APOPTOSIS-INDUCING AGENTS

Abstract

Provided are certain Bcl-2 inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Claims

1-24. (canceled)

25. A compound of formula (I), ##STR00508## or a pharmaceutically acceptable salt thereof, wherein Q.sup.1 is ##STR00509## Q.sup.2 is selected from ##STR00510## L.sup.1 is —CH.sub.2—; L.sup.2 is a bond or —O—; X.sup.1 is N; X.sup.2 is N; X.sup.3 is —CH.sub.2—; Z is C; R.sup.1 is NO.sub.2 or SO.sub.2CF.sub.3; R.sup.2 is hydrogen; R.sup.3 is hydrogen; m is 1; n is 1; p is 1; R.sup.4a and R.sup.4b are independently selected from hydrogen and methyl; Q.sup.3 is heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R.sup.X; Y.sup.1 is NH; Y.sup.2 is O; Y.sup.3 is CR.sup.6aR.sup.6b; Y.sup.4 is C; L.sup.3 is selected from —(CR.sup.CR.sup.D).sub.u—, —(CR.sup.CR.sup.D).sub.uO(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uC(O)(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uOC(O)(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uC(O)O(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uNR.sup.AC(O)(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uC(O)NR.sup.A(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uNR.sup.AC(O)O(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uS(O).sub.r(CR.sup.CR.sup.D).sub.t— and —(CR.sup.C5CR.sup.D5).sub.uNR.sup.AS(O).sub.r(CR.sup.CR.sup.D).sub.t—; each R.sup.5a is independently selected from C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.X; L.sup.4 is selected from —(CR.sup.CR.sup.D)—; R.sup.5b is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 heterocyclyl, CN, —OR.sup.A5, —NR.sup.A5R.sup.B5, —NR.sup.A5C(O)OR.sup.B5, —N═S(O)R.sup.A5R.sup.B5, —C(O)R.sup.A5, —C(O)OR.sup.A5, —C(O)NR.sup.A5R.sup.B5 and —S(O).sub.rR.sup.A5; each R.sup.6a and R.sup.6b are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A6R.sup.B6, —OR.sup.A6, —C(O)R.sup.A6, —C(═NR.sup.E6)R.sup.A6, —C(═N—OR.sup.B6)R.sup.A6, —C(O)OR.sup.A6, —OC(O)R.sup.A6, —C(O)NR.sup.A6R.sup.B6, —NR.sup.A6C(O)R.sup.B6, —C(═NR.sup.E6)NR.sup.A6R.sup.B6, —NR.sup.A6C(═NR.sup.E6)R.sup.B6, —OC(O)NR.sup.A6R.sup.B6, —NR.sup.A6C(O)OR.sup.B6, —NR.sup.A6C(O)NR.sup.A6R.sup.B6, —NR.sup.A6C(S)NR.sup.A6R.sup.B6, —NR.sup.A6C(═NR.sup.E6)NR.sup.A6R.sup.B6, —S(O).sub.rR.sup.A6, —S(O)(═NR.sup.E6)R.sup.B6, —N═S(O)R.sup.A6R.sup.B6, —S(O).sub.2OR.sup.A6, —OS(O).sub.2R.sup.A6, —NR.sup.A6S(O).sub.rR.sup.B6—NR.sup.A6S(O)(═NR.sup.E6)R.sup.B6, —S(O).sub.rNR.sup.A6R.sup.B6, —S(O)(═NR.sup.E6)NR.sup.A6R.sup.B6, —NR.sup.A6S(O).sub.2NR.sup.A6R.sup.B6, —NR.sup.A6S(O)(═NR.sup.E6)NR.sup.A6R.sup.B6, —P(O)R.sup.A6R.sup.B6 and —P(O)(OR.sup.A6)(OR.sup.B6), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.X; or R.sup.6a and R.sup.6b together with the carbon atoms to which they are attached form a 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; each R.sup.A, R.sup.A5, R.sup.A6, R.sup.B5 and R.sup.B6 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.X; or each “R.sup.A5 and R.sup.B5” and “R.sup.A6 and R.sup.B6” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; each R.sup.C and R.sup.D are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.X; each R.sup.E6 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; each R.sup.X is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1)NR.sup.a1C(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(S)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.2OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOS(O).sub.2R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tP(O)R.sup.a1R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tP(O)(OR.sup.a1)(OR.sup.b1), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; each R.sup.a1 and each R.sup.b1 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; or R.sup.a1 and R.sup.b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.c1 and each R.sup.d1 are independently selected from hydrogen, halogen, C.sub.-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; or R.sup.c1 and R.sup.d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.e1 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, CN, NO.sub.2, —OR.sup.a2, —SR.sup.a2, —(O).sub.rR.sup.a2, —C(O)R.sup.a2, —C(O)OR.sup.a2, —S(O).sub.rNR.sup.a2 R.sup.b2 and —C(O)NR.sup.a2R.sup.b2; each R.sup.Y is independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC (═NR.sup.e2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═N—OR.sup.b2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(S)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tN═S(O)R.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.2OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOS(O).sub.2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.2NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tP(O)R.sup.a2R.sup.b2 and —(CR.sup.c2R.sup.d2).sub.tP(O)(OR.sup.a2)(OR.sup.b2), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.a2 and each R.sup.b2 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.a2 and R.sup.b2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.c2 and each R.sup.d2 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.c2 and R.sup.d2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.e2 is independently selected from hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, —C(O)C.sub.1-4 alkyl, —C(O)C.sub.3-10 cycloalkyl, —C(O)OC.sub.1-4 alkyl, —C(O)OC.sub.3-10 cycloalkyl, —C(O)N(C.sub.1-4 alkyl).sub.2, —C(O)N(C.sub.3-10 cycloalkyl).sub.2, —S(O).sub.2C.sub.1-4 alkyl, —S(O).sub.2C.sub.3-10 cycloalkyl, —S(O).sub.2N(C.sub.1-4 alkyl).sub.2 and —S(O).sub.2N(C.sub.3-10 cycloalkyl).sub.2; q is selected from 0 and 1; each r is independently selected from 0, 1 and 2; each t is independently selected from 0 and 1; and each u is independently selected from 0, 1 and 2.

26. The compound of claim 25, wherein Q.sup.2 is ##STR00511##

27. The compound of claim 25, wherein Q.sup.2 is ##STR00512##

28. The compound of claim 25, wherein L.sup.2 is —O—.

29. The compound of claim 25, wherein R.sup.1 is NO.sub.2

30. The compound of claim 25, wherein R.sup.1 is SO.sub.2CF.sub.3.

31. The compound of claim 25, wherein R.sup.4a and R.sup.4b are each methyl.

32. The compound of claim 25, wherein L.sup.3 is selected from a bond, —CH.sub.2—, —(CH.sub.2).sub.2—, —CH.sub.2O—, —(CH.sub.2).sub.2O—, —(CH.sub.2).sub.2OC(O)—, —C(O)—, —C(O)O—, —CH.sub.2C(O)O—, —CH.sub.2OC(O)—m, —C(O)NCH.sub.3—, —CH.sub.2NHC(O)—, —CH.sub.2NHC(O)O—, —(CH.sub.2).sub.2NHC(O)—, —(CH.sub.2).sub.2NHC(O)O, —(CH.sub.2).sub.2SO.sub.2—, and —CH.sub.2NHSO.sub.2—.

33. The compound of claim 25, wherein q is 0.

34. The compound of claim 25, wherein q is 1.

35. The compound of claim 25, wherein R.sup.5a is selected from phenyl, pyridinyl, ##STR00513## which are unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

36. The compound of claim 25, wherein R.sup.5b is selected from hydrogen, fluoro, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, —OCH.sub.2, —N(CH.sub.3).sub.2, —N—S(O)(CH.sub.3).sub.2, —NHC(O)OCH.sub.3, —C(O)CH.sub.3. —C(O)C.sub.2H.sub.5, —C(O)-c-C.sub.3H.sub.7, —C(O)OCH.sub.3, —C(O)OC(CH.sub.3).sub.3, —C(O)N(CH.sub.3).sub.2, —SOCH.sub.3, and —S(O).sub.2CH.sub.3.

37. The compound of claim 25, wherein R.sup.5b is selected from —NR.sup.A5R.sup.B5 and —N═S(O)R.sup.A5R.sup.B5, wherein R.sup.A5 and R.sup.B5 together with the atom to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2, or 3 R.sup.X groups.

38. A pharmaceutical composition, comprising a compound of claim 25, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

39. A method for treating a cell-proliferative disorder, comprising administering to a subject in need thereof an effective amount of the compound of claim 25 or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the cell-proliferative disorder is selected from lymphoma, osteosarcoma, melanoma, or a breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine, or gastrointestinal tumor.

Description

EXAMPLES

[0284] Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.

[0285] It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.

[0286] Ae compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

[0287] The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc).

[0288] The N-oxides of the a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80° C. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.

[0289] Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.

[0290] Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0291] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); pt (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et.sub.2O (diethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TB S (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chomatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

[0292] References to ether or Et.sub.2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions were conducted under an inert atmosphere at RT unless otherwise noted.

[0293] .sup.1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

[0294] Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co.,Ltd).

Synthetic Schemes

[0295] Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.

[0296] The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.

[0297] As an illustration, one of the synthetic approach of the compounds of formula I of the present disclosure in outlined in Scheme 1. As shown in the Scheme, the compounds of formula I can be disassembled into the intermediates III and II the preparation of which is known in the literature. Coupling of carboxylic acid II with sulfonamide III via a condensation reaction leads to compounds of formula I.

##STR00175##

[0298] As an illustration of the preparation of intermediates of formula III, a preparation of compound IIIa is shown in Scheme 2. Starting from benzo-fused heterocycle IIIa-A, which is either commercially available or known in the literature, sulfonyl chloride IIIa-B is prepared by treating of with chlorosulfonic acid. Nitration of IIIa-B under conditions such as HNO.sub.3/H.sub.2SO.sub.4 gives IIIa-C, which can be further converted to sulfonamide IIIa-D by reacting IIIa-C with NH.sub.3. Intermediate IIIa can be obtained by the coupling of IIIa-D with IIIa-E through a substitution reaction.

##STR00176##

[0299] As a further illustration of the preparation of intermediates of formula III, a preparation of compound IIIb is illustrated in Scheme 3. Bromination of the commercially available IIIb-A results in IIIb-B, and then reaction of IIIb-B with IIIb-C provides Intramolecular cyclization of IIIb-D using metal catalyzed coupling conditions such as Buchwald reaction or other coupling conditions known in the literature gives IIIb-G. Alternatively intermediate IIIb-G can be obtained via a three-step sequence of mesylation of hydroxyl group of IIIb-D, SN2 reaction and intramolecular cyclization. Coupling of IIIb-G with IIIa-E leads to the desired intermediate IIIb.

##STR00177##

[0300] Another illustration of the preparation of intermediates of formula III is shown is Scheme 4 which demonstrates preparation of compound IIIc. Starting from the commercially available IIIc-A, selective reaction of the hydroxyl group at C-3 nitrobenzene in with the commercially available IIIc-B in the presence of base provides IIIc-C. Treatment of IIIc-C with an acid such as HBr/AcOH followed by intramolecular cyclization via an etherification reaction promoted by a base results in IIIc-D. Mesylation of the hydroxyl group in into a leaving Group gives IIIc-E. Sulfonylation of IIIc-E using chlorosulfonic acid in the presence of PCl.sub.5 provides IIIc-F and treatment of IIIc-F with NH.sub.3 gives IIIc-G. Compounds of formula IIIc can be prepared by the coupling of the resulting with IIIa-E.

##STR00178##

[0301] In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Preparation of Intermediates

Intermediate A

(S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A)

[0302] ##STR00179##

(S)-indolin-2-ylmethanol (A-1)

[0303] (S)-indolin-2-ylmethanol (A-1) was prepared according to the method described in WO2009/109364.

(S)-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indol-3-one (A-2)

[0304] A mixture of (S)-indolin-2-ylmethanol (A-1) (1.63 g, 10.9 mmol) and CDI (1.78 g, 10.9 mmol) in THF (25 mL) was stirred at 60° C. for 2.5 h. The mixture was concentrated and extracted by EtOAc, the extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated, the residue was purified by column chromatography on silica gel eluting with PE/EtOAc (8:1˜6:1) to give the title compound (S)-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indol-3-one (A-2). MS-ESI (m/z): 176 [M+1].sup.+.

(S)-3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-3)

[0305] To sulfurochloridic acid (1 mL) was added (S)-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indol-3-one (A-2) (0.10 g, 0.6 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and quenched by ice water (20 mL) at 0° C. The mixture was extracted by EtOAc (2×50 mL), the extracts were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated to give the crude product of (S)-3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-3), which was used for next step directly.

(S)-5-nitro-3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-4)

[0306] To a solution of (S)-3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-3) (0.05 g, 0.18 mmol) in Con.H.sub.2SO.sub.4 (1 mL) was added KNO.sub.3 (0.038 g, 0.36 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and quenched by ice water (20 mL) at 0° C. The mixture was extracted by EtOAc, washed with brine (15 mL), dried with Na.sub.2SO.sub.4. Filtered, and evaporated to give the crude product of (S)-5-nitro-3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-4), which was used for next step directly.

(S)-(7-nitro-5-sulfamoylindolin-2-yl)methyl carbamate (A-5)

[0307] A mixture of (S)-5-nitro -3-oxo-9,9a-dihydro-1H,3H-oxazolo[3,4-a]indole-7-sulfonyl chloride (A-4) (51 mg, 0.16 mmol) and NH.sub.3 in MeOH (3 mL) was stirred at RT for 1 h. The mixture was concentrated to give the crude product of (S)-(7-nitro-5-sulfamoylindolin-2-yl)methyl carbamate (A-5), which was used for next step directly. MS-ESI (m/z): 315 [M−1].sup.−.

(S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6)

[0308] A mixture of (S)-(7-nitro-5-sulfamoylindolin-2-yl)methyl carbamate (A-5) (21 mg, 0.068 mmol) and NaOH (2 N, 0.2 mL) in MeOH (1 mL) was stirred at 50° C. for 3.5 h. The mixture was extracted with DCM, and the water phase was adjusted with 1N HCl to pH=4˜5. The mixture was extracted with EtOAc (4×80 mL), the extracts were washed with brine (100 mL), dried with Na.sub.2SO.sub.4 and concentrated to give the crude product of (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6), which was used for next step directly. MS-ESI (m/z): 272 [M−1].sup.−.

(S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A)

[0309] To a solution of (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6) (0.2 g, 0.73 mmol), PPh.sub.3 (0.48 g, 1.83 mmol) and imidazole (0.12 g, 1.83 mmol) in CH.sub.3CN (10 mL) was added I.sub.2 (0.37 g, 1.46 mmol) at 0° C. for 10 min. The mixture was warmed to RT slowly and stirred at RT overnight. The reaction was quenched with saturated Na.sub.2S.sub.2O.sub.3 aqueous solution (50 mL) and extracted with EtOAc (2×30 mL). The extracts were washed with brine (30 mL), dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/EtOAc (4:1˜2:1) to give the title compound (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A). MS-ESI (m/z): 384 [M+1].sup.+.

Intermediate B

(R)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate B)

[0310] ##STR00180##

[0311] The title compound (R)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate B) was prepared according to the synthetic method of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A) by replacing (S)-indolin-2-ylmethanol (A-1) with (R)-indolin-2-ylmethanol. MS-ESI (m/z): 384 [M+1].sup.+.

Intermediate C

(R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C)

[0312] ##STR00181##

3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1)

[0313] A mixture of 4-chloro-3-nitrobenzenesulfonamide (10 g, 42.5 mmol) in Con.H.sub.2SO.sub.4 (30 mL) was stirred at 50° C. and added NBS (11 g, 61.8 mmol) in portions. The mixture was warmed to 60° C. and stirred at 60° C. for 2 h. Then the mixture was poured into ice (200 g), after stirred for 10 min and filtered. The filtered cake was washed with water (30 mL) and evaporated to give the crude product of 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1), which was used for next step directly. MS-ESI (m/z): 313 [M−1].sup.−.

methyl O-(tert-butyldimethylsilyl)-L-serinate (C-2)

[0314] methyl O-(tert-butyldimethylsilyl)-L-serinate (C-2) was prepared according to the method described in Synthesis 2009, 6, 951.

(R)-2-amino-3-((tert-butyldimethylsilyl)oxy)propan-1-ol (C-3)

[0315] (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)propan-1-ol (C-3) was prepared according to the method described in Synthesis 2009, 6, 951.

(R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4)

[0316] A mixture of 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1) (2.9 g, 9.26 mmol) and (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)propan-1-ol (C-3) (1.73 g, 8.44 mmol) and DIPEA (5.5 g, 42.6 mmol) in CH.sub.3CN (25 mL) was stirred at 80° C. overnight. Concentrated, the residue was purified by column chromatography on silica gel eluting to give the title compound (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4). MS-ESI (m/z): 484 [M+1].sup.+.

(R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1, 4]oxazine-7-sulfonamide (C-5)

[0317] A mixture of (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) (10 mg, 0.021 mmol), Me.sub.4phen (2.5 mg, 0.010 mmol), CuI (4.0 mg, 0.021 mmol) and Cs.sub.2CO.sub.3 (10 mg, 0.032 mmol) in toluene (1.5 mL) was stirred at 105° C. for 5 h under N.sub.2 atmosphere. The mixture was cooled to RT and concentrate. The residue was purified by column chromatography on silica gel eluting to give the title compound (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5). MS-ESI (m/z): 404 [M+1].sup.+.

(S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6)

[0318] A mixture of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) (1.7 mg, 0.042 mmol), 2 N HCl (0.3 mL) in MeOH (1 mL) was stirred at RT for 0.5 h. The reaction was quenched by saturated NaHCO.sub.3 aqueous solution (10 mL) and extracted with EtOAc. The organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6), which was used for next step directly. MS-ESI (m/z): 290 [M+1].sup.+.

(R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C)

[0319] To a solution of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) (10.0 mg, 0.0346 mmol) in DCM/CH.sub.3CN (2 mL/0.5 mL) was added MSCl (4.8 mg, 0.415 mmol) at 0° C. A solution of TEA (3.5 mg, 0.0346 mmol) in DCM was added. The mixture was stirred at 0° C. for 5 min. The reaction was quenched with saturated NaHCO.sub.3 aqueous solution and the mixture was extracted with DCM. The organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C), which was used for next step directly. MS-ESI (m/z): 368 [M+1].sup.+.

Intermediate D

(S)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate D)

[0320] ##STR00182##

[0321] The title compound (S)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H -benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate D) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) by replacing methyl O-(tert-butyldimethylsilyl)-L-serinate (C-2) with methyl O-(tert-butyldimethylsilyl)-D-serinate. MS-ESI (m/z): 368 [M+1].sup.+.

Intermediate E

(R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate E)

[0322] ##STR00183##

methyl D-homoserinate hydrochloride (E-1)

[0323] To a solution of D-homoserine (4.76 g, 40.0 mmol) in MeOH (100 mL) was added SOCl.sub.2 (3.5 mL, 40.0 mmol) under ice-water bath. Then, the mixture was stirred at 50° C. for 1 h. Concentrated to give the crude product of methyl D-homoserinate hydrochloride (E-1), which was used for next step directly. MS-ESI (m/z): 170 [M+1].sup.+.

(R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesulfonamide (E-2)

[0324] The title compound (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesulfonamide (E-2) was prepared according to the synthetic method of (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) by replacing methyl L-serinate hydrochloride with methyl D-homoserinate hydrochloride (E-1). MS-ESI (m/z): 418 [M+1].sup.+.

(R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1, 4]oxazine-7-sulfonamide (E-3)

[0325] The title compound (R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-3) was prepared according to the synthetic method of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) by replacing (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) with (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesul fonamide (E-2). MS-ESI (m/z): 418 [M+1].sup.+.

(R)-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfona mide (E-4)

[0326] The title compound (R)-3-(2-hydroxyethyl)-5-nitro-3 ,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-4) was prepared according to the synthetic method of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) by replacing (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) with (R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-3). MS-ESI (m/z): 304 [M+1].sup.+.

(R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate E)

[0327] The title compound (R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate E) was prepared according to the synthetic method of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A) by replacing (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6) with (R)-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-4). MS-ESI (m/z): 414 [M+1].sup.+.

Intermediate F

(S)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate F)

[0328] ##STR00184##

[0329] The title compound (S)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (Intermediate F) was prepared according to the synthetic method of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate E) by replacing D-homoserine with L-homoserine. MS-ESI (m/z): 414 [M+1].sup.+.

Intermediate G

(R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (Intermediate G)

[0330] ##STR00185##

(S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-1)

[0331] The title compound (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-1) was prepared according to the synthetic method of (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) by replacing D-serinate hydrochloride with L-serinate hydrochloride. MS-ESI (m/z): 484 [M+1].sup.+.

(R)-2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2)

[0332] The title compound (R)-2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) with (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-1). MS-ESI (m/z): 562 [M+1].sup.+.

(R)-S-(2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl) ethanethioate (G-3)

[0333] To the solution of (R)-S-(2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) (0.5 g, 0.89 mmol) in DMF (10 mL) was added AcSK (0.3 g, 2.6 mmol). The mixture was stirred at RT for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (2×25 mL). The organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:4) to give title compound (R)-S-(2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl) ethanethioate (G-3). MS-ESI (m/z): 542 [M+1].sup.+.

(R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-4)

[0334] To the solution of (R)-S-(2((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-ethanethioate (G-3) (0.3 g, 0.55 mmol) in MeOH (15 mL) was added K.sub.2CO.sub.3 (0.26 g, 1.88 mmol). The mixture was stirred at RT for 10 min. The reaction was quenched with water and adjusted with Con. HCl to pH=6˜7. The mixture was extracted with DCM (3×25 mL). The extracts were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated to give title compound (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-4). MS-ESI (m/z): 500 [M+1].sup.+.

(R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1, 4]thiazine-7-sulfonamide (G-5)

[0335] The title compound (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-5) was prepared according to the synthetic method of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) by replacing (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) with (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropan-2-yl)amino)-5-nitrobenzenesulfonamide (G-4). MS-ESI (m/z): 420 [M +1].sup.+.

(R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-6)

[0336] The title compound (R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-6) was prepared according to the synthetic method of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) by replacing (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) with (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-5). MS-ESI (m/z): 306 [M+1].sup.+.

(R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (Intermediate G)

[0337] The title compound (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (Intermediate G) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H -benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) with (R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-6). MS-ESI (m/z): 384 [M+1].sup.+.

Intermediate H

(R)-2-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethyl methanesulfonate (Intermediate H)

[0338] ##STR00186##

[0339] The title compound (R)-2-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethyl methanesulfonate (Intermediate H) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (Intermediate G) by replacing (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-n itrobenzenesulfonamide (G-1) with (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesul fonamide (E-2). MS-ESI (m/z): 398 [M+1].sup.+.

Intermediate I

(S)-(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methyl methanesulfonate (Intermediate I)

[0340] ##STR00187##

(S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-1)

[0341] To the solution of (R)-2((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) (30 mg, 0.0534 mmol) in DMF (1.5 mL) was added NaN.sub.3 (17 mg, 0.267 mmol). The mixture was stirred at 30° C. overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×25 mL). The organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:5˜1:3) to give title compound (S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-1). MS-ESI (m/z): 509 [M+1].sup.+.

(S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-2)

[0342] To a solution of (S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-1) (0.235 g, 0.463 mmol) in H.sub.2O/THF (0.125 mL/5 mL) was added PPh.sub.3 (0.346 g, 1.388 mmol) under N.sub.2 atmosphere. The mixture was stirred at 35° C. overnight under N.sub.2 atmosphere. The reaction was quenched with water and the mixture was extracted with DCM. The organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/DCM (50:1˜20:1) to give title compound (S)-4-(1-amino-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (1-2). MS-ESI (m/z): 483 [M+1].sup.30 .

(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-3)

[0343] A mixture of (S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-2) (20 mg, 0.0415 mmol), Me.sub.4phen (10 mg, 0.0415 mmol), CuI (12 mg, 0.0622 mmol) and Cs.sub.2CO.sub.3 (20 mg, 0.0622 mmol) in dioxane (1.5 mL) was stirred at 100° C. for 5 h under N.sub.2 atmosphere. The mixture was cooled to RT and concentrate. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:3˜1:1) to give the title compound (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-3). MS-ESI (m/z): 403 [M+1].sup.+.

(S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxahne-6-sulfonamide (I-4)

[0344] The title compound (S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-4) was prepared according to the synthetic method of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) by replacing (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) with (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-3). MS-ESI (m/z): 289 [M+1].sup.+.

(S)-(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxahn-2-yl)methyl methanesulfonate (Intermediate I)

[0345] The title compound (S)-(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methyl methanesulfonate (Intermediate I) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) with (S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-4). MS-ESI (m/z): 367 [M+1].sup.+.

Example 1-1

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morphohnomethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-1)

[0346] ##STR00188##

(S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a)

[0347] A mixture of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A) (15.3 mg, 0.04 mmol), K.sub.2CO.sub.3 (6.0 mg, 0.04 mmol) and morpholine (0.1 mL) in CH.sub.3CN (1.5 mL) was stirred at 60° C. for 4 h. The mixture was extracted with EtOAc (2×30 mL), the extracts were washed with brine (100 mL), dried with Na.sub.2SO.sub.4 and concentrate. The residue was purified by preparative TLC eluting with DCM/MeOH (20:1) to give the title compound (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a). MS-ESI (m/z): 343 [M+1].sup.+.

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b)

[0348] The title compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b) was prepared according to the method described in US 2014/0275540, (Al). MS-ESI (m/z): 571 [M+1].sup.+.

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-1)

[0349] A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b) (0.010 g, 0.02 mmol), (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) (6.7 mg, 0.02 mmol), EDCI (0.011 g, 0.06 mmol), Et.sub.3N (6.0 mg, 0.06 mmol) and DMAP (8.0 mg, 0.06 mmol) in DCM (4 mL) was stirred at 30° C. for 20 h. The mixture was extracted by DCM (25 mL), washed with brine (15 mL), dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC eluting with DCM/MeOH (15:1) to give the title compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-1). MS-ESI (m/z): 895 [M+1].sup.+.

Example 1-2

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-2)

[0350] ##STR00189##

(S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1-2a)

[0351] A mixture of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A) (1.04 g, 2.72 mmol) and NaCN (160 mg, 3.26 mmol) in DMF (12 mL) was stirred at 60° C. for 3 h. The mixture was extracted by EtOAc, washed with brine, dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (60:1˜15:1) to give title compound (S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1-2a). MS-ESI (m/z): 283 [M+1].sup.+.

(S)-2-(7-nitro-5-sulfamoylindolin-2-yl)acetic acid (1-2b)

[0352] A mixture of (S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1-2a) (265 mg, 0.94 mmol) in Con.HCl (5 mL) was stirred at 100° C. for 2.5 h. The reaction mixture was evaporated to give the crude product of (S)-2-(7-nitro-5-sulfamoylindolin-2-yl)acetic acid (1-2b), which was used for next step directly. MS-ESI (m/z): 302 [M+1].sup.30 .

(S)-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c)

[0353] A mixture of (S)-2-(7-nitro-5-sulfamoylindolin-2-yl)acetic acid (1-2b) (52 mg, 0.173 mmol), EDCI (66 mg, 0.35 mmol), HOBT (47 mg, 0.35 mmol), Et.sub.3N (48 ml, 0.35 mmol) and morpholine (50 ml, 0.35 mmol) in DMF (1.5 mL) was stirred at 30° C. overnight, and then more EDCI (40 mg, 0.21 mmol) and HOBT (25 mg, 0.19 mmol) was added. The resulted mixture was stirred at 30° C. for 6 h. The mixture was extracted by EtOAc, washed with brine, dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give title compound (S)-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c). MS-ESI (m/z): 371 [M+1].sup.+.

(S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d)

[0354] To a solution of (S)-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c) (18.0 mg, 0.048 mmol) in THF (1 ml) was added BH.sub.3 (150 ml, 0.144 mmol) in THF at RT The mixture was stirred at RT overnight, and then, a solution of MeOH (0.5 ml) and Con.HCl (0.1 mL) was added. It was stirred at 80° C. for 3 h. The mixture was cooled to RT and adjusted with 4 N Na.sub.2CO.sub.3 to pH=10. The mixture was extracted with EtOAc. The extracts were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give title compound (S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d). MS-ESI (m/z): 357 [M+1].sup.+.

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morphohnoethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-2)

[0355] The title compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide (1-2) was prepared according to the synthetic method of 1-1 by replacing (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) with (S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d). MS-ESI (m/z): 909 [M+1].sup.+.

[0356] Following essentially the same procedures described for Examples 1-1˜1-2 or using similar synthetic methods or strategies, Examples 1-3˜1-27 listed in Table 1 were prepared. The structures and names of Examples 1-3˜1-27 are given in Table 1.

TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 1-3 [00190] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-methylpiperazin-n-2-yl)methyl)- 7-nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 908 [M + 1].sup.+ 1-4 [00191] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-hydroxy-4-methylpiperidin- 1-yl)methyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 1-5 [00192] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((dimethylamino)methyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 853 [M + 1].sup.+ 1-6 [00193] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(hydroxymethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 1-7 [00194] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)- 7-nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 908 [M + 1].sup.+ 1-8 [00195] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(morpholinomethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 895 [M + 1].sup.+ 1-9 [00196] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-hydroxy-4-methylpiperidin- 1-yl)methyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 1-10 [00197] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((dimethylamino)methyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 853 [M + 1].sup.+ 1-11 [00198] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(hydroxymethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 1-12 [00199] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(4-methylpiperazin-1-yl) ethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 922 [M + 1].sup.+ 1-13 [00200] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(4-hydroxy-4-methylpiperidin- 1-yl)ethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 937 [M + 1].sup.+ 1-14 [00201] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(dimethylamino)ethyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 867 [M + 1].sup.+ 1-15 [00202] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl) oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)-N-((2-(2-(4-methylpiperazin-1- yl)ethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 922 [M + 1].sup.+ 1-16 [00203] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 1-17 [00204] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(4-hydroxy-4-methylpiperidin- 1-yl)ethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 937 [M + 1].sup.+ 1-18 [00205] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(dimethylamino)ethyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 867 [M + 1].sup.+ 1-19 [00206] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-hydroxyethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 840 [M + 1].sup.+ 1-20 [00207] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-hydroxyethyl)-7-nitroindolin- 5-yl)sulfonyl)benzamide MS-ESI (m/z): 840 [M + 1].sup.+ 1-21 [00208] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((2-(morpholinomethyl)-7-nitro-1H- indol-5-yl)sulfonyl)benzamide MS-ESI (m/z): 893 [M + 1].sup.+ 1-22 [00209] methyl (S)-2-(5-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-7-nitro- indolin-2-yl)acetate MS-ESI (m/z): 868 [M + 1].sup.+ 1-23 [00210] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(dimethylamino)-2-oxoethyl)- 7-nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 881 [M + 1].sup.+ 1-24 [00211] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-morpholino-2-oxoethyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 1-25 [00212] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(4-methylpiperazin-1-yl)- 2-oxoethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS-ESI (m/z): 936 [M + 1].sup.+ 1-26 [00213] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-morpholino-2-oxoethyl)-7- nitroindolin-5-yl)sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 1-27 [00214] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((2-(morpholinomethyl)-4-nitro-1H- benzo[d]imidazol-6-yl)sulfonyl)benzamide MS-ESI (m/z): 894 [M + 1].sup.+

Example 2-1

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-1)

[0357] ##STR00215##

(S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2-1a)

[0358] A mixture of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) (11.0 mg, 0.03 mmol), 1-methylpiperazine (12.0 mg,0.12 mmol) and K.sub.2CO.sub.3 (20.7 mg, 0.15 mmol) in CH.sub.3CN (4 mL) was stirred at 80° C. for 1.5 h. The reaction was quenched by water and extracted with EtOAc (2×30 mL). The extracts were washed with brine (30 mL), dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (10:1) to give the title compound (S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2-1a). MS-ESI (m/z): 372 [M+1].sup.+.

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-1)

[0359] The title compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-1) was prepared according to the synthetic method of 1-1 by replacing (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) with (S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2-1a). MS-ESI (m/z): 924 [M+1].sup.+.

Example 2-2

(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morphohnoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-2)

[0360] ##STR00216##

[0361] The title compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-2) was prepared according to the synthetic method of 1-1 by replacing (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A) with (R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate E). MS-ESI (m/z): 925 [M+1].sup.+.

Example 2-3

(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3-A and 2-3-B)

[0362] ##STR00217##

methyl (R)-2-amino-2-(4-hydroxyphenyl)acetate (2-3a)

[0363] To a solution of (R)-2-amino-2-(4-hydroxyphenyl)acetic acid (1.0 g, 6.0 mmol) in MeOH (10 mL) was added SOCl.sub.2 (1.3 ml, 18.0 mmol) dropwise. The mixture was stirred at RT for 0.5 h. The mixture was concentrated to give the crude product of the title compound methyl (R)-2-amino-2-(4-hydroxyphenyl)acetate (2-3a). MS-ESI (m/z): 182 [M+1].sup.+.

methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b)

[0364] To a suspension of methyl (R)-2-amino-2-(4-hydroxyphenyl)acetate (2-3a) (1.0 g, 5.5 mmol) in 1,4-dioxane (10 mL) was added K.sub.2CO.sub.3 (1.2 g, 8.8 mmol) and (Boc).sub.2O (1.3 g, 6.0 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by recrystallized with PE/EtOAc to give title compound methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b). MS-ESI (m/z): 282 [M+1].sup.+.

tert-butyl (R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c)

[0365] To a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b) (1.0 g, 3.55 mmol) in THF (40 mL) was added LAH (445 mg, 11.7 mmol) in portions, and the mixture was stirred at 0° C. for 1 h. To the reaction mixture was added Na.sub.2SO.sub.4.10.H.sub.2O at 0° C. The mixture was filtered through Celite, and filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting to give title compound tert-butyl (R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c). MS-ESI (m/z): 254 [M+1].sup.+.

tert-butyl (R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3d)

[0366] A mixture of tert-butyl (R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c) (847 mg, 3.33 mmol), DMP (3.05 g, 29.34 mmol) and BF.sub.3.Et.sub.2O (40 μl, 0.33 mmol) in Acetone (3 mL) was stirred at RT for 4 h, The reaction was quenched by ice water and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (6:1) to give title compound tert-butyl (R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3d). MS-ESI (m/z): 294 [M+1].sup.+.

tert-butyl (R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e)

[0367] A mixture of tert-butyl (R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3d) (760 mg, 2.55 mmol) and PtO.sub.2 (100 mg) in IPA (60 mL) and HOAc (4 mL) was stirred at RT under H.sub.2 atmosphere for 48 hours. The reaction mixture was filtered through celite and concentrated to give the crude product of title compound tert-butyl (R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e) which was used directly for next step. MS-ESI (m/z): 300 [M+1].sup.+.

tert-butyl (R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3f)

[0368] A mixture of tert-butyl (R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e) (233 mg, 0.773 mmol) and DMP (424 mg, 2.18 mmol) in DCM (10 mL) was stirred at RT for 1.5 h. The reaction mixture was washed with saturated NaHCO.sub.3 aqueous solution (30 mL), The organic layer was concentrated. The residue was purified by column chromatography on silica gel eluting to give title compound tert-butyl (R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3f). MS-ESI (m/z): 298 [M+1].sup.+.

tert-butyl (R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3g)

[0369] To a solution of tert-butyl (R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3f) (200 mg, 0.87 mmol) in THF (6 mL) was added MeLi (1.5 mL, 1.6 M) at −78˜−40° C. The mixture was stirred at −78˜−40° C. for 1 h, The reaction was quenched by saturated NH.sub.4Cl aqueous solution and the mixture was extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, and evaporated to give the crude product of tert-butyl (R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3g), which was used for next step directly. MS-ESI (m/z): 314 [M+1].sup.+.

(R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexan-1-ol trifluoroacetate (2-3 h)

[0370] A mixture of tert-butyl (R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3g) (200 mg, 0.63 mmol) and TFA (0.5 mL, 5 mmol) in DCM (5 mL) was stirred at RT for 45 min. The reaction mixture was evaporated to give the crude product of (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexan-1-ol trifluoroacetate (2-3 h), which was used for next step directly. MS-ESI (m/z): 174 [M+1].sup.+.

(R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A and 2-3i-B)

[0371] A mixture of (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexan-1-ol trifluoroacetate (2-3 h) (250 mg, 0.81 mmol), 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1) (250 mg, 0.138 mmol) and DIPEA (500.0 mg, 3.815 mmol) in ACN (6 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative TLC upper spot to give title compound (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A). And purified by preparative TLC lower spot to give title compound (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-B) MS-ESI (m/z): 452 [M+1].sup.+.

(R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-A)

[0372] A mixture of (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)-ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A) (50 mg, 0.11 mmol), Pd.sub.2(dba).sub.3 (15 mg, 0.016 mmol), Xantphos (16 mg, 0.028 mmol) and Cs.sub.2CO.sub.3 (71 mg, 0. 22 mmol) in dioxane (5 mL) was stirred at 100° C. for 1.5 h. The mixture was cooled to RT. The mixture was filtered through Celite, and filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give title compound (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-A). MS-ESI (m/z): 372 [M+1].sup.+.

(R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-B)

[0373] The title compound (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b ][1,4]-oxazine-7-sulfonamide (2-3j-B) was prepared according to the synthetic method of 2-3j-A by replacing (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)-ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A) with (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-B). MS-ESI (m/z): 372 [M+1].sup.+.

(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3-A and 2-3-B)

[0374] The title compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3A and 2-3B) was prepared according to the synthetic method of 1-1 by replacing (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) with (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-A) or (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-B). MS-ESI (m/z): 924 [M+1].sup.+.

[0375] Following essentially the same procedures described for Examples 2-1˜2-3 or using similar synthetic methods or strategies, Examples 2-4˜2-252 listed in Table 2 were prepared. The structures and names of Examples 2-4˜2-252 are given in Table 2.

TABLE-US-00002 TABLE 2 EXAMPLE STRUCTURE NAME DATA 2-4 [00218] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1].sup.+ 2-5 [00219] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(morpholinomethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-6 [00220] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxy-4-methylpiperidin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-7 [00221] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((dimethylamino)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 869 [M + 1].sup.+ 2-8 [00222] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(hydroxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 842 [M + 1].sup.+ 2-9 [00223] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-methylpiperazin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-10 [00224] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-morpholinoethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-11 [00225] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-hydroxy-4-methylpiperidin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 953 [M + 1].sup.+ 2-12 [00226] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(dimethylamino)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 883 [M + 1].sup.+ 2-13 [00227] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-hydroxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-14 [00228] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-methylpiperazin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-15 [00229] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-hydroxy-4-methylpiperidin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 953 [M + 1].sup.+ 2-16 [00230] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(dimethylamino)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 883 [M + 1].sup.+ 2-17 [00231] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-hydroxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 856 [M + 1].sup.+ 2-18 [00232] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(morpholinomethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-19 [00233] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxy-4-methylpiperidin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-20 [00234] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((dimethylamino)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 869 [M + 1].sup.+ 2-21 [00235] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((3-hydroxy-3-methylazetidin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-22 [00236] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(((R)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-23 [00237] 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(((R)-2-methylmorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-24 [00238] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((3-hydroxyazetidin-1-yl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 897 [M + 1].sup.+ 2-25 [00239] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((3-hydroxy-3-methylazetidin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-26 [00240] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((R)-3,4-dimethylpiperazin-1- yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-27 [00241] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((5)-3-(((5)-3,4-dimethylpiperazin-1- yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-28 [00242] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((4-(oxetan-3-yl)piperazin-n- 1-yl)methyl)-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 966 [M + 1].sup.+ 2-29 [00243] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((R)-3-methyl-4-(oxetan-3-yl) piperazin-1-yl)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-30 [00244] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((S)-3-methyl-4-(oxetan-3-yl) piperazin-1-yl)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-31 [00245] 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((S)-2-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-32 [00246] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((R)-2-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-33 [00247] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethy-3,4,5,6-tetra- hydro-[1,1l′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-((dimethyl(oxo)-16-sulfan ylidene)amino)ethyl)-5-nitro-3,4-dihydro-2 H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 931 [M + 1].sup.+ 2-34 [00248] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(3-hydroxyazetidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-35 [00249] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(3-hydroxy-3-methylazetidin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-36 [00250] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3(2-((R)-3,4-dimethylpiperazin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-37 [00251] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(2-((5)-3,4-dimethylpiperazin-1- yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-38 [00252] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1l′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(2-(4-(oxetan-3-yl) piperazin-1-yl)ethyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-39 [00253] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(2-((R)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 994 [M + 1].sup.+ 2-40 [00254] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(2-((S)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 994 [M + 1].sup.+ 2-41 [00255] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydo- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(2-((S)-2-methylmorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-42 [00256] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydo- [1,1′-biphenyl]2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(2-((R)-2-methylmorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-43 [00257] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-((dimethyl(oxo)-16- sulfanylidene)amino)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 931 [M + 1].sup.+ 2-44 [00258] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(3-hydroxyazetidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-45 [00259] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(3-hydroxy-3-methylazetidin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-46 [00260] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((R)-3,4-dimethylpiperazin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-47 [00261] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((5)-3,4-dimethylpiperazin- 1-yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-48 [00262] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(2-(4-(oxetan-3-yl) piperazin-1-yl)ethyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-49 [00263] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((R)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 994 [M + 1].sup.+ 2-50 [00264] 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((S)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 994 [M + 1].sup.+ 2-51 [00265] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((5)-2-methylmorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-52 [00266] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(2-((R)-2-methylmorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-53 [00267] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-(acetamidomethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)benzamide MS-ESI (m/z): 883 [M + 1].sup.+ 2-54 [00268] (S)-N-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)tetrahydro-2H-pyran-4-carboxamide MS-ESI (m/z): 953 [M + 1].sup.+ 2-55 [00269] (S)-N-((7-(N-(2-(1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)morpholine-4-carboxamide MS-ESI (m/z): 954 [M + 1].sup.+ 2-56 [00270] (S)-N-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridrin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide MS-ESI (m/z): 967 [M + 1].sup.+ 2-57 [00271] (R)-N-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)ethyl)tetrahydro-2H-pyran-4-carboxamide MS-ESI (m/z): 967 [M + 1].sup.+ 2-58 [00272] (S)-N-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)ethyl)morpholine-4-carboxamide MS-ESI (m/z): 968 [M + 1].sup.+ 2-59 [00273] (R)-N-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)ethyl)morpholine-4-carboxamide MS-ESI (m/z): 968 [M + 1].sup.+ 2-60 [00274] methyl (S)-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5- yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)carbamate MS-ESI (m/z): 899 [M + 1].sup.+ 2-61 [00275] tetrahydro-2H-pyran-4-yl (S)-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5- yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)carbamate MS-ESI (m/z): 969 [M + 1].sup.+ 2-62 [00276] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-(2-acetamidoethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)benzamide MS-ESI (m/z): 897 [M + 1].sup.+ 2-63 [00277] methyl (R)-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) ethyl)carbamate MS-ESI (m/z): 913 [M + 1].sup.+ 2-64 [00278] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(methylsulfonyl)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 918 [M + 1].sup.+ 2-65 [00279] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-methoxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 870 [M + 1].sup.+ 2-66 [00280] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(methylsulfonamidomethyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 919 [M + 1].sup.+ 2-67 [00281] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((morpholine-4-sulfonamido) methyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 990 [M + 1].sup.+ 2-68 [00282] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(methylsulfonamido)ethyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 933 [M + 1].sup.+ 2-69 [00283] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(morpholine-4-sulfonamido) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 1004 [M + 1].sup.+ 2-70 [00284] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(((dimethyl(oxo)-λ.sup.6-sulfanylidene) amino)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 917 [M + 1].sup.+ 2-71 [00285] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((1-oxidotetrahydro- 1λ6-thiophen-1-ylidene)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 943 [M + 1].sup.+ 2-72 [00286] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((4-oxido-1,4λ.sup.6-oxathian- 4-ylidene)amino)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 959 [M + 1].sup.+ 2-73 [00287] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(2-((1-oxidotetrahydro- 1λ6-thiophen-1-ylidene)amino)ethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 957 [M + 1].sup.+ 2-74 [00288] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(2-((4-oxido-1,4λ6- oxathian-4-ylidene)amino)ethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-75 [00289] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(((dimethyl(oxo)-λ.sup.6-sulfanylidene) amino)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 917 [M + 1].sup.+ 2-76 [00290] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((1-oxidotetrahydro- 1λ.sup.6-thiophen-1-ylidene)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 943 [M + 1].sup.+ 2-77 [00291] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((4-oxido-1,4λ.sup.6-oxathian- 4-ylidene)amino)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 959 [M + 1].sup.+ 2-78 [00292] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(2-((4-oxido-1,4.sup.λ6- oxathian-4-ylidene)amino)ethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-79 [00293] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(((S)-2-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-80 [00294] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(((S)-3-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-81 [00295] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1,′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-(((R)-3-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-82 [00296] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4- ((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-83 [00297] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((R)-3-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4- ((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-84 [00298] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-1-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-85 [00299] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((S)-3-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-86 [00300] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((S)-3-(((R)-3-methylmorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-87 [00301] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((S)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4- ((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-88 [00302] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((S)-3-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4- ((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-89 [00303] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-1-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-90 [00304] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-(methylsulfonyl)piperazin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 988 [M + 1].sup.+ 2-91 [00305] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-((4-acetylpiperazin-1-yl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-92 [00306] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((4-propionylpiperazin- 1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 966 [M + 1].sup.+ 2-93 [00307] methyl (R)-4-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)piperazin-1-carboxylate MS-ESI (m/z): 968 [M + 1].sup.+ 2-94 [00308] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-(cyclopropanecarbonyl) piperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 978 [M + 1].sup.+ 2-95 [00309] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-(methylsulfonyl)piperazin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 988 [M + 1].sup.+ 2-96 [00310] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-((4-acetylpiperazin-1-yl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzamide MS-ESI (m/z): 952 [M + 1].sup.+ 2-97 [00311] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((4-propionylpiperazin- 1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 966 [M + 1].sup.+ 2-98 [00312] methyl (S)-4-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)piperazin-1-carboxylate MS-ESI (m/z): 968 [M + 1].sup.+ 2-99 [00313] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-(cyclopropanecarbonyl) piperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 978 [M + 1].sup.+ 2-100 [00314] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-methyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 2-101 [00315] methyl (R)-7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl) oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazine-3- carboxylate MS-ESI (m/z): 870 [M + 1].sup.+ 2-102 [00316] (R)-7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl) oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-N,N- dimethyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazine-3-carboxamide MS-ESI (m/z): 883 [M + 1].sup.+ 2-103 [00317] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(morpholine-4-carbonyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-104 [00318] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methylpiperazin--1carbonyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-105 [00319] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-methyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 2-106 [00320] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-methyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 2-107 [00321] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-ethyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 840 [M + 1].sup.+ 2-108 [00322] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-isopropyl-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 854 [M + 1].sup.+ 2-109 [00323] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-cyclopropyl-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 852 [M + 1].sup.+ 2-110 [00324] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(methoxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 856 [M + 1].sup.+ 2-111 [00325] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1yl)-N-((3-methyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 826 [M + 1].sup.+ 2-112 [00326] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-ethyl-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 840 [M + 1].sup.+ 2-113 [00327] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-isopropyl-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 854 [M + 1].sup.+ 2-114 [00328] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-cyclopropyl-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 852 [M + 1].sup.+ 2-115 [00329] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(cyanomethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 851 [M + 1].sup.+ 2-116 [00330] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(methoxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 856 [M + 1].sup.+ 2-117 [00331] (R)-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5- yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl morpholine-4-carboxylate MS-ESI (m/z): 955 [M + 1].sup.+ 2-118 [00332] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-methoxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 870 [M + 1].sup.+ 2-119 [00333] methyl (S)-2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) acetate MS-ESI (m/z): 884 [M + 1].sup.+ 2-120 [00334] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(methylsulfonyl)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 918 [M + 1].sup.+ 2-121 [00335] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1,1-dioxidothiomorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 959 [M + 1].sup.+ 2-122 [00336] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-(methylimino)-1-oxido- 1λ.sup.6-thiomorpholino)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 972 [M + 1].sup.+ 2-123 [00337] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-(ethylimino)-1-oxido-1λ.sup.6- thiomorpholino)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 986 [M + 1].sup.+ 2-124 [00338] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-(cyclopropylimino)-1-oxido- 1λ.sup.6-thiomorpholino)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 998 [M + 1].sup.+ 2-125 [00339] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-((dimethyl(oxo)-λ.sup.6- sulfanylidene)amino)piperidin-1-yl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 1000 [M + 1].sup.+ 2-126 [00340] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(1,1-dioxidothiomorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-127 [00341] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(1-(methylimino)-1-oxido- 1λ.sup.6-thiomorpholino)ethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 986 [M + 1].sup.+ 2-128 [00342] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-y)-N-((3-(2-(1-(ethylimino)-1-oxido- 1λ.sup.6-thiomorpholino)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 1000 [M + 1].sup.+ 2-129 [00343] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(1-(cyclopropylimino)-1- oxido-1λ.sup.6-thiomorpholino)ethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 1012 [M + 1].sup.+ 2-130 [00344] methyl (R)-(4-(2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)ethyl)-1oxido-1λ.sup.6-thiomorpholin-1- ylidene)carbamate MS-ESI (m/z): 1030 [M + 1].sup.+ 2-131 [00345] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-((dimethyl(oxo)-λ.sup.6- sulfanylidene)amino)piperidin-1-yl)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 1014 [M + 1].sup.+ 2-132 [00346] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-benzyl-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4′- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 902 [M + 1].sup.+ 2-133 [00347] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-2-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 903 [M + 1].sup.+ 2-134 [00348] methyl (R)-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5- yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)carbamate MS-ESI (m/z): 899 [M + 1].sup.+ 2-135 [00349] (S)-2-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) ethyl morpholine-4-carboxylate MS-ESI (m/z): 969 [M + 1].sup.+ 2-136 [00350] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(methylsulfonamidomethyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 919 [M + 1].sup.+ 2-137 [00351] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(ethylsulfonamidomethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 933 [M + 1].sup.+ 2-138 [00352] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(cyclopropanesulfonamidomethyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 945 [M + 1].sup.+ 2-139 [00353] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((tetrahydro-2H-pyran)- 4-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 989 [M + 1].sup.+ 2-140 [00354] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((4-methyl-3-(morpholinomethyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 2-141 [00355] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-4-methyl-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)benzamide MS-ESI (m/z): 937 [M + 1].sup.+ 2-142 [00356] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-morpholino-2-oxoethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-143 [00357] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-morpholino-2-oxoethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 939 [M + 1].sup.+ 2-144 [00358] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(cyanomethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 851 [M + 1].sup.+ 2-145 [00359] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((methylsulfonyl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 904 [M + 1].sup.+ 2-146 [00360] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((2-oxooxazolidin-3- yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-147 [00361] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((methylsulfonyl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 904 [M + 1].sup.+ 2-148 [00362] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((2-oxooxazolidin-3- yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 911 [M + 1].sup.+ 2-149 [00363] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1,1-dioxidothiomorpholino) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 959 [M + 1].sup.+ 2-150 [00364] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-((dimethyl(oxo)-16-sulfanylidene) amino)piperidin-1-yl)methyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 1000 [M + 1].sup.+ 2-151 [00365] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-(methylsulfonamido)piperidin- 1-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 1002 [M + 1].sup.+ 2-152 [00366] methyl (R)-(1-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)piperidin-4-yl)carbamate MS-ESI (m/z): 982 [M + 1].sup.+ 2-153 [00367] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(1,1-dioxidothiomorpholino) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-154 [00368] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methyl-4-oxido-1,4- azaphosphinan-1-yl)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 957 [M + 1].sup.+ 2-155 [00369] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-methyl-4-oxido-1,4- azaphosphinan-1-yl)ethyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 971 [M + 1].sup.+ 2-156 [00370] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-benzyl-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4′-chloro- 5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide MS-ESI (m/z): 902 [M + 1].sup.+ 2-157 [00371] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-fluorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 920 [M + 1].sup.+ 2-158 [00372] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-fluorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 920 [M + 1].sup.+ 2-159 [00373] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-chlorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b]+0[1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 936 [M + 1].sup.+ 2-160 [00374] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-chlorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 936 [M + 1].sup.+ 2-161 [00375] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((3-((5-methoxypyridin-2-yl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 933 [M + 1].sup.+ 2-162 [00376] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((5-methoxypyridin-2-yl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 933 [M + 1].sup.+ 2-163 [00377] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-3-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 903 [M + 1].sup.+ 2-164 [00378] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-4-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 903 [M + 1].sup.+ 2-165 [00379] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-phenyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 888 [M + 1].sup.+ 2-166 [00380] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-fluorophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 906 [M + 1].sup.+ 2-167 [00381] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-chlorophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 922 [M + 1].sup.+ 2-168 [00382] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-(methylsulfonyl)phenyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 966 [M + 1].sup.+ 2-169 [00383] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxyphenyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 918 [M + 1].sup.+ 2-170 [00384] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-cyanophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 913 [M + 1].sup.+ 2-171 [00385] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-2-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 889 [M + 1].sup.+ 2-172 [00386] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-phenyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 888 [M + 1].sup.+ 2-173 [00387] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-fluorophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 906 [M + 1].sup.+ 2-174 [00388] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-chlorophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 922 [M + 1].sup.+ 2-175 [00389] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-(methylsulfonyl)phenyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 966 [M + 1].sup.+ 2-176 [00390] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxyphenyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 918 [M + 1].sup.+ 2-177 [00391] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-2-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 889 [M + 1].sup.+ 2-178 [00392] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-fluoropyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 907 [M + 1].sup.+ 2-179 [00393] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-methoxypyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 919 [M + 1].sup.+ 2-180 [00394] 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((5-nitro-3-((tetrahydro-2H-pyran-4- yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-181 [00395] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((tetrahydro-2H-pyran- 4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-182 [00396] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((tetrahydro-2H-pyran- 4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-183 [00397] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((tetrahydro-2H-pyran- 4-yl)oxy)methyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 926 [M + 1].sup.+ 2-184 [00398] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((tetrahydro-2H-pyran- 4-yl)oxy)methyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 926 [M + 1].sup.+ 2-185 [00399] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 896 [M + 1].sup.+ 2-186 [00400] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 896 [M + 1].sup.+ 2-187 [00401] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 896 [M + 1].sup.+ 2-188 [00402] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-189 [00403] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-fluorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 920 [M + 1].sup.+ 2-190 [00404] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-fluorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 920 [M + 1].sup.+ 2-191 [00405] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-chlorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 936 [M + 1].sup.+ 2-192 [00406] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((5-(methylsulfonyl)pyridin- 2-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 981 [M + 1].sup.+ 2-193 [00407] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-methylpiperidin-4-yl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 923 2-194 [00408] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-((1-acetylpiperidin-4-yl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzamide MS-ESI (m/z): 951 [M + 1].sup.+ 2-195 [00409] methyl (S)-4-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)piperidine-1-carboxylate MS-ESI (m/z): 967 [M + 1].sup.+ 2-196 [00410] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-(methylsulfonyl)piperidin- 4-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 987 [M + 1].sup.+ 2-197 [00411] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-fluoropyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 907 [M + 1].sup.+ 2-198-A [00412] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-chloropyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-198-B [00413] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-chloropyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-199 [00414] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-2-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 903 [M + 1].sup.+ 2-200 [00415] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((5-methoxypyridin-2-yl) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 933 [M + 1].sup.+ 2-201 [00416] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-methylpiperidin-4-yl) methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-202 [00417] methyl (R)-4-((7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methyl)piperidine-1-carboxylate MS-ESI (m/z): 967 [M + 1].sup.+ 2-203 [00418] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-((1-acetylpiperidin-4-yl)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzamide MS-ESI (m/z): 951 [M + 1].sup.+ 2-204 [00419] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((1-(methylsulfonyl)piperidin- 4-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 987 [M + 1].sup.+ 2-205 [00420] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-cyanopyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 914 [M + 1].sup.+ 2-206 [00421] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-cyanophenyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 913 [M + 1].sup.+ 2-207 [00422] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-chlorobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 936 [M + 1].sup.+ 2-208 [00423] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-cyanobenzyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 927 [M + 1].sup.+ 2-209 [00424] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N- (((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4- ((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro- 1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-210 [00425] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3(((R)-3-methyl-4-(oxetan-3-yl) piperazin-1-yl)methyl)-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 980 [M + 1].sup.+ 2-211 [00426] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(pyridin-2-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 903 [M + 1].sup.+ 2-212 [00427] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 896 [M + 1].sup.+ 2-213 [00428] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 896 [M + 1].sup.+ 2-214 [00429] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-4-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-215 [00430] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1].sup.+ 2-216 [00431] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxy-4-methylcyclohexyl) methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-217 [00432] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(5-chloropyridin-2-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-218 [00433] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(5-chloropyridin-2-yl)-8-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 2-219 [00434] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxy-4-methylcyclohexyl) methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1].sup.+ 2-220 [00435] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(hydroxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 842 [M + 1].sup.+ 2-221 [00436] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-4-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-222 [00437] tert-butyl (R)-4-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) piperidine-1-carboxylate MS-ESI (m/z): 995 [M + 1].sup.+ 2-223 [00438] methyl (R)-4-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b]+0[1,4]oxazin-3-yl) piperidine-1-carboxylate MS-ESI (m/z): 953 [M + 1].sup.+ 2-224 [00439] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-(1-acetylpiperidin-4-yl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzamide MS-ESI (m/z): 937 [M + 1].sup.+ 2-225 [00440] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(1-(methylsulfonyl)piperidin- 4-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-226 [00441] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-4-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 895 [M + 1].sup.+ 2-227 [00442] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(1-methylpiperidin-4-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-228 [00443] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(piperidin-4-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 895 [M + 1].sup.+ 2-229 [00444] tert-butyl (S)-4-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) piperidine-1-carboxylate MS-ESI (m/z): 995 [M + 1].sup.+ 2-230 [00445] methyl (S)-4-(7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzoyl)sulfamoyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) piperidine-1-carboxylate MS-ESI (m/z): 953 [M + 1].sup.+ 2-231 [00446] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- N-((3-(1-acetylpiperidin-4-yl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)benzamide MS-ESI (m/z): 937 [M + 1].sup.+ 2-232 [00447] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(1-(methylsulfonyl)piperidin- 4-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 973 [M + 1].sup.+ 2-233 [00448] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(1-methylpiperidin-4-yl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 909 [M + 1].sup.+ 2-234 [00449] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-(((tetrahydro-2H-pyra 4-yl)oxy)methyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 926 [M + 1].sup.+ 2-235 [00450] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((5-nitro-3-((tetrahydro-2H-pyran- 4-yl)methyl)-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-236 [00451] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(isopropoxymethyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 884 [M + 1].sup.+ 2-237 [00452] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(isopropoxymethyl)-5-nitro-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 884 [M + 1].sup.+ 2-238 [00453] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-cyclohexyl-5-nitro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)sulfonyl) benzamide MS-ESI (m/z): 894 [M + 1].sup.+ 2-239A [00454] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1].sup.+ 2-239B [00455] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1].sup.+ 2-240A [00456] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 2-240B [00457] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1] .sup.+ 2-241 [00458] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(cyclopropoxymethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 882 [M + 1] .sup.+ 2-242 [00459] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(cyclopropoxymethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 882 [M + 1] .sup.+ 2-243 [00460] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-((((1r,4R)-4-hydroxycyclohexyl) oxy)methyl)-5-nitro-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 940 [M + 1] .sup.+ 2-244A [00461] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-244B [00462] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-hydroxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-245A [00463] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1] .sup.+ 2-245B [00464] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 910 [M + 1] .sup.+ 2-246A [00465] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methoxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1] .sup.+ 2-246B [00466] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methoxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1] .sup.+ 2-247A [00467] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-247B [00468] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-248A [00469] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-248B [00470] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-methoxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 924 [M + 1] .sup.+ 2-249A [00471] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methoxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1] .sup.+ 2-249B [00472] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra- hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methoxycyclohexyl)methyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 938 [M + 1] .sup.+ 2-250 [00473] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-((((1r,4R)-4-hydroxycyclohexyl) oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 940 [M + 1] .sup.+ 2-251 [00474] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-((((1r,4R)-4-methoxycyclohexyl) oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 954 [M + 1] .sup.+ 2-252 [00475] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-(((R)-3-((((1r,4R)-4-methoxycyclohexyl) oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo [b][1,4]oxazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 954 [M + 1] .sup.+

Example 3-1

(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-1)

[0376] ##STR00476##

[0377] The title compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-1) was prepared according to the synthetic method of 2-1 by replacing (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate C) with (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (Intermediate G). MS-ESI (m/z): 940 [M+1].sup.+.

Example 3-2

(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morphohnoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-2)

[0378] ##STR00477##

[0379] The title compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-2) was prepared according to the synthetic method of 2-1 by replacing 1-methylpiperazine and (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) with morpholine and (R)-2-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethyl methanesulfonate (Intermediate H). MS-ESI (m/z): 941 [M+1].sup.+.

[0380] Following essentially the same procedures described for Examples 3-1˜3-2 or or using similar synthetic methods or strategies, Examples 3-3˜3-20 listed in Table 3 were prepare. The structures and names of Examples 3-3˜3-20 are given in Table 3.

TABLE-US-00003 TABLE 3 EXAMPLE STRUCTURE NAME DATA 3-3  [00478] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(morpholinomethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 927 [M + 1].sup.+ 3-4  [00479] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((dimethylamino)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 885 [M + 1].sup.+ 3-5  [00480] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(hydroxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 858 [M + 1].sup.+ 3-6  [00481] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(methoxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 872 [M + 1].sup.+ 3-7  [00482] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(hydroxymethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 858 [M + 1].sup.+ 3-8  [00483] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((dimethylamino)methyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 885 [M + 1].sup.+ 3-9  [00484] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-((4-methylpiperazin-1-yl) methyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]thiazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 940 [M + 1].sup.+ 3-10 [00485] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(morpholinomethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 927 [M + 1].sup.+ 3-11 [00486] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-hydroxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 872 [M + 1].sup.+ 3-12 [00487] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-methoxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 886 [M + 1].sup.+ 3-13 [00488] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(dimethylamino)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 899 [M + 1].sup.+ 3-14 [00489] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-methylpiperazin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]thiazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 954 [M + 1].sup.+ 3-15 [00490] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-hydroxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 872 [M + 1].sup.+ 3-16 [00491] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-methoxyethyl)-5-nitro-3,4- dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 886 [M + 1].sup.+ 3-17 [00492] 2-((S)-7-(N-(2-((1H-pyrrolo[2,3-b]pyridin- 5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl) methyl)piperazin-1-yl)benzoyl)sulfamoyl)- 5-nitro-3,4-dihydro-2H-benzo[b][1,4] thiazin-3-yl)ethyl methanesulfinate MS-ESI (m/z): 934 [M + 1].sup.+ 3-18 [00493] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(methylsulfonyl)ethyl)-5- nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin- 7-yl)sulfonyl)benzamide MS-ESI (m/z): 934 [M + 1].sup.+ 3-19 [00494] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-(4-methylpiperazin-1-yl) ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] thiazin-7-yl)sulfonyl)benzamide MS-ESI (m/z): 954 [M + 1].sup.+ 3-20 [00495] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(2-morpholinoethyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl) sulfonyl)benzamide MS-ESI (m/z): 941 [M + 1].sup.+

Example 4-1

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxalth-6-yl)sulfonyl)benzamide (4-1)

[0381] ##STR00496##

[0382] The title compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxalin-6-yl)sulfonyl)benzamide (4-1) was prepared according to the synthetic method of 2-1 by replacing (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) with (S)-(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methyl methanesulfonate (Intermediate I). MS-ESI (m/z): 923 [M+1].sup.+.

[0383] Following essentially the same procedures described for Examples 4-1 or using similar synthetic strategies or methods, Examples 4-2˜4-5 listed in Table 4 was prepared. The structures and names of Examples 4-2˜4-5 is given in Table 4.

TABLE-US-00004 TABLE 4 EXAMPLE STRUCTURE NAME DATA 4-2 [00497] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(morpholinomethyl)-8-nitro- 1,2,3,4-tetrahydroquinoxalin-6-yl)sulfonyl) benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 4-3 [00498] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)- 8-nitro-1,2,3,4-tetrahydroquinoxalin- 6-yl)sulfonyl)benzamide MS-ESI (m/z): 923 [M + 1].sup.+ 4-4 [00499] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(morpholinomethyl)-8-nitro- 1,2,3,4-tetrahydroquinoxalin-6-yl)sulfonyl) benzamide MS-ESI (m/z): 910 [M + 1].sup.+ 4-5 [00500] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(2-(4-methylpiperazin-1-yl) ethyl)-8-nitro-1,2,3,4-tetrahydroquinoxalin- 6-yl)sulfonyl)benzamide MS-ESI (m/z): 937 [M + 1].sup.+

Example 5-1

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)benzamide (5-1)

[0384] ##STR00501##

3-nitrobenzene-1,2-diol (5-1a)

[0385] The title compound 3-nitrobenzene-1,2-diol (5-1a) was prepared according to the method described in WO2012/92880.

(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (5-1b)

[0386] The title compound (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (5-1b) was prepared according to the method described in US2006/63814.

(S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-nitrophenol (5-1c)

[0387] To a solution of 3-nitrobenzene-1,2-diol (5-1a) (0.10 g, 0.65 mmol) in DMSO (1.5 mL) was added NaOH(52 g, 1.3 mmol) at 25° C. The mixture was stirred at 25° C. for 15 min. Then (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (5-1b) was added to the mixture at 25° C. and stirred at 80° C. for 12 h. The mixture was poured into ice water (20 mL) at 0° C. The mixture was extracted by EtOAc, washed with brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-nitrophenol (5-1c), which was used for next step directly.

(S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (5-1d)

[0388] To a solution of (S)-2((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-nitrophenol (5-1d) (0.17 g, 0.63 mmol) in HOAc (0.7 mL) was added HBr (35% in HOAc, 0.45 mL) at 25° C. The mixture was stirred at 25° C. for 2 h. Then EtOH (3.0 mL) and NaOH(50% in H.sub.2O, 1.4 mL) was added to the mixture at 25° C. and stirred at 25° C. for 12 h. Then Con.HCl (1.4 mL) was added to the mixture at 25° C. The mixture was extracted by EtOAc, washed with brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:4) to give title compound (S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (5-1d).

(R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1e)

[0389] The title compound (R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1e) was prepared according to the synthetic method of (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (C-6) with (S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (5-1d).

(R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1f)

[0390] To a solution of PCl.sub.5 (0.27 g, 1.3 mmol) in sulfurochloridic acid (1.0 mL) was added (R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1e) (0.19 g, 0.67 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h. The mixture was poured into ice water (20 mL) at 0° C.The mixture was extracted by EtOAc, washed with brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1f), which was used for next step directly.

(R)-(8-nitro-6-sulfamoyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1g)

[0391] To a solution of (R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-10 (0.21 g, 0.57 mmol) in EtOAc (3.0 mL) was added NH.sub.3.H.sub.2O (0.2 mL) at 25° C. The mixture was stirred at 25° C. for 10 min. The mixture was poured into ice water (10 mL) at 0° C.The mixture was extracted by EtOAc, washed with brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (R)-(8-nitro-6-sulfamoyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1g), which was used for next step directly.

(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)benzamide (5-1)

[0392] The title compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzo [b][1,4]dioxin-6-yl)sulfonyl)benzamide (5-1) was prepared according to the synthetic method of 2-1 by replacing (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-1-benzo [b][1,4]oxazin-3-yl)methyl methanesulfonate (Intermediate C) with (R)-(8-nitro-6-sulfamoyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (5-1g). MS-ESI (m/z): 912 [M+1].sup.+.

[0393] Following essentially the same procedures described for Examples 5-1 or using similar synthetic methods or strategies, Examples 5-2˜5-4 listed in Table 5 was prepared. The structures and names of Examples 5-2˜5-4 is given in Table 5.

TABLE-US-00005 TABLE 5 EXAMPLE STRUCTURE NAME DATA 5-2 [00502] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-(4-hydroxycyclohexyl)-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+ 5-3 [00503] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1′-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-(morpholinomethyl)-8-nitro- 2,3-dihydrobenzo[b][1,4]dioxin-6-yl) sulfonyl)benzamide MS-ESI (m/z): 912 [M + 1].sup.+ 5-4 [00504] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[1,1'-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)- 8-nitro-2,3-dihydrobenzo[b][1,4] dioxin-6-yl)sulfonyl)benzamide MS-ESI (m/z): 925 [M + 1].sup.+

Example 6-1

N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide (6-1)

[0394] ##STR00505##

4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid (6-1a)

[0395] 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid (6-1a) was prepared according to the method described in WO2017/132474.

(R)-3-(((1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (6-1b)

[0396] The title compound (R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (6-1b) was prepared according to the synthetic method of 2-1a by replacing methyl O-(tert-butyldimethylsilyl)-L-serinate (C-2) and 1-methylpiperazine with methyl O-(tert-butyldimethylsilyl)-D-serinate and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane. MS-ESI (m/z): 371 [M+1].sup.+.

N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2. 2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide (6-1)

[0397] The title compound N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide (6-1) was prepared according to the synthetic method of 1-1 by replacing (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b) with (R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (6-1b) and 4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid (6-1a). MS-ESI (m/z): 947 [M+1].sup.+.

[0398] Following essentially the same procedures described for Examples 6-1 or using similar synthetic methods or strategies, Examples 6-2˜6-3 listed in Table 5 was prepared. The structures and names of Examples 6-2˜6-3 is given in Table 6.

TABLE-US-00006 TABLE 6 EXAMPLE STRUCTURE NAME DATA 6-2 [00506] (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)-N-((3-cyclopropyl-5-nitro- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) sulfonyl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e] pyridin-1(5H)-yl)benzamide MS-ESI (m/z): 876 [M + 1].sup.+ 6-3 [00507] (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazin-1-yl)-N-((5-nitro-3-(pyridin-2- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)sulfonyl)-2-(pyrazolo[4,3-b] pyrrolo[3,2-e]pyridin-1(5H)-yl) benzamide MS-ESI (m/z): 927 [M + 1].sup.+

Cell Proliferation Assays

[0399] MTS testing kit was purchased from Promega. The RPMI-1640, Fetal bovine serum and Penicillin-Streptomycin were purchased from Gibco. Dimethyl sulfoxide (DMSO) was purchased from Sigma.

[0400] To investigate whether a compound is able to inhibit the activity of BCL-2 in cells, a mechanism-based assay using DOHH2 (DSMZ No.® ACC 47) and RS4;11 (ATCC® CRL-1873™) cell was developed. In this assay, inhibition of Bcl-2 was detected by the inhibition of DOHH2 cells proliferation. DOHH2 cells were cultured in culture flasks to 40-80% confluence in RPMI-1640 plus 10% fetal bovine serum. Cells were collected and plated onto 96-well plates at desired cell density (5000 cells/well). Plates were incubated overnight at 37° C., with 5% CO.sub.2 to adhere. Compounds were added to the plates, and the final compound concentrations were 10000, 3333, 1111, 270, 124, 41, 14, 4.6 and 1.5 nM. Plates plated with DOHH2 or RS4;11 cells were placed at 37° C., with 5% CO.sub.2 for 120 h (DOHH2) or 72 h (RS4;11) respectively. 20 μl MTS/100 μl medium mixture solution were added to each well and incubate the plates for exactly 2 hours. The reaction was stopped by adding 25 μl 10% SDS per well. Measure absorbance at 490 nm and 650 nm (reference wavelength). IC.sub.50 was calculated using GraphPad Prism 5.0.

[0401] Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table 7.

TABLE-US-00007 DOHH2 RS4; 11 Example IC.sub.50 (nM) IC.sub.50 (nM) 1-1 80 48 1-2 79 38 1-3 20 8 1-4 308 / 1-5 211 51 1-6 221 / 1-7 26 3 1-8 27 1 1-9 66 80 1-10 33 16 1-11 154 69 1-12 299 58 1-13 91 74 1-14 57 52 1-15 50 15 1-16 73 16 1-17 61 56 1-18 5 18 1-19 96 93 1-20 170 / 1-21 12 1 1-22 175 47 1-23 57 20 1-24 41 73 1-25 6 6 1-26 102 12 1-27 51 / 2-1 6 1 2-2 8 2 2-3A 16 1 2-3B 33 8 2-4 139 / 2-5 12 3 2-6 18 2 2-7 95 72 2-8 67 14 2-9 33 10 2-10 28 9 2-11 53 12 2-12 19 1 2-13 33 9 2-14 15 4 2-15 50 20 2-16 34 4 2-17 20 8 2-18 9 4 2-19 70 36 2-20 59 29 2-21 8 1 2-22 2 1 2-23 33 7 2-24 115 72 2-25 10 8 2-26 19 6 2-27 12 1 2-28 1 1 2-29 7 1 2-30 8 1 2-31 18 7 2-32 34 18 2-33 25 11 2-34 41 14 2-35 30 5 2-36 33 7 2-37 25 1 2-38 27 1 2-39 33 9 2-40 36 22 2-41 23 2 2-42 38 6 2-43 10 1 2-44 51 46 2-45 17 12 2-46 7 1 2-47 12 22 2-48 9 14 2-49 12 16 2-50 22 9 2-51 13 10 2-52 31 25 2-53 543 53 2-54 134 61 2-56 571 41 2-57 392 / 2-58 868 / 2-59 730 / 2-60 82 1 2-61 444 48 2-62 230 / 2-63 64 12 2-64 70 25 2-65 14 20 2-66 13 18 2-67 1316 / 2-68 83 26 2-70 28 5 2-71 43 58 2-72 24 6 2-73 69 79 2-74 108 64 2-75 64 1 2-76 120 / 2-77 602 50 2-78 15 6 2-79 55 7 2-80 49 7 2-81 14 3 2-82 9 1 2-83 13 1 2-84 82 26 2-85 434 / 2-86 648 / 2-87 26 7 2-88 14 2 2-89 55 50 2-90 22 8 2-91 49 5 2-92 79 5 2-93 16 40 2-94 1 20 2-95 19 45 2-96 85 72 2-97 23 23 2-98 38 17 2-99 20 8 2-100 31 22 2-102 95 10 2-103 490 16 2-104 173 7 2-105 51 35 2-106 19 9 2-107 22 8 2-108 51 16 2-109 56 11 2-110 96 2 2-111 26 28 2-112 15 11 2-113 20 6 2-114 48 1 2-115 38 6 2-116 83 16 2-117 41 44 2-118 649 11 2-121 48 36 2-122 660 / 2-124 649 / 2-125 43 19 2-126 11 5 2-127 42 23 2-128 28 20 2-129 16 9 2-130 26 14 2-131 39 9 2-132 28 2 2-133 8 1 2-134 39 2 2-135 186 / 2-136 378 / 2-137 139 / 2-138 166 72 2-139 338 88 2-142 28 3 2-143 35 35 2-144 14 3 2-145 87 1 2-146 160 / 2-147 135 16 2-149 247 50 2-150 67 45 2-151 2 1 2-152 1 1 2-153 8 1 2-154 201 24 2-155 459 66 2-156 6 19 2-157 39 10 2-158 135 43 2-159 47 29 2-160 168 95 2-161 20 17 2-162 325 43 2-163 53 29 2-164 16 34 2-165 77 / 2-166 300 82 2-167 29 / 2-168 32 33 2-169 39 / 2-170 464 / 2-171 302 / 2-172 14 / 2-173 24 / 2-174 23 / 2-175 139 53 2-176 547 64 2-177 119 13 2-178 28 / 2-179 380 18 2-180 15 8 2-181 84 45 2-182 16 3 2-183 20 4 2-184 11 3 2-185 3 1 2-186 13 1 / / / 2-187 14 2 2-188 19 1 2-189 148 78 2-190 25 8 2-191 153 / 2-192 143 5 2-193 28 1 2-194 74 5 2-195 138 4 2-196 94 6 2-197 412 / 2-198B 444 / 2-199 55 18 2-200 218 3 2-201 145 22 2-202 63 36 2-203 96 20 2-204 17 26 2-206 312 21 2-207 402 / 2-208 110 17 2-209 35 1 2-210 35 7 2-211 92 35 2-212 27 8 2-213 41 8 2-214 465 16 2-215 65 3 2-216 268 13 2-217 715 / 2-218 507 / 2-219 662 / 2-220 36 8 2-221 474 30 2-222 3 25 2-223 11 1 2-224 3 4 2-225 15 2 2-226 48 10 2-227 6 1 2-228 48 / 2-229 1 38 2-230 2 1 2-231 5 1 2-232 1 6 2-233 13 17 2-234 6 14 2-235 23 10 2-236 6 1 2-237 3 14 2-238 18 9 2-239A 5 1 2-239B 1 1 2-240A 5 1 2-240B 1 1 2-241 11 4 2-243 1 9 2-244A 7 3 2-244B 1 3 2-245A 1 1 2-245B 1 1 2-246B 13 29 2-247A 19 24 2-247B 36 45 2-248A 27 35 2-248B 14 64 2-250 7 1 2-251 44 1 2-252 83 29 3-1 3 1 3-2 13 3 3-3 58 35 3-4 41 12 3-5 12 8 3-6 14 8 3-7 31 10 3-8 67 17 3-9 24 13 3-10 32 11 3-11 16 11 3-12 120 84 3-13 2 2 3-14 9 4 3-15 48 13 3-16 132 33 3-17 49 19 3-18 54 20 3-19 6 1 3-20 9 2 4-1 13 1 4-2 29 9 4-3 38 46 4-4 28 14 4-5 232 / 5-1 17 9 5-2 25 1 5-3 12 4 5-4 13 34 6-1 73 2 6-2 264 / 6-3 185 / / / / / / /