 3,24-dicarbamoyl-8-ethyl-10,18- Method 1H NMR (400 LCMS 178 dimethyl-7,20-dioxo- 19 MHz, CD.sub.3OD) δ Method A: 8,11,12,13,14,15,20,21,28,29, ppm 8.01-7.95 Rt = 31,32-dodecahydro-1H (m, 2H), 7.86- 1.356 benzo[4,5]imidazo[2,1- 7.80 (m, 2H), min, b]benzo[4,5]imidazo[1,2- 7.50-7.36 (m, [M + H].sup.+ = i]dipyrazolo[5,1-m:4′,3′- 2H), 6.72-6.59 834.7 t][1,3,6,9,11,14] (m, 1H), 4.76 (t, hexaazacyclodocosine-30-carboxylate   [00413] J = 6 Hz, 1H), 4.65 (t, J = 6 Hz, 1H), 4.45-4.42 (m, 4H), 4.32 (s, 1H), 3.78-3.65 (m, 4H), 2.84 (d, J = 8 Hz, 2H), 2.71 (d, J = 8 Hz, 2H), 2.27 (s, 1H), 2.72-2.20 (m, 2H), 2.16 (s, 1H), 1.88-1.78 (m, 2H), 1.52-1.43 (m, 2H), 1.37- 1.32 (m, 3H), 1.23-1.16 (m, 2H), 0.80 (s, 4H), 0.72 (s, 3H) Example 8-Ethyl-10,18-dimethyl-7,20- Method 1H NMR (400 LCMS 179 dioxo- 19 MHz, CD.sub.3OD) δ Method A: 7,8,11,12,13,14,15,20,21,28,29, 8.06-8.06 (m, Rt = 1.23 30,31,32-tetradecahydro-1H 1H), 8.01 (s, 1H), min, benzo[4,5]imidazo[2,1- 7.95-7.90 (m, [M + H].sup.+ = b]benzo[4,5]imidazo[1,2- 2H), 7.68 (d, J = 734.0 i]dipyrazolo[5,1-m:4′,3′- 8.0 Hz, 1H), 7.60 t][1,3,6,9,11,14] (d, J = 12 Hz, hexaazacyclodocosine-3,24-dicarboxamide, 1H), 6.85 (s, 1H), trifluoroacetic acid salt   [00414] 4.74-4.71 (m, 3H), 4.51 (q, J = 6.7 Hz, 2H), 4.35 (t, J = 8.0 Hz, 2H), 3.80-3.77 (m, 2H), 3.67 (t, J = 4 Hz, 2H), 2.80 (t, J = 8 Hz, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 1.90-1.83 (m, 2H), 1.46-1.39 (m, 2H), 1.33 (t, J = 8.0 Hz, 3H), 1.26-1.18 (s, 2H) Example 8-Ethyl-30-glycyl-10,18- Method 1H NMR (400 LCMS 180 dimethyl-7,20-dioxo- 19 MHz, CD.sub.3OD) δ Method A: 6,7,8,11,12,13,14,15,20,21,29, 8.01-7.98 (m, Rt = 1.21 30,31,32-tetradecahydro-28H- 2H), 7.95-7.88 min, benzo[4,5]imidazo[2,1- (m, 2H), 7.65- [M + H].sup.+ = b]benzo[4,5]imidazo[1,2- 7.50 (m, 2H), 791.6 i]dipyrazolo[5,1-m:4′,3′- 6.67-6.53 (m, t][1,3,6,9,11,14] 1H), 4.76 (t, J = 6 hexaazacyclodocosine-3,24-dicarboxamide Hz, 3H), 4.65- trifluoroacetic acid salt   [00415] 4.60 (m, 1H), 4.54-4.50 (m, 2H), 4.44-4.41 (m, 1H), 3.91- 3.88 (m, 1H), 3.80-3.72 (m, 1H), 3.45-3.45 (m, 3H), 3.40- 3.37 (m, 3H), 2.19 (t, J = 14 Hz, 3H), 2.05 (s, 1H), 1.85-1.76 (m, 2H), 1.36 (t, J = 6.0 Hz, 2H), 1.29 (t, J 6.0 Hz, 2H), 1.19- 1.12 (m, 2H) Example Structure not determined, is one Method 1H NMR (400 LCMS 181 of the following compounds: 19 MHz, DMSO-d.sub.6) δ Method A: 8-ethyl-10,18-dimethyl-7,20- ppm 8.03 (s, 3H), Rt = dioxo- 7.84 (d, J = 8.0 1.489 6,7,8,11,12,13,14,15,20,21,28, Hz, 1H), 7.66 (d, min, 29,30,31- J = 8.0 Hz, 1H), [M + H].sup.+ = tetradecahydrobenzo[4,5]imidazo 7.57-7.55 (s, 676.9 [1,2-a]benzo[4,5]imidazo[2,1- 1H), 7.37 (s, 1H), p]dipyrazolo[5,1-e:4′,3′- 7.28-7.22 (m, l][1,3,6,15,17]pentaazacyclohenicosine- 2H), 7.13 (s, 1H), 24-carboxamide   [00416] 7.00 (s, 1H), 6.58 (s, 1H), 5.84 (s, 1H), 4.75 (t, 2H), 4.47 (q, J = 8.0 Hz, 2H), 4.28- 4.22 (m, 4H), 2.82 (t, J = 8.0 Hz, 2H), 2.68- 2.66 (m, 1H), 2.34-2.33 (m, 1H), 2.16 (s, 2H), 2.09(s, 2H), 1.91 (s, 2H), 1.81 (s, 2H), 1.51-1.47 (m, 4H), 1.29 (t, J = 8.0 Hz, 2H), 1.23 (s, 2H) 8-Ethyl-10,18-dimethyl-7,20- dioxo- 6,7,8,11,12,13,14,15,20,21,28, 29,30,31- tetradecahydrobenzo[4,5]imidazo [1,2-a]benzo[4,5]imidazo[2,1- p]dipyrazolo[5,1-e:4′,3′- l][1,3,6,15,17] pentaazacyclohenicosine-3-carboxamide [00417] Example Structure not determined, is one Method 1H NMR (400 LCMS 182 of the following compounds: 19 MHz, DMSO-d.sub.6) δ Method A: 8-ethyl-10,18-dimethyl-7,20- ppm 8.03-7.99 Rt = dioxo- (m, 2H), 7.84- 1.489 6,7,8,11,12,13,14,15,20,21,28, 7.80 (m, 1H), min, 29,30,31- 7.62-7.54 (m, [M + H].sup.+ = tetradecahydrobenzo[4,5]imidazo 3H), 7.38-7.35 677.0 [1,2-a]benzo[4,5]imidazo[2,1- (m, 1H), 7.61- p]dipyrazolo[5,1-e:4′,3′- 7.54 (m, 2H), l][1,3,6,15,17] 7.10 (s, 1H), 6.97 pentaazacyclohenicosine-24-carboxamide   [00418] (s, 1H), 6.57- 6.55 (m, 1H), 4.77-4.72 (m, 2H), 4.50-4.45 (m, 2H), 4.27- 4.22 (m, 3H), 2.85-2.80 (m, 2H), 2.69-2.67 (m, 1H), 2.34- 2.32 (m, 1H), 2.17-2.13 (m, 3H), 2.10-2.07 (m, 3H), 1.93- 1.89 (m, 3H), 1.83-1.79 (m, 2H), 1.51-1.46 (m, 2H), 1.40- 1.35 (m, 2H), 1.29 (t, J = 6.0 Hz, 2H), 1.24- 1.22 (m, 1H) 8-Ethyl-10,18-dimethyl-7,20- dioxo- 6,7,8,11,12,13,14,15,20,21,28, 29,30,31- tetradecahydrobenzo[4,5]imidazo [1,2-a]benzo[4,5]imidazo[2,1- p]dipyrazolo[5,1-e:4′,3′- l][1,3,6,15,17] pentaazacyclohenicosine-3-carboxamide Example 10,18-dimethyl-7,20-dioxo- Method .sup.1H NMR (400 LCMS 183 6,7,8,11,12,13,14,- 19 MHz, DMSO) δ Method A: 15,20,21,28,29,30,31- 12.91 (s, 1H), Rt = tetradecahydrobenzo[4,5]imidazo 12.76 (s, 1H), 1.283 [1,2-a]benzo[4,5]imidazo[2,1- 8.03 (s, 4H), 7.83 min, p]dipyrazolo[5,1-e:4′,3′- (m, 2H), 7.69- [M + H].sup.+ = l][1,3,6,15,17] 7.62 (m, 2H), 691.2 pentaazacyclohenicosine-3,24-dicarboxamide   [00419] 7.37 (br. s, 2H), 6.57 (s, 1H), 4.75 (br. s, 2H), 4.26 (br. s, 4H), 2.87 (br. S, 2H), 2.16- 1.24 (m, 17H) Example (E)-7-(aminomethyl)-1-(4-(5- Method 9 .sup.1H NMR (400 LCMS 184 carbamoyl-2-(1-ethyl-3-methyl- MHz, DMSO-d.sub.6) δ Method A: 1H-pyrazole-5-carboxamido)-7- ppm 8.15 (s, 1H), Rt = methoxy-1H-benzo[d]imidazol- 7.95 (t, J = 14.8 1.205 1-yl)but-2-en-1-yl)-2-(1-ethyl-3- Hz, 3H), 7.68 (d, min, methyl-1H-pyrazole-5- J = 25.8 Hz, 2H), [M + H].sup.+ = carboxamido)-1H- 7.35 (d, J = 18.1 735.8 benzo[d]imidazole-5- Hz, 3H), 6.52 (d, carboxamide   [00420] J = 18.5 Hz, 2H), 5.76 (d, J = 15.9 Hz, 1H), 5.54 (d, J = 15.8 Hz, 1H), 5.08 (s, 2H), 4.88 (s, 2H), 4.51 (d, J = 6.7 Hz, 4H), 3.95 (s, 2H), 3.76 (s, 3H), 2.10 (d, J = 1.8 Hz, 6H), 1.26 (td, J = 7.1, 4.5 Hz, 6H) Example (E)-7-(aminomethyl)-1-(4-(5- Method 9 .sup.1H NMR (400 LCMS 185 carbamoyl-2-(1-ethyl-3-methyl- MHz, DMSO-d.sub.6) δ Method A: 1H-pyrazole-5-carboxamido)-7- ppm 8.15 (s, 1H), Rt = (3-hydroxypropoxy)-1H- 7.95 (t, J = 17.8 1.186min, benzo[d]imidazol-1-yl)but-2-en- Hz, 3H), 7.70 (s, [M + H].sup.+ = 1-yl)-2-(1-ethyl-3-methyl-1H- 1H), 7.64 (s, 1H), 779.8 pyrazole-5-carboxamido)-1H- 7.34 (m, 3H), benzo[d]imidazole-5- 6.52 (d, J = 9.9 carboxamide   [00421] Hz, 2H), 5.78 (d, J = 15.9 Hz, 1H), 5.56 (d, J = 15.8 Hz, 1H), 5.09 (s, 2H), 4.90 (s, 2H), 4.52 (d, J = 6.6 Hz, 4H), 4.04 (s, 2H), 3.91 (s, 2H), 3.41 (s, 2H), 2.10 (s, 6H), 1.62 (m, 2H), 1.27 (t, J = 7.1 Hz, 6H) Example 1,1′-(butane-1,4-diyl)bis(2-(1- Method .sup.1H NMR (400 LCMS 186 allyl-3-methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 12.81 (s, 2 Rt = 0.83 benzo[d]imidazole-5- H), 7.97 (s, 4 H), min, carboxamide)   [00422] 7.76 (d, J = 8.34 Hz, 2 H), 7.53 (d, J = 8.34 Hz, 2 H), 7.33 (br. s., 2 H), 6.64 (s, 2 H), 5.93-6.05 (m, 2 H), 5.21 (d, J = 4.80 Hz, 4 H), 5.02 (dd, J = 10.36, 1.01 Hz, 2 H), 4.89 (dd, J = 17.18, 1.01 Hz, 2 H), 4.27 (br. s., 4 H), 2.10 (s, 6H), 1.86 (br. s., 4 H) [M + H].sup.+ = 703.6 Example 1,1′-(butane-1,4-diyl)bis(2-(1- Method .sup.1H NMR (400 LCMS 187 ethyl-4-iodo-3-methyl-1H- 11 MHz, DMSO-d.sub.6) δ Method C: pyrazole-5-carboxamido)-1H- ppm 12.92 (s, 2 Rt = 1.01 benzo[d]imidazole-5- H), 8.00 (d, min, carboxamide)   [00423] J = 1.01 Hz, 2 H), 7.98 (br. s., 2 H), 7.78 (dd, J = 8.46, 1.39 Hz, 2 H), 7.57 (d, J = 8.34 Hz, 2 H), 7.35 (br. s., 2 H), 4.52 (q, J = 7.07 Hz, 4 H), 4.35 (br. s., 4 H), 2.14 (s, 6 H), 1.91 (br. s., 4 H), 1.28 (t, J = 7.07 Hz, 6 H) [M + H].sup.+ = 931.5. Example 1-allyl-2-(1-(5-(5-((1-allyl-5- Method 7 .sup.1H NMR (400 LCMS 188 carbamoyl-1H-benzo[d]imidazol- MHz, DMSO-d.sub.6) δ Method C: 2-yl)carbamoyl)-1-ethyl-3- ppm 12.88 (s, 1 Rt = 0.93 methyl-1H-pyrazol-4-yl)pentyl)- H), 12.81 (s, 1 min, 3-methyl-1H-pyrazole-5- H), 7.99-8.02 [M + H].sup.+ = carboxamido)-1H- (m, 2 H), 7.97 745.7 benzo[d]imidazole-5- (br. s., 2 H), 7.77 carboxamide   [00424] (ddd, J = 8.34, 3.66, 1.39 Hz, 2 H), 7.41 (dd, J = 16.93, 8.34 Hz, 2 H), 7.34 (br. s., 2 H), 6.65 (s, 1 H), 5.87- 6.02 (m, 2 H), 4.99-5.22 (m, 4 H), 4.82 (dd, J = 11.62, 4.80 Hz, 4 H), 4.50- 4.61 (m, 4 H), 2.73 (t, J = 7.45 Hz, 2 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 1.71-1.85 (m, 2 H), 1.45- 1.55 (m, 2 H), 1.27-1.34 (m, 5 H) Example 8-ethyl-10,18-dimethyl-7,20- Method 7 Data provided for Data 189 dioxo- the trans-isomer provided 6,7,8,11,12,13,14,15,20,21,28, .sup.1H NMR (400 for the 31- MHz, DMSO-d.sub.6) δ trans- dodecahydrobenzo[4,5]imidazo ppm 12.87 (s, 1 isomer [1,2-a]benzo[4,5]imidazo[2,1- H), 12.84 (s, 1 LCMS p]dipyrazolo[5,1-e:4′,3′- H), 7.98 (br. s., 4 Method C: 1][1,3,6,15,17] H), 7.77 (dd, Rt = 0.82 pentaazacyclohenicosine-3,24-dicarboxamide J = 7.71, 3.16 Hz, min, 7:1 trans:cis mixture   [00425] 2 H), 7.33-7.48 (m, 4 H), 6.55 (s, 1 H), 5.89-5.98 (m, 1 H), 5.66- 5.75 (m, 1 H), 4.90 (d, J = 7.83 Hz, 4 H), 4.73 (t, J = 6.95 Hz, 2 H), 4.47 (q, J = 6.99 Hz, 2 H), 2.72- 2.80 (m, 2 H), 2.17 (s, 3 H), 2.10 (s, 3 H), 1.72 (br. s., 2 H), 1.44 (br. s., 2 H), 1.30 (t, J = 7.07 Hz, 5 H) [M + H].sup.+ = 717.6. Example 2-(1-(5-(5-((5-carbamoyl-1- Method .sup.1H NMR (400 LCMS 190 propyl-1H-benzo[d]imidazol-2- 22 MHz, DMSO-d.sub.6) δ Method C: yl)carbamoyl)-1-ethyl-3-methyl- ppm 12.84 (s, 1 Rt = 0.97 1H-pyrazol-4-yl)pentyl)-3- H), 12.78 (s, 1 min, methyl-1H-pyrazole-5- H), 8.00 (d, [M + H].sup.+ = carboxamido)-1-propyl-1H- J = 2.27 Hz, 2 H), 749.7 benzo[d]imidazole-5- 7.97 (br. s., 2 H), carboxamide   [00426] 7.78 (d, J = 7.07 Hz, 2 H), 7.49- 7.58 (m, 2 H), 7.33 (br. s., 2 H), 6.63 (s, 1 H), 4.51-4.65 (m, 4 H), 4.07-4.20 (m, 4 H), 2.76 (t, J = 7.07 Hz, 2 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 1.69-1.83 (m, 6 H), 1.48-1.59 (m, 2 H), 1.28- 1.36 (m, 5 H), 0.83-0.91 (m, 6 H) Example ethyl 4-(2-(1-(5-(5-((1-allyl-5- Method .sup.1H NMR (400 LCMS 191 carbamoyl-1H-benzo[d]imidazol- 23 MHz, CDCl.sub.3: Method 2-yl)carbamoyl)-1-ethyl-3- METHANOL- D: Rt = methyl-1H-pyrazol-4-yl)pentyl)- d.sub.4, 1:1) δ ppm 1.01 min, 3-methyl-1H-pyrazole-5- 7.89 (s, 1 H), [M + H].sup.+ = carboxamido)-5-carbamoyl-1H- 7.87 (s, 1 H), 819.7 benzo[d]imidazol-1-yl)butanoate   [00427] 7.82 (d, J = 8.28 Hz, 1 H), 7.78 (d, J = 8.28 Hz, 1 H), 7.37 (d, J = 8.53 Hz, 1 H), 7.24 (d, J = 8.53 Hz, 1 H), 6.68 (s, 1 H), 5.83-5.95 (m, 1 H), 5.20 (d, J = 10.29 Hz, 1 H), 5.07 (d, J = 17.32 Hz, 1 H), 4.77 (d, J = 4.27 Hz, 2 H), 4.59-4.65 (m, 2 H), 4.54 (q, J = 6.94 Hz, 2 H), 4.23 (t, J = 6.65 Hz, 2 H), 4.03 (q, J = 7.19 Hz, 2 H), 2.79 (t, J = 7.40 Hz, 2 H), 2.38 (t, J = 6.90 Hz, 2 H), 2.23 (s, 3 H), 2.15 (s, 3 H), 2.08-2.14 (m, 2 H), 1.80-1.92 (m, 2 H), 1.51- 1.63 (m, 2 H), 1.36 (t, J = 7.03 Hz, 5 H), 1.15 (t, J = 7.03 Hz, 3 H) Example ethyl 4-(5-carbamoyl-2-(1-(5-(5- Method .sup.1H NMR (400 LCMS 192 ((5-carbamoyl-1H- 23 MHz, DMSO-d.sub.6) δ Method benzo[d]imidazol-2- ppm 7.11 (s, 1 D: Rt = yl)carbamoyl)-1-ethyl-3-methyl- H), 7.07 (s, 1 H), 0.88 min, 1H-pyrazol-4-yl)pentyl)-3- 6.99 (dd, J = 8.44, [M + H].sup.+ = methyl-1H-pyrazole-5- 1.34 Hz, 1 H), 779.6 carboxamido)-1H- 6.91 (dd, J = 8.31, benzo[d]imidazol-1-yl)butanoate   [00428] 1.47 Hz, 1 H), 6.58 (d, J = 8.56 Hz, 1 H), 6.54 (d, J = 8.56 Hz, 1 H), 5.78 (s, 1 H), 4.04 (br. s., 5 H), 3.75 (t, J = 6.85 Hz, 2 H), 3.54 (q, J = 6.85 Hz, 2 H), 3.37 (t, J = 6.72 Hz, 2 H), 3.14 (q, J = 7.09 Hz, 2 H), 1.84 (t, J = 7.09 Hz, 2 H), 1.50- 1.57 (m, 2 H), 1.33 (s, 3 H), 1.32 (s, 3 H), 1.19-1.28 (m, 2 H), 0.92-1.02 (m, 2 H), 0.64- 0.73 (m, 2 H), 0.52 (t, J = 7.09 Hz, 3 H), 0.40- 0.49 (m, 2 H), 0.28 (t, J = 7.21 Hz, 3 H) Example 3-(2-(1-(5-(5-((1-2- Method .sup.1H NMR (400 LCMS 193 (((benzyloxy)carbonyl)amino) 23 MHz, Method E: ethyl)-5-carbamoyl-1H- METHANOL-d.sub.4) δ Rt = 0.81 benzo[d]imidazol-2- ppm 7.91 (s, 1 min, yl)carbamoyl)-1-ethyl-3-methyl- H), 7.77-7.82 [M + H].sup.+ = 1H-pyrazol-4-yl)pentyl)-3- (m, 2 H), 7.70 914.5 methyl-1H-pyrazole-5- (dd, J = 8.56, 1.47 carboxamido)-5-carbamoyl-1H- Hz, 1 H), 7.44 (d, benzo[d]imidazol-1-yl)propanoic J = 8.31 Hz, 1 H), acid   [00429] 7.33 (d, J = 8.56 Hz, 1 H), 7.12- 7.30 (m, 5 H), 6.69 (s, 1 H), 4.93 (s, 2 H), 4.49-4.65 (m, 4 H), 4.41 (t, J = 6.85 Hz, 2 H), 4.30 (t, J = 5.75 Hz, 2 H), 3.55 (t, J = 5.75 Hz, 2 H), 2.88 (t, J = 6.72 Hz, 2 H), 2.75- 2.82 (m, 2 H), 2.21 (s, 3 H), 2.16 (s, 3H), 1.81-1.91 (m, 2 H), 1.53-1.63 (m, 2 H), 1.36 (t, J = 7.09 Hz, 5 H) Example methyl 1-(4-(5-carbamoyl-2-(1- Method .sup.1H NMR (400 LCMS 194 ethyl-3-methyl-1H-pyrazole-5- 11 MHz, DMSO-d.sub.6) δ Method C: carboxamido)-1H- ppm 12.66- Rt = 0.93 benzo[d]imidazol-1-yl)butyl)-2- 13.03 (m, 2 H) min, (1-ethyl-3-methyl-1H-pyrazole- 7.97 (s, 2 H) [M + H].sup.+ = 5-carboxamido)-7-methoxy-1H- 7.78 (s, 2 H) 724.6 benzo[d]imidazole-5-carboxylate   [00430] 7.50-7.57 (m, 1 H) 7.37 (d, J = 1.01 Hz, 2 H) 6.59 (s, 2 H) 4.57 (br. s., 4 H) 4.34-4.44 (m, 2 H) 4.20-4.31 (m, 2 H) 3.88 (d, J = 3.79 Hz, 6 H) 2.11 (s, 6 H) 1.86 (br. s., 4 H) 1.27-1.37 (m, 6 H) Example 2-(1-ethyl-3-methyl-1H- Method .sup.1H NMR (400 LCMS 195 pyrazole-5-carboxamido)-1-(4- 11 MHz, DMSO-d6) Method C: (2-(1-ethyl-3-methyl-1H- δ ppm 1.25 (t, Rt = 0.88 pyrazole-5-carboxamido)-1H- J = 6.95 Hz, 6 H) min, benzo[d]imidazol-1-yl)butyl)- 1.76 (br. s., 4 H) [M + H]+ 1H-benzo[d]imidazole-5- 2.10 (s, 6H) = 636.5 carboxamide   [00431] 4.11 (br. s., 4 H) 4.50-4.68 (m, 4 H) 6.35 (s, 2 H) 6.84-7.03 (m, 4 H) 7.12 (d, J = 7.07 Hz, 2 H) 7.36-7.52 (m, 2 H) 7.68 (br. s., 1 H) 8.00 (s, 1 H) Example tert-butyl bis(2-(5-carbamoyl-2- Method .sup.1H NMR (400 LCMS 196 (1-ethyl-3-methyl-1H-pyrazole- 15 MHz, Method C: 5-carboxamido)-1H- METHANOL-d4) δ Rt = 0.83 benzo[d]imidazol-1- ppm 0.96-1.17 min, yl)ethyl)carbamate   [00432] (m, 9 H) 1.25- 1.49 (m, 6 H) 2.08-2.37 (m, 6 H) 3.58 (br. s., 4 H) 4.05-4.39 (m, 4 H) 4.62 (br. s., 4 H) 6.38- 6.63 (m, 2 H) 7.06-7.30 (m, 2 H) 7.63 (br. s., 2 H) 7.96 (br. s., 2 H) [M + H]+ = 794.7 Example 7,7′-(propane-1,3- Method .sup.1H NMR (400 LCMS 197 diylbis(oxy))bis(1-allyl-2-(1- 21 MHz, DMSO-d6) Method C: ethyl-3-methyl-1H-pyrazole-5- δ ppm 1.34 (t, Rt = 0.94 carboxamido)-1H- J = 7.07 Hz, 6 H) min, benzo[d]imidazole-5- 2.18 (s, 6H) [M + H]+ = carboxamide), 2Trifluoroacetic 2.33-2.46 (m, 2 777.7 acid salt   [00433] H) 4.41 (t, J = 5.81 Hz, 4 H) 4.60 (q, J = 7.07 Hz, 4 H) 4.85- 5.11 (m, 8 H) 5.97-6.11 (m, 2 H) 6.64 (s, 2 H) 7.39 (br. s., 2 H) 7.45 (s, 2 H) 7.69 (s, 2 H) 8.02 (br. s., 2 H)

AlexaFluor-488 FRET Assay Ligand 3′,6′-Diamino-5-((2-(1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-4′,5′-disulfonic acid

[1465] ##STR00434## ##STR00435##

1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid dihydrochloride

[1466] ##STR00436##

[1467] To methyl 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylate bis trifluoroacetic acid salt (400 mg, 0.434 mmol, Example 23) in THF (3.47 mL), MeOH (3.47 mL) and water (1.74 mL) at RT was added 8 M potassium hydroxide (1.09 mL, 8.68 mmol). After stirring overnight, the reaction was concentrated, and water was added. The mixture was acidified to pH 4-5 with 7 N aq HCl, and the resulting grey solid was collected by filtration to yield the title compound (335 mg, 0.423 mmol, 97% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.82-12.95 (m, 3H), 8.08 (s, 1H), 7.99 (br. s., 2H), 7.83 (d, J=8.34 Hz, 1H), 7.78 (d, J=8.34 Hz, 1H), 7.58 (t, J=7.33 Hz, 2H), 7.36 (br. s., 1H), 6.60 (d, J=4.80 Hz, 2H), 4.58 (d, J=6.57 Hz, 4H), 4.29 (br. s., 4 H,) 2.10 (s, 6H), 1.88 (br. s., 4H), 1.31 (t, J=6.95 Hz, 6H); LCMS (LCMS Method C): Rt=0.83 min, [M+H].sup.+=680.5

Step 1: N-(2-Aminoethyl)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide trifluoroacetic acid salt

[1468] ##STR00437##

[1469] 1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid (10 mg, 0.015 mmol) was dissolved (with sonication) in DMSO (300 μL) at 37° C. To this was added a solution of (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate hydrochloride (6.9 mg, 0.022 mmol) and HATU (7.6 mg, 0.020 mmol) in DMSO (100 μL) followed by DIEA (10 μL, 0.057 mmol). After stirring overnight, the reaction was diluted with DMF (600 μL), 4-methylpiperidine (400 μL) was added and the reaction was stirred at RT 1 hr. The mixture was concentrated, and the resulting residue diluted with 1:1 DMSO: MeOH (<1 mL) and purified by reverse-phase chromatography (Jupiter C18 preparative column, 10 mL/min), eluting with 30-100% (9:1 ACN: water) in water (0.1% TFA additive) to yield the title compound (8.45 mg, 10.1 μmol, 69% yield). LCMS (LCMS Method G): Rt=0.62 min, [M+H].sup.+=722.4

Step 2: 3′,6′-Diamino-5-((2-(1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-4′,5′-disulfonic acid

[1470] ##STR00438##

[1471] N-(2-Aminoethyl)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide trifluoroacetic acid salt (8.45 mg, 10.1 μmol) was dissolved in DMF (200 μl) and added to solid (5,6-) Alexa Fluor 488-ONSu (5.00 mg, 7.92 μmol). The commercial Alexa Fluor 488-ONSu reagent was a mixture of the 5- and 6-positional isomers.

##STR00439##

[1472] When solution was effected, DIPEA (2 μL, 0.01 mmol) was added, and the mixture was agitated (by vortex action) overnight in the absence of light. LCMS revealed formation of early and late eluting product peaks with the anticipated molecular weight ([M+H] 1238.6). The reaction was concentrated, and the residue was dissolved in 1:1 DMSO: MeOH (<1 mL) and purified by reverse-phase chromatography (Jupiter C18 preparative column, 10 mL/min), eluting with 15-100% (9:1 ACN: water) in water (0.1% TFA additive). The early eluting positional isomer was obtained in high purity. In contrast, the fractions of the late eluting isomer also contained unreacted starting material. These fractions containing the impure late eluting isomer were pooled and concentrated. This residue was dissolved in 1:1 DMSO: MeOH (<1 mL) and purified by reverse-phase chromatography (Waters SymmetryPrep preparative column, 10 mL/min), eluting with 15-100% (9:1 ACN: water) in water (0.1% TFA additive) to yield the title compound (late eluting isomer, 1.94 mg, 1.49 μmol, 19% yield). LCMS (LCMS Method H): Rt=0.69 min, [M+H].sup.+=1238.6. Note that the putative structure of the title compound (5-isomer) is not based on rigorous structural determination but instead is based on previous observations that the 5- positional isomer is typically the later eluting isomer by reverse phase HPLC methods.

Biological Assays and Data

[1473] As stated above, the compounds of present invention are modulators of STING, and are useful in the treatment of diseases mediated by STING. The biological activities of the compounds of present invention can be determined using any suitable assay for determining the activity of a compound as a modulator of STING, as well as tissue and in vivo models.

[1474] The pIC.sub.50 value for each compound was either reported in at least one experiment or the average of multiple experiments. It is understood that the data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments.

Binding Assays

[1475] (1) SPA

[1476] A radioligand binding assay was developed to measure quantitate interactions of compounds of Formula (I-N), (I-P) or (I) and the carboxy terminal domain (CTD) of STING by competition with 3H-cGAMP (tritium-labeled cyclic guanine (2′,5′) monophosphate-adenine (3′,5′) monophosphate). See also Li et al. (Nature Chemical Biology, 10, 1043-1048, (2014)). A protein encoding the sequence of human STING spanning residues 149 to 379 (Gene ID 340061) was expressed in bacteria with a carboxy terminal Flag® peptide fused to AviTag™ for biotinylation and hexahistidine tag for affinity purification. The purified STING-Flag-AviTag-6×his protein was biotinylated to completion using the enzyme BirA (Beckett D. et al, Protein Science, 1999, 8:921-929). The relative potency of compounds of Formula (I-N), (I-P) or (I) were determined by competition in equilibrium binding reactions containing 50 nM biotinylated-STING, 50 nM 3H-cGAMP, and 1.25 mg/mL streptavidin-coated scintilation proximity assay beads (Perkin Elmer) in phosphate-buffered saline buffer. Binding reactions were incubated at room temperature for 30 minutes and read using a luminescence plate reader. Dose response curves were normalized to a control that reflect complete inhibition of 3H-cGAMP binding by 10 μM unlabeled cGAMP and no compound control. The apparent pIC.sub.50 was determined using a conventional two-state binding model. Under these conditions, the apparent inhibition constant for positive control compound cGAMP is 40-50 nM which is approximately ten-fold greater than its actual affinity of 4-5 nM (Zhang X et al, Molecular Cell, 2013, 51:1-10).

[1477] (2) FRET Assay

[1478] The binding potency of molecules to the C-terminal Domain (CTD) of human STING was determined using a competition binding assay. In this assay, STING (149-379) recombinant protein with a C-terminal biotinylated Avi-tag was employed. When bound to STING, an Alexa488-labeled active site probe (see pages 226-229 for the synthesis for the FRET assay ligand) accepts the 490 nm emission from Tb-Streptavidin-Avi-STING and an increase in fluorescence is measured at 520 nm. Molecules that compete for the probe binding site will result in a low 520 nm signal. The assay was run in Greiner black 384-well plates (Catalog #784076) containing 100 nL compounds in neat DMSO. A solution of 500 pM STING, 500 pM Streptavidin-Lumi4-Tb, and 100 nM Alexa488 probe in phosphate buffered saline containing 0.02% (w/v) pluronic F127 and 0.02% (w/v) bovine serum albumin was added to the plate using a Combi liquid handler (ThermoFisher). Plates were centrifuged for 1 min at 500 rpm, incubated for 15 min at room temperature, and then fluorescence emission at 520 nm following 337 nm laser excitation on an Envision plate reader (Perkin-Elmer) was measured. The pIC.sub.50 values were determined using a standard four parameter curve fit in ABASE XE.

[1479] Using the SPA assay described above, the compounds of Examples 1-9, 11, 13, 15, 16, 23, 25-30, 33-35, 47, 49, 50, 54, 55, 57-61, 63-66, 68-74, 76-79, 81-83, 85-88, 90, 92, 102, 104, 105, 107-110, 112-114, 117, 118, 120, 122-144, 146-149, 151-160, 163-167, 169, 170, 172-183, and 186-197 exhibited pIC.sub.50 values in the range of 3.6 to 7.7. For example, the compounds of Example 1 and Example 5, above, inhibited binding of 3H-cGAMP to STING in the above method with mean pIC.sub.50 of 7.5 (#1, n=4; #5, n=2).

[1480] Using the FRET assay described above, Examples 1-106, 110, 112-125, 129, 131, 133, 134, 138, 142-144, 146-153, 155-186, 188-193, and 196 exhibited pIC.sub.50 values in the range of 4.1 to beyond the upper limit of the assay at 9.9. For example, pIC.sub.50 of FRET assay for following examples are:

TABLE-US-00017 Example No FRET assay (pIC50) 10 9.5 11 9.8 13 9.7 14 9.6 16 9.3 18 9.6 19 9.1 21 9.4 27 9.9 31 9.5

Cellular Functional Assays

[1481] The function of compounds of Formula (I) may be determined in cellular assays that detect STING specific activation and/or inhibition of IFNβ protein secretion. [1482] (1) Functional Assay I (PBMC antagonist assay): Inhibition of STING by compounds of Formula (I-N), (I-P) or (I) may be determined by measuring loss of interferon R secreted from PBMCs stimulated with Bacmam virus, a double stranded DNA virus, following treatment with different doses of compounds of Formula (I-N), (I-P) or (I). Frozen PBMC cells were thawed and diluted in media (RPMI-1640 with 1.5 g/L NaHCO.sub.3, 4.5 g/L glucose, 10 mM Hepes and 1 mM NaPyruvate, 10% FBS) to a final concentration of 5×10.sup.5 cells/mL followed by infection with Bacmam virus at a final MOI of 43. The PBMC-Bacmam virus suspension was dispensed into a 384-well tissue culture plate (Griener 781073) at a density of 25,000 cells per well containing 250 nL of compound diluted in DMSO. The level IFNβ protein secreted into the growth media was measured after 24 hours of incubation at 37° C. using a human IFNβ electrochemiluminescence kit (Meso Scale Diagnostics) following the manufacturer's instructions. Percent inhibition was determined relative to controls that lack compound treatment or Bacmam virus infection and plotted as a function of compound concentration to determine pIC.sub.50 using a standard two-state model of receptor-ligand inhibition. [1483] (2) Functional Assay II (PBMC agonist assay): Activation of STING by compounds of Formula I was determined by measuring levels of IFNβ secreted from human peripheral blood mononuclear cells (PBMC) treated with different doses of compounds of Formula I. Frozen PBMC cells were thawed, resuspended in media (RPMI-1640 with 1.5 g/L NaHCO.sub.3, 4.5 g/L glucose, 10 mM Hepes and 1 mM NaPyruvate, 10% FBS, 10 ng/mL lipopolysaccharide) to a final concentration of 5×10.sup.5 cells/mL and dispensed into a 384-well tissue culture plate (Griener 781073) at a density of 15,000 cells per well containing 250 nL of compound diluted in DMSO. The level of IFNβ protein secreted into the growth media was measured after three hours of incubation at 37° C. using a human IFNβ electrochemiluminescence kit (Meso Scale Diagnostics) following the manufacturer's instructions. Percent activation was determined relative to control DMSO treatment and plot as a function of compound concentration to determine pEC50 using a standard model of receptor activation. [1484] (3) Functional Assay III (HEK WT agonist assay): Activation of STING in cells may be determined using a luciferase reporter assay in human embryonic kidney cells (HEK293T) co-transfected with plasmids expressing STING and the enzyme firefly luciferase driven by the interferon stimulated response element promoter (pISRE-Luc) (Agilent Technologies). Full-length human STING (Gene ID 340061) and full-length human cyclic guanine adenine synthase (cGAS) (reference sequence NM_138441.2) was cloned into mammalian cell expression vectors containing a cytomegalovirus promoter. Transfections were prepared using a cell suspension with Fugene® 6 following the manufacturer's instructions (3:1 Fugene®:DNA). Fifty microliters of the transfection suspension was dispensed into wells of a 384-well plate containing 250 nL of a compound of Formula (I-N), (I-P) or (I). The final well composition contained 20,000 cells/well, 1 ng STING, 20 ng pISRE-Luc, and empty vector pcDNA3.1(Invitrogen) to bring the total DNA concentration to 125 ng. Control wells expected to generate maximal activation of STING were cotransfected with a cGAS expression plasmid. Plates were sealed and incubated for 24 hours at 37° C. The expression of firefly luciferase was processed using Steady-Glo® luciferase assay system (Promega) and was analyzed using a standard laboratory luminescence plate reader. Data was normalized to luminescence response in the presence of cGAS, was plotted as a function of compound concentration, and fit using a standard model of receptor activation to derive the pEC.sub.50. [1485] Using the functional assay III (HEK WT agonist assay) described above, Examples 1-23, 25-42, 44, 47-55, 57-61, 63-94, and 97-197 exhibited pEC.sub.50 values in the range of 4.4 to beyond the upper limit of the assay at 9.1. Examples 1, 3, 8, 100, 116, and 194 exhibited pEC.sub.50 lower than 4.3. For example, pEC.sub.50 of for following examples are:

TABLE-US-00018 Example No HEK WT agonist assay (pEC50) 10 7.5 11 7.8 13 7.4 14 7.5 16 7.6 18 7.5 19 7.5 21 7.3 27 7.6 31 7.8