RU2782469C2 - Apoptosis-inducing agents - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes specific compounds indicated in cl. 1 of the claims, and a pharmaceutical composition based on them.

EFFECT: compounds having inhibitory activity relatively to Bcl-2.

14 cl, 7 tbl, 311 ex

Description

[1] This application claims priority under US Provisional Application Nos. 62/486,965 and 62/572,417, the contents of which are hereby incorporated by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[2] Certain compounds or pharmaceutically acceptable salts thereof are provided that can inhibit anti-apoptotic Bcl-2 family proteins and may be useful in the treatment of hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.

BACKGROUND OF THE INVENTION

[3] Hyperproliferative diseases such as cancer and inflammation are attracting the scientific community in terms of providing therapeutic effects. In this regard, efforts have been made to identify and identify specific mechanisms that play a role in the spread of diseases.

[4] Protein–protein interactions (PPIs) control many biological processes such as cell proliferation, growth, differentiation, signal transduction, and cell apoptosis. Anomalous regulation of PPM leads to various diseases. Thus, PPIs represent an important class of molecular targets for novel human treatments.

[5] The B-cell lymphoma-2 (Bcl-2) protein family plays a central role in the regulation of apoptosis, which is vital for proper tissue development and cellular homeostasis. Apoptosis occurs through the activation of two different pathways. The extrinsic pathway is triggered by activation of the intrinsic pathway involving members of the Bcl-2 protein family. The Bcl-2 family protein includes anti-apoptotic proteins such as Bcl-2, Bcl-X _L and Mcl-1 and pro-apoptotic proteins including Bid, Bim, Bad, Bak and Bax.

[6] In many cases, anti-apoptotic members of the Bcl-2 family appear to be upregulated in cancers and are associated with disease stage and prognosis. Therefore, Bcl-2 proteins are being investigated as potential therapeutic drug targets, which include, for example, Bcl-2 and Bcl-X _L . Expression of Bcl-2 proteins is an independent indicator of poor prognosis in tumors including chronic lymphocytic leukemia (CLL), prostate cancer and small cell lung cancer (SCLC). In other tumors, such as colorectal cancer, Bcl-X _L expression is associated with grade and stage, and in hepatocellular cancer, Bcl-X _L expression is an independent marker of poorer overall and disease-free survival.

[7] Therefore, a compound having a Bcl-2 inhibitory activity would be useful for preventing or treating cancer. In this regard, a new class of Bcl-2 inhibitors has been provided. Although Bcl-2 inhibitors have been described in the art, for example in WO 2011149492, many suffer from short half-lives or toxicity. Therefore, there is a need for new Bcl-2 inhibitors that have at least one advantageous property selected from activity, stability, selectivity, toxicity, pharmacodynamic and pharmacokinetic properties as an alternative for the treatment of hyperproliferative diseases. In this regard, a new class of Bcl-2 inhibitors has been provided.

DISCLOSURE OF THE INVENTION

[8] Certain novel compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, and their use as pharmaceuticals are disclosed herein.

[9] In one aspect, a compound of formula (I) is disclosed herein:

(I)

(I)

or a pharmaceutically acceptable salt thereof, wherein:

L^one, L², L³ and L^four independently selected from –(CR^CR^D)_u–, –(CR^CR^D)_uO(CR^CR^D)_t–, –(CR^CR^D)_uNR^A(CR^CR^D5)_t–, –(CR^CR^D)_uS(CR^CR^D)_t–, –(CR^CR^D)_uC(O)(CR^CR^D)_t–, –(CR^CR^D)_uC(=NR^E)(CR^CR^D)_t–, –(CR^CR^D)_uC(S)(CR^CR^D)_t–, –(CR^CR^D)_uC(O)O(CR^CR^D)_t–, –(CR^CR^D)_uOC(O)(CR^CR^D)_t–, –(CR^CR^D)_uC(O)NR^A(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(O)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(O)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uC(=NR^E)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uNR^BC(=NR^E)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(=NR^E)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uC(S)NR^A(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(S)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(S)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uS(O)_r(CR^CR^D)_t–, –(CR^CR^D)_uS(O)_rNR^A(CR^CR^D)_t–, –(CR^C5R^D5)_uNR^AS(O)_r(CR^CR^D)_t– and –(CR^CR^D)_uNR^AS(O)_rNR^B(CR^CR^D)_t-;

Q ¹ and Q ² are independently selected from aryl and heteroaryl, where aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents independently selected from R ^X ;

Q ³ is selected from aryl, C _3-10 cycloalkyl, heteroaryl and heterocyclyl, where aryl, cycloalkyl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from R ^X ;

when Q ³ is C _3-10 cycloalkyl, Y ¹ , Y ² and Y ³ are independently selected from (CR ^6a R ^6b ) _o , where cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

when Q ³ is heteroaryl, Y ¹ , Y ² and Y ³ are independently selected from bond, C, N, O and S, where heteroaryl is unsubstituted or substituted with at least one or two substituents independently selected from R ^X ;

when Q ³ is heterocyclyl, Y ¹ , Y ² and Y ³ are independently selected from (CR ^6a R ^6b ) _o , N, O and S, wherein the heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

X ¹ and X ² are independently selected from C and N;

X ³ is selected from CR ^4c R ^4d and O;

Y ⁴ is selected from C and N;

Z is selected from C and N;

each R ¹ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A1 R ^B1 , –OR ^A1 , –C(O)R ^A1 , – C(=NR ^E1 )R ^A1 , –C(=N–OR ^B1 )R ^A1 , –C(O)OR ^A1 , –OC(O)R ^A1 , –C(O)NR ^A1 R ^B1 , –NR ^A1 C(O)R ^B1 , –C(=NR ^E1 )NR ^A1 R ^B1 , –NR ^A1 C(=NR ^E1 )R ^B1 , –OC(O)NR ^A1 R ^B1 , –NR ^A1 C(O)OR ^B1 , –NR ^A1 C(O)NR ^A1 R ^B1 , –NR ^A1 C(S)NR ^A1 R ^B1 , –NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , –S(O) _r R ^A1 , –S (O)(=NR ^E1 )R ^B1 , –N=S(O)R ^A1 R ^B1 , –S(O) ₂ OR ^A1 , –OS(O) ₂ R ^A1 , –NR ^A1 S(O) _r R ^B1 , –NR ^A1 S(O)(=NR ^E1 )R ^B1 , –S(O) _r NR ^A1 R ^B1 , –S(O)(=NR ^E1 )NR ^A1 R ^B1 , –NR ^A1 S(O) ₂ NR ^A1 R ^B1 , –NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , –P(O)R ^A1 R ^B1 and –P(O)(OR ^A1 )(OR ^B1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

each R ² is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A2 R ^B2 , –OR ^A2 , –C(O)R ^A2 , – C(=NR ^E2 )R ^A2 , –C(=N–OR ^B2 )R ^A2 , –C(O)OR ^A2 , –OC(O)R ^A2 , –C(O)NR ^A2 R ^B2 , –NR ^A2 C(O)R ^B2 , –C(=NR ^E2 )NR ^A2 R ^B2 , –NR ^A2 C(=NR ^E2 )R ^B2 , –OC(O)NR ^A2 R ^B2 , –NR ^A2 C(O)OR ^B2 , –NR ^A2 C(O)NR ^A2 R ^B2 , –NR ^A2 C(S)NR ^A2 R ^B2 , –NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , –S(O) _r R ^A2 , –S (O)(=NR ^E2 )R ^B2 , –N=S(O)R ^A2 R ^B2 , –S(O) ₂ OR ^A2 , –OS(O) ₂ R ^A2 , –NR ^A2 S(O) _r R ^B2 , –NR ^A2 S(O)(=NR ^E2 )R ^B2 , –S(O) _r NR ^A2 R ^B2 , –S(O)(=NR ^E2 )NR ^A2 R ^B2 , –NR ^A2 S(O) ₂ NR ^A2 R ^B2 , –NR ^A2 S(O)(=NR ^E2 )NR ^A2 R ^B2 , –P(O)R ^A2 R ^B2 and –P(O)(OR ^A2 )(OR ^B2 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

each R ³ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A3 R ^B3 , –OR ^A3 , –C(O)R ^A3 , – C(=NR ^E3 )R ^A3 , –C(=N–OR ^B3 )R ^A3 , –C(O)OR ^A3 , –OC(O)R ^A3 , –C(O)NR ^A3 R ^B3 , –NR ^A3 C(O)R ^B3 , –C(=NR ^E3 )NR ^A3 R ^B3 , –NR ^A3 C(=NR ^E3 )R ^B3 , –OC(O)NR ^A3 R ^B3 , –NR ^A3 C(O)OR ^B3 , –NR ^A3 C(O)NR ^A3 R ^B3 , –NR ^A3 C(S)NR ^A3 R ^B3 , –NR ^A3 C(=NR ^E3 )NR ^A3 R ^B3 , –S(O) _r R ^A3 , –S (O)(=NR ^E3 )R ^B3 , –N=S(O)R ^A3 R ^B3 , –S(O) ₂ OR ^A3 , –OS(O) ₂ R ^A3 , –NR ^A3 S(O) _r R ^B3 , –NR ^A3 S(O)(=NR ^E3 )R ^B3 , –S(O) _r NR ^A3 R ^B3 , –S(O)(=NR ^E3 )NR ^A3 R ^B3 , –NR ^A3 S(O) ₂ NR ^A3 R ^B3 , –NR ^A3 S(O)(=NR ^E3 )NR ^A3 R ^B3 , –P(O)R ^A3 R ^B3 and –P(O)(OR ^A3 )(OR ^B3 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

R ^4a , R ^4b , R ^4c and R ^4d are independently selected from hydrogen, halogen, C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _{1 –4} alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A4 R ^B4 , –OR ^A4 , – C(O)R ^A4 , –C(=NR ^E4 )R ^A4 , –C(=N–OR ^B4 )R ^A4 , –C(O)OR ^A4 , –OC(O)R ^A4 , –C(O) NR ^A4 R ^B4 , –NR ^A4 C(O)R ^B4 , –C(=NR ^E4 )NR ^A4 R ^B4 , –NR ^A4 C(=NR ^E4 )R ^B4 , –OC(O)NR ^A4 R ^B4 , – NR ^A4 C(O)OR ^B4 , –NR ^A4 C(O)NR ^A4 R ^B4 , –NR ^A4 C(S)NR ^A4 R ^B4 , –NR ^A4 C(=NR ^E4 )NR ^A4 R ^B4 , –S( O) _r R ^A4 , –S(O)(=NR ^E4 )R ^B4 , –N=S(O)R ^A4 R ^B4 , –S(O) ₂ OR ^A4 , –OS(O) ₂ R ^A4 , – NR ^A4 S(O) _r R ^B4 , –NR ^A4 S(O)(=NR ^E4 )R ^B4 , –S(O) _r NR ^A4 R ^B4 , –S(O)(=NR ^E4 )NR ^A4 R ^B4 , –NR ^A4 S(O) ₂ NR ^A4 R ^B4 , –NR ^A4 S(O)(=NR ^E4 )NR ^A4 R ^B4 , –P(O)R ^A4 R ^B4 and –P(O)(OR ^A4 ) (OR ^B4 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one with it a substituent such as one, two, three or four substituents independently selected from R ^X ;

or "R ^4a and R ^4b " or "R ^4c and R ^4d " 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 ^X groups;

each R ^5a is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one , two, three or four substituents independently selected from R ^X ;

R ^5b is selected from hydrogen, halogen, C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _{1 –4} alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A5 R ^B5 , –OR ^A5 , –C(O)R ^A5 , –C( =NR ^E5 )R ^A5 , –C(=N–OR ^B5 )R ^A5 , –C(O)OR ^A5 , –OC(O)R ^A5 , –C(O)NR ^A5 R ^B5 , –NR ^A5 C( O)R ^B5 , –C(=NR ^E5 )NR ^A5 R ^B5 , –NR ^A5 C(=NR ^E5 )R ^B5 , –OC(O)NR ^A5 R ^B5 , –NR ^A5 C(O)OR ^B5 , – NR ^A5 C(O)NR ^A5 R ^B5 , –NR ^A5 C(S)NR ^A5 R ^B5 , –NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , –S(O) _r R ^A5 , –S(O )(=NR ^E5 )R ^B5 , –N=S(O)R ^A5 R ^B5 , –S(O) ₂ OR ^A5 , –OS(O) ₂ R ^A5 , –NR ^A5 S(O) _r R ^B5 , –NR ^A5 S(O)(=NR ^E5 )R ^B5 , –S(O) _r NR ^A5 R ^B5 , –S(O)(=NR ^E5 )NR ^A5 R ^B5 , –NR ^A5 S(O) ₂ NR ^A5 R ^B5 , –NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , –P(O)R ^A5 R ^B5 and –P(O)(ORA5)(ORB5), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent such as one, two , three or four substituents independently selected from R ^X ;

each R ^6a and R ^6b is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl , heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A6 R ^B6 , –OR ^A6 , –C(O)R ^A6 , –C(=NR ^E6 )R ^A6 , –C(=N–OR ^B6 )R ^A6 , –C(O)OR ^A6 , –OC(O)R ^A6 , –C(O)NR ^A6 R ^B6 , –NR ^A6 C(O)R ^B6 , –C(=NR ^E6 )NR ^A6 R ^B6 , –NR ^A6 C(=NR ^E6 )R ^B6 , –OC(O)NR ^A6 R ^B6 , –NR ^A6 C(O )OR ^B6 , –NR ^A6 C(O)NR ^A6 R ^B6 , –NR ^A6 C(S)NR ^A6 R ^B6 , –NR ^A6 C(=NR ^E6 )NR ^A6 R ^B6 , –S(O) _r R ^A6 , –S(O)(=NR ^E6 )R ^B6 , –N=S(O)R ^A6 R ^B6 , –S(O) ₂ OR ^A6 , –OS(O) ₂ R ^A6 , –NR ^A6 S(O ) _r R ^B6 , –NR ^A6 S(O)(=NR ^E6 )R ^B6 , –S(O) _r NR ^A6 R ^B6 , –S(O)(=NR ^E6 )NR ^A6 R ^B6 , –NR ^A6 S (O) ₂ NR ^A6 R ^B6 , –NR ^A6 S(O)(=NR ^E6 )NR ^A6 R ^B6 , –P(O)R ^A6 R ^B6 and –P(O)(OR ^A6 )(OR ^B6 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substitution a parent such as one, two, three or four substituents independently selected from R ^X ;

or R ^6a and R ^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 ^X groups;

each R ^A , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^B , R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 and R ^B6 independently selected from hydrogen, C _{1– 10} alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _{1– 4} alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R ^X ;

or each "R ^A and R ^B ", "R ^A1 and R ^B1 ", "R ^A2 and R ^B2 ", "R ^A3 and R ^B3 ", "R ^A4 and R ^B4 ", "R ^A5 and R ^B5 " and "R ^A6 and R ^B6 " together with the atom(s) to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus , and optionally substituted with 1, 2 or 3 R ^X groups;

each RC and ^RD is independently selected from hydrogen, halogen, ^C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl , heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least at least one substituent, such as one, two, three or four substituents independently selected from R ^X ;

or ^RC and ^RD together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1, 2 or 3 R ^X groups;

each R ^E , R ^E1 , R ^E2 , R ^E3 , R ^E4 , R ^E5 and R ^E6 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , –S(O) _r R ^a1 , –C(O)R ^a1 , C(O)OR ^a1 , –C(O)NR ^a1 R ^b1 and –S(O) _r NR ^a1 R ^b1 , where alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from R ^Y ;

each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 –4} alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, halogen, CN, NO ₂ , –(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t OR ^b1 , –(CR ^c1 R ^d1 ) _t C(O)R ^a1 , –(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , –(CR ^c1 R ^d1 ) _t C(=N– OR ^b1 )R ^a1 , –(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , –(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , –(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , –(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C (=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , –(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t N=S(O )R ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , –(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and –(CR ^c1 R ^d1 ) _t P(O)( OR ^a1 )(OR ^b1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^Y ;

each R ^a1 and each R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted at least one substituent such as one, two, three or four substituents independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a 4-12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted at at least one substituent such as one, two, three or four substituents independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1, 2 or 3 groups R ^Y ;

each ^Re1 is independently selected from hydrogen, C _1–10 alkyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, CN, NO ₂ , –OR ^a2 , –SR ^a2 , –S(O) _r R ^a2 , –C(O)R ^a2 , –C(O)OR ^a2 , –S(O) _r NR ^a2 R ^b2 and –C(O)NR ^a2 R ^b2 ;

each R ^{Y is} independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, halogen, CN, NO ₂ , –(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t OR ^b2 , –(CR ^c2 R ^d2 ) _t C(O)R ^a2 , –(CR ^c2 R ^d2 ) _t C(=NR ^e2 )R ^a1 , –(CR ^c2 R ^d2 ) _t C(=N–OR ^b2 )R ^a2 , –(CR ^c2 R ^d2 ) _t C(O)OR ^b2 , –(CR ^c2 R ^d2 ) _t OC(O)R ^b2 , –(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , –(CR ^c2 R ^d2 ) _t C(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(= NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)OR ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(S)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , – (CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , –(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t N=S(O)R ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t S(O) ₂ OR ^b2 , –(CR ^c2 R ^d2 ) _t OS(O) ₂ R ^b2 , –(CR ^c2 R ^d2 ) _t N R ^a2 S(O) _r R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 and –(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )( OR ^b2 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from OH, CN, amino, halogen , C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^a2 and each R ^b2 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _{1 –10} alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1–10 alkylamino, C _3–10 cycloalkylamino, di(C _1–10 alkyl)amino, heterocyclyl, heterocyclyl–C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl each is unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl )amino;

or R ^a2 and R ^b2 together with the atom(s) to which they are attached form a 4-12-membered heterocyclic ring 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 halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _{3- 10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1–10 alkylamino, C _3–10 cycloalkylamino, di(C _1–10 alkyl)amino, heterocyclyl, heterocyclyl– C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3–10 cycloalkyl, OH, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, amino, C _1–10 alkylamino, C _3–10 cycloalkylamino, and di(C _{1– 10} alkyl)amino;

or R ^c2 and R ^d2 together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1 or 2 substituents independently selected from halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each ^Re2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, - C(O)C _1–4 alkyl, –C(O)C _3–10 cycloalkyl, –C(O)OC _1–4 alkyl, –C(O)OC _3–10 cycloalkyl, –C(O)N( C _1–4 alkyl) ₂ , –C(O)N(C _3–10 cycloalkyl) ₂ , –S(O) ₂ C _1–4 alkyl, –S(O) ₂ C _3–10 cycloalkyl, –S( O) ₂ N(C _1–4 alkyl) ₂ and –S(O) ₂ N(C _3–10 cycloalkyl) ₂ ;;

m is selected from 0, 1, 2 and 3;

n is selected from 0, 1, 2 and 3;

o is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is chosen from 0 and 1;

each r is independently selected from 0, 1, and 2;

each t is independently selected from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3 and 4.

[10] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[11] In yet another aspect, the present disclosure provides methods for modulating Bcl-2 comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof, thereby modulating said Bcl-2.

[12] In yet another aspect, a method is disclosed for treating, alleviating, or preventing a condition that responds to Bcl-2 inhibition, comprising administering to a system or subject in need of such treatment, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or its pharmaceutical compositions, and optionally in combination with a second therapeutic agent, thereby treating said condition.

[13] Alternatively, the present disclosure provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition mediated by Bcl-2. In specific embodiments, the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by Bcl-2.

[14] Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed for the treatment of a condition mediated by Bcl-2.

[15] In particular, the condition herein includes, but is not limited to, an autoimmune disease, graft versus host disease, an infectious disease, or a cell proliferative disorder.

[16] In addition, the disclosure provides methods for treating a cell proliferative disorder comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

[17] Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a cell proliferative disorder. In specific examples, the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent for the treatment of a cell proliferative disorder.

[18] In particular, the cell proliferative disorder disclosed herein includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or tumor of the breast, kidney, prostate, colon, thyroid, ovary, pancreas, neuronal tumor , tumor of the lung, uterus or gastrointestinal tract.

[19] In the above methods of using the compounds of the disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system containing cells or tissues, or to a subject including a mammalian subject such as a human or animal.

Certain terminology

[20] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as is generally known to a person skilled in the art to which the claimed subject matter relates. All patents, patent applications, published materials, which are referenced in the entire disclosure of this document, unless otherwise indicated, are incorporated by reference in their entirety. In the event that there are multiple definitions for terms in this document, those in this section shall prevail.

[21] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should also be noted that the use of "or" means "and/or" unless otherwise noted. In addition, the use of the term "including", as well as other forms such as "include", "includes" and "included", is not limiting. Likewise, the use of the term "comprising" as well as other forms such as "comprise", "comprises", and "comprised" is not intended to be limiting.

[22] Definitions of standard chemical terms can be found in reference publications, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4th Edition" Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR spectroscopy and UV/visible spectroscopy and pharmacology are used in the art. Unless specifically defined, the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry and the laboratory procedures and methods of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are known to those skilled in the art. the field of technology. Standard techniques can be used for chemical syntheses, chemical analyses, drug substance preparation, formulation and delivery, and patient management. Reactions and purification methods can be performed, for example, using sets of manufacturer's specifications, or as they are usually performed in the art, or as described herein. The above techniques and procedures can generally be performed by conventional methods well known in the art, and are described in various general and more specific references, which are cited and discussed in the present description. Throughout the description, the groups and their substituents can be selected by those skilled in the art to obtain stable fragments and compounds.

[23] Where groups of substituents are defined by their traditional left-to-right chemical formulas, they equally cover chemically identical substituents that would result from right-to-left writing of the structure. As a non-limiting example, CH ₂ O is equivalent to OCH ₂ .

[24] The term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. It should be understood that substitution at a given atom is limited by valence. In all definitions, the term "C _i-j " denotes a range that includes endpoints, where i and j are integers and indicate the number of carbon atoms. Examples include C _1-4 , C _1-10 , C _3-10 and the like.

[25] The term "alkyl", used alone or in combination with other terms, refers to both branched and linear saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. Unless otherwise indicated, "alkyl" refers to C _1-10 alkyl. For example, C _1-6 as in "C _1-6 alkyl" is defined as including groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement. For example, "C _1-8 alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

[26] The term "cycloalkyl", used alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system. Monocyclic cycloalkyl is a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A monocyclic ring may contain one or two alkylene bridges, each of which consists of one, two or three carbon atoms, each of which links two non-adjacent carbon atoms of the ring system. Representative examples of such bridged cycloalkyl ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. 1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03.7]nonane and tricyclo[3.3.1.13.7]decane (adamantane). Monocyclic and bridged cycloalkyl can be attached to the original molecular fragment through any substitutable atom contained in the ring system.

[27] The term "alkenyl", whether used alone or in combination with other terms, refers to a non-aromatic hydrocarbon radical, linear, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus "C _2-6 alkenyl" means an alkenyl radical having 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.

[28] The term "alkynyl", used alone or in combination with other terms, refers to a hydrocarbon radical, linear, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Thus "C _2-6 alkynyl" means an alkynyl radical having 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and 3-methylbutynyl. The linear, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

[29] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine.

[30] The term "alkoxy", used alone or in combination with other terms, refers to an alkyl radical that is connected by a single bond to an oxygen atom. The point of attachment of the alkoxy radical to the molecule is through the oxygen atom. An alkoxy radical can be depicted as -O-alkyl. The term "C _1-10 alkoxy" refers to an alkoxy radical containing from one to ten carbon atoms, having straight or branched moieties. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

[31] The term "cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl radical that is connected by a single bond to an oxygen atom. The point of attachment of the cycloalkoxy radical to the molecule is through the oxygen atom. The cycloalkoxy radical can be depicted as -O-cycloalkyl. "C _3-10 cycloalkoxy" refers to a cycloalkoxy radical containing three to ten carbon atoms. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[32] The term "alkylthio", used alone or in combination with other terms, refers to an alkyl radical that is connected by a single bond to a sulfur atom. The point of attachment of the alkylthio radical to the molecule is through the sulfur atom. The alkylthio radical can be depicted as -S-alkyl. The term "C _1-10 alkylthio" refers to an alkylthio radical containing from one to ten carbon atoms, having linear or branched moieties. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

[33] The term "cycloalkylthio", used alone or in combination with other terms, refers to a cycloalkyl radical that is connected by a single bond to a sulfur atom. The point of attachment of the cycloalkylthio radical to the molecule is through the sulfur atom. A cycloalkylthio radical can be depicted as -S-cycloalkyl. "C _3-10 cycloalkylthio" refers to a cycloalkylthio radical containing three to ten carbon atoms. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

[34] The term "alkylamino", used alone or in combination with other terms, refers to an alkyl radical that is connected by a single bond to a nitrogen atom. The point of attachment of the alkylamino radical to the molecule is through the nitrogen atom. The alkylamino radical can be denoted as –NH(alkyl). The term "C _1-10 alkylamino" refers to an alkylamino group containing from one to ten carbon atoms, having linear or branched moieties. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, and the like.

[35] The term "cycloalkylamino", alone or in combination with other terms, refers to a cycloalkyl radical that is connected by a single bond to a nitrogen atom. The point of attachment of the cycloalkylamino radical to the molecule is through the nitrogen atom. The cycloalkylamino radical may be denoted as –NH(cycloalkyl). "C _3-10 cycloalkylamino" refers to a cycloalkylamino group containing three to ten carbon atoms. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.

[36] The term "di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl radicals that are connected by a single bond to a nitrogen atom. The point of attachment of the di(alkyl)amino radical to the molecule is through the nitrogen atom. The di(alkyl)amino radical may be denoted as –N(alkyl) ₂ . The term "di(C _1-10 alkyl)amino" refers to a di(C _1-10 alkyl)amino radical, where each of the alkyl radicals independently contains from one to ten carbon atoms having linear or branched moieties.

[37] The term "aryl", used alone or in combination with other terms, includes: 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indan and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, such as fluorene. In cases where the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, the attachment is meant to be through an aromatic ring.

[38] For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5-7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is on the carbocyclic aromatic ring. Divalent radicals formed from substituted benzene derivatives and having free valencies at the ring atoms are called substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in "-yl" by removing one hydrogen atom from the free-valence carbon atom are named by adding "-iden" to the name of the corresponding monovalent radical, e.g., naphthyl group with two dots addition is called naphthylidene. Aryl, however, does not in any way encompass or overlap with heteroaryl, as specifically defined below. Therefore, when one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is heteroaryl and not aryl as defined herein.

[39] The term "heteroaryl", used alone or in combination with other terms, refers to

5-8 membered aromatic monocyclic rings containing one or more, for example 1 to 4, or in some embodiments 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;

8-12-membered bicyclic rings containing one or more, for example, from 1 to 4 or, in some embodiments, from 1 to 3, heteroatoms selected from N, O and S, with the remaining atoms of the ring representing carbon, and where at least one heteroatom is present in the aromatic ring; and

11-14-membered tricyclic rings containing one or more, for example, 1 to 4 or, in some embodiments, 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and where at least one heteroatom is present in the aromatic ring.

[40] When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no more than 1.

[41] Examples of heteroaryl groups include, but are not limited to (as numbered from the position of the bond assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2 ,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, indolinyl, pyridizinyl , triazolyl, quinolinyl, pyrazolyl and 5,6,7,8-tetrahydroisoquinoline.

[42] Other heteroaryl groups include, but are not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. As in the following definition of a heterocycle, "heteroaryl" also includes the N-oxide derivative of any nitrogen-containing heteroaryl.

[43] Divalent radicals derived from monovalent heteroaryl radicals whose names end in "-yl" by removing one hydrogen atom from a free-valent atom are named by adding "-iden" to the name of the corresponding monovalent radical, e.g., a pyridyl group with two points of attachment is pyridylidene. Heteroaryl does not span or overlap with aryl as defined above.

[44] In cases where the heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, the attachment is understood to be through an aromatic ring or through a ring containing a heteroatom, respectively.

[45] The term "heterocycle", whether used alone or in combination with other terms (and variations thereof such as "heterocyclic" or "heterocyclyl"), broadly refers to a single aliphatic ring, typically with 3-12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three, heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, as well as combinations comprising at least one of the above heteroatoms. Alternatively, a heterocycle as defined above may be a multicyclic ring system (e.g., bicyclic) in which two or more rings may be fused or linked together by a bridge or one common atom, where at least one such ring contains one or more heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. "Heterocycle" also refers to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, fused to a 5- and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at heterocyclic ring. Rings may be saturated or have one or more double bonds (ie, partially unsaturated). The heterocycle may be substituted with oxo or imino, and the imino may be unsubstituted or substituted. The point of attachment may be carbon or a heteroatom in the heterocyclic ring, provided that the attachment results in a stable structure. When a heterocyclic ring has substituents, it is understood that substituents may be attached to any atom in the ring, be it a heteroatom or a carbon atom, provided that a stable chemical structure results. The heterocycle does not overlap with the heteroaryl.

[46] Suitable heterocycles include, for example (as numbered from the position of the bond given priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl, 2,5-piperazinyl, 1,4-piperazinyl and 2,3-pyridazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered, with oxygen given priority 1). The substituted heterocycle also includes ring systems substituted with one or more oxo groups, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl. Bicyclic heterocycles include, for example:

[47] As used herein, the term "aryl-alkyl" refers to an alkyl moiety substituted with an aryl group. Examples of aryl-alkyl groups include benzyl, phenethyl and naphthylmethyl groups. In some embodiments, aryl-alkyl groups have 7 to 20 or 7 to 11 carbon atoms. When used in the phrase "aryl-C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.

[48] As used herein, the term "heterocyclyl-alkyl" refers to alkyl substituted with heterocyclyl. When used in the phrase "heterocyclyl-C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.

[49] As used herein, the term "cycloalkyl-alkyl" refers to alkyl substituted with cycloalkyl. When used in the phrase "C _3-10 cycloalkyl-C _1-4 alkyl", the term "C _3-10 " refers to the cycloalkyl part of the fragment and does not describe the number of atoms in the alkyl part of the fragment, and the term "C _1-4 " refers to the alkyl part of the fragment and does not describe the number of atoms in the cycloalkyl part of the fragment.

[50] As used herein, the term "heteroaryl-alkyl" refers to alkyl substituted with heteroaryl. When used in the phrase "heteroaryl-C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.

[51] For the avoidance of doubt, reference to, for example, substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of these groups individually, as well as substitutions of combinations of these groups. That is, if R ¹ is aryl-C _1-4 alkyl, the aryl portion may be unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from R ^X , and the alkyl portion also may be unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from R ^X .

[52] The term "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases may be selected from, for example, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, ferric manganese, ferrous manganese, potassium, sodium and zinc salts. In addition, for example, pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form may exist in one or more crystal structures, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected from, for example, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -ethylmorpholine, N -ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine , polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

[53] When the compound disclosed herein is basic, salts can be prepared using at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. Such an acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic , phosphoric, succinic, sulfuric, tartaric and p-toluenesulfonic acids. In some embodiments, such an acid may be selected from, for example, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.

[54] The terms "administration" and/or "use" of a compound or a pharmaceutically acceptable salt thereof should be understood as meaning the provision of a compound or a pharmaceutically acceptable salt thereof to an individual in whom a recognized need for treatment is recognized.

[55] The term "effective amount" means the amount of a compound or pharmaceutically acceptable salt that will elicit a biological or medical response in a tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or other clinician.

[56] The term "composition" as used herein is intended to cover a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts. Such a term in relation to a pharmaceutical composition is intended to cover a product containing the active ingredient(s) and the inert ingredient(s) that constitute(s) the carrier, as well as any product that is directly or indirectly obtained by combining, complexing or aggregating any two or more ingredients, or by dissociating one or more ingredients, or by other types of reactions or interactions of one or more ingredients.

[57] The term "pharmaceutically acceptable" means that it is compatible with the other ingredients of the formulation and is not unacceptably harmful to its recipient.

[58] The term "subject" as used herein in relation to individuals suffering from a disorder, condition, and the like, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees, and other species of higher apes and apes; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[59] The terms "treat", "treating" or "treatment" and other grammatical equivalents as used herein include alleviating, alleviating or ameliorating a disease or condition, preventing additional symptoms, reducing or preventing the underlying metabolic causes of symptoms, inhibiting disease or condition, such as arresting the progress of the disease or condition, ameliorating the disease or condition, causing remission of the disease or condition, alleviating the condition caused by the disease or condition, or cessation of the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic effect and/or a prophylactic effect. The therapeutic effect is understood as the elimination or reduction of the intensity of the underlying disease to be treated. In addition, the therapeutic effect is achieved by the elimination or reduction of one or more physiological symptoms associated with the underlying disorder, so that the patient is improved, despite the fact that the patient may still be affected by the underlying disorder. For prophylactic purposes, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though the disease may not be diagnosed.

[60] The term "protecting group" or "Pg" refers to a substituent that can typically be used to block or protect certain functionality when interacting with other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy-protecting group" refers to a substituent on a hydroxy-group that blocks or protects hydroxy-functionality. Suitable protecting groups include, but are not limited to, acetyl and silyl. "Carboxy-protecting group" refers to a substituent on a carboxy group that blocks or protects the carboxy functionality. Common carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulphenyl)ethyl, 2 -(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons , New York, 1991.

[61] The term "NH-protecting group" as used herein includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl , tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl , leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N, N -dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy -1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexyloxyloxyl ethoxydexylethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohe xylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-hydroxycyclo-hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2 H -1,3-dioxol-4-yl-methyl, trimethylsilyl , triethylsilyl and triphenylsilyl.

[62] The term "C(O)OH-protecting group" as used herein includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, t-butyl, phenyl , naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2 ,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2 -methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[63] The term "OH- or SH-protecting group" as used herein includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl , 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl , 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmeth yl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl , triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[64] Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z " represents higher order substituents on the same side of a carbon–carbon or carbon–nitrogen double bond, as defined in the Kahn–Ingold–Prelog priority rules. The compounds of the present invention may also exist as a mixture of "E-" and "Z-" isomers. Substituents around a cycloalkyl or heterocycloalkyl are designated as having the cis- or trans-configuration. In addition, the invention contemplates various isomers and mixtures thereof resulting from the removal of substituents around the adamantane ring system. Two substituents around the same ring in an adamantane ring system are referred to as having a Z– or E– relative configuration. For example, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758–2760.

[65] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R- or S-configuration, in which the terms "R" and "S" are defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry (Section E, Fundamental Stereochemistry, Pure Appl Chem (1976) 45, 13-10). Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at these carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably in excess of about 85-90%, more preferably in excess of about 95-99%, and even more preferably in excess of more than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labeled compounds.

[66] The compounds of the invention may exist in an isotopically labeled or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most common in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Compounds which contain other isotopes of these and/or other atoms are within the scope of the present invention.

[67] In another embodiment, the isotopically labeled compounds contain isotopes of deuterium ( ² H), tritium ( ³ H), or ¹⁴ C. The isotopically labeled compounds of the present invention can be prepared by conventional methods well known to those skilled in the art. Such isotopically labeled compounds can be conveniently prepared by following the procedures disclosed in the examples disclosed herein and the Schemes, by substituting a readily available isotopically labeled reagent for an unlabeled reagent. In some cases, compounds can be treated with isotopically labeled reagents to replace the normal atom with its isotope, for example, hydrogen for deuterium can be replaced by the action of a deuterated acid such as D ₂ SO ₄ /D ₂ O. In addition to the above, the appropriate procedures and intermediates products are disclosed, for example, in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, SJ et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT Publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Patent Nos. 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and US Patent Applications No. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, the methods are incorporated herein by reference.

[68] Isotopically labeled compounds of the invention can be used as standards to determine the effectiveness of Bcl-2 inhibitors in binding assays. Isotope-containing compounds have been used in pharmaceutical research to study the metabolic pathway of compounds in vivo by evaluating the mechanism of action and metabolic pathway of the non-isotopically labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)) . Such metabolic studies are important for the development of safe and effective therapeutic drugs, either because the active compound administered to the patient is in vivo or because the metabolites generated from the parent compound are found to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol 14, pp. 2-36, Academic press, London, 1985 Kato et al., J. Labeled Comp. Radiopharmaceut., 36(10):927-932 (1995), Kushner et al., Can. J Physiol Pharmacol 77 79-88 (1999).

[69] In addition, non-radioactive isotope-containing drugs, such as deuterated drugs, called "heavy drugs", can be used to treat diseases and conditions associated with Bcl-2 activity. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of enrichment amounts include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%. Substitution of up to 15% of a normal atom by a heavy isotope has been achieved and maintained for days or weeks in mammals, including rodents and dogs, with minimal observed side effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201:357). Short-term replacement of up to 15%–23% of hydrogen in human fluids with deuterium has been found to cause no toxicity (Blagojevic N et al. in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994 (Advanced Medical Publishing, Madison Wis. pp. 125–134; Diabetes Metab. 23: 251 (1997)).

[70] Stable isotope labeling of a drug can alter its physicochemical properties such as pKa and lipid solubility. These effects and changes can influence the pharmacodynamic response of a drug molecule if the isotopic substitution affects the region involved in the ligand-receptor interaction. Although some physical properties of a molecule labeled with a stable isotope differ from those of an unlabeled molecule, the chemical and biological properties are the same, with one important exception: due to the increased mass of a heavy isotope, any bond between a heavy isotope and another atom will be stronger than the same bond between a light isotope and that atom. Accordingly, incorporation of an isotope into a site of metabolism or enzymatic conversion will slow down these reactions, potentially changing the pharmacokinetic profile or efficacy compared to a non-isotopic compound.

[71] In Embodiment (1), the present invention provides a compound of formula (I),

(I)

or a pharmaceutically acceptable salt thereof, where:

L^one, L², L³ and L^four independently selected from –(CR^CR^D)_u–, –(CR^CR^D)_uO(CR^CR^D)_t–, –(CR^CR^D)_uNR^A(CR^CR^D5)_t–, –(CR^CR^D)_uS(CR^CR^D)_t–, –(CR^CR^D)_uC(O)(CR^CR^D)_t–, –(CR^CR^D)_uC(=NR^E)(CR^CR^D)_t–, –(CR^CR^D)_uC(S)(CR^CR^D)_t–, –(CR^CR^D)_uC(O)O(CR^CR^D)_t–, –(CR^CR^D)_uOC(O)(CR^CR^D)_t–, –(CR^CR^D)_uC(O)NR^A(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(O)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(O)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uC(=NR^E)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uNR^BC(=NR^E)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(=NR^E)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uC(S)NR^A(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(S)(CR^CR^D)_t–, –(CR^CR^D)_uNR^AC(S)NR^B(CR^CR^D)_t–, –(CR^CR^D)_uS(O)_r(CR^CR^D)_t–, –(CR^CR^D)_uS(O)_rNR^A5(CR^C5R^D5)_t–, –(CR^C5R^D5)_uNR^AS(O)_r(CR^CR^D)_t– and –(CR^CR^D)_uNR^AS(O)_rNR^B(CR^CR^D)_t-;

Q ¹ and Q ² are independently selected from aryl and heteroaryl, where aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents independently selected from R ^X ;

Q ³ is selected from aryl, C _3-10 cycloalkyl, heteroaryl and heterocyclyl, where aryl, cycloalkyl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from R ^X ;

when Q ³ is C _3-10 cycloalkyl, Y ¹ , Y ² and Y ³ are independently selected from (CR ^6a R ^6b ) _o , where cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

when Q ³ is heteroaryl, Y ¹ , Y ² and Y ³ are independently selected from bond, C, N, O and S, where heteroaryl is unsubstituted or substituted with at least one or two substituents independently selected from R ^X ;

when Q ³ is heterocyclyl, Y ¹ , Y ² and Y ³ are independently selected from (CR ^6a R ^6b ) _o , N, O and S, wherein the heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

X ¹ and X ² are independently selected from C and N;

X ³ is selected from CR ^4c R ^4d and O;

Y ⁴ is selected from C and N;

Z is selected from C and N;

each R ¹ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A1 R ^B1 , –OR ^A1 , –C(O)R ^A1 , – C(=NR ^E1 )R ^A1 , –C(=N–OR ^B1 )R ^A1 , –C(O)OR ^A1 , –OC(O)R ^A1 , –C(O)NR ^A1 R ^B1 , –NR ^A1 C(O)R ^B1 , –C(=NR ^E1 )NR ^A1 R ^B1 , –NR ^A1 C(=NR ^E1 )R ^B1 , –OC(O)NR ^A1 R ^B1 , –NR ^A1 C(O)OR ^B1 , –NR ^A1 C(O)NR ^A1 R ^B1 , –NR ^A1 C(S)NR ^A1 R ^B1 , –NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , –S(O) _r R ^A1 , –S (O)(=NR ^E1 )R ^B1 , –N=S(O)R ^A1 R ^B1 , –S(O) ₂ OR ^A1 , –OS(O) ₂ R ^A1 , –NR ^A1 S(O) _r R ^B1 , –NR ^A1 S(O)(=NR ^E1 )R ^B1 , –S(O) _r NR ^A1 R ^B1 , –S(O)(=NR ^E1 )NR ^A1 R ^B1 , –NR ^A1 S(O) ₂ NR ^A1 R ^B1 , –NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , –P(O)R ^A1 R ^B1 and –P(O)(OR ^A1 )(OR ^B1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

each R ² is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A2 R ^B2 , –OR ^A2 , –C(O)R ^A2 , – C(=NR ^E2 )R ^A2 , –C(=N–OR ^B2 )R ^A2 , –C(O)OR ^A2 , –OC(O)R ^A2 , –C(O)NR ^A2 R ^B2 , –NR ^A2 C(O)R ^B2 , –C(=NR ^E2 )NR ^A2 R ^B2 , –NR ^A2 C(=NR ^E2 )R ^B2 , –OC(O)NR ^A2 R ^B2 , –NR ^A2 C(O)OR ^B2 , –NR ^A2 C(O)NR ^A2 R ^B2 , –NR ^A2 C(S)NR ^A2 R ^B2 , –NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , –S(O) _r R ^A2 , –S (O)(=NR ^E2 )R ^B2 , –N=S(O)R ^A2 R ^B2 , –S(O) ₂ OR ^A2 , –OS(O) ₂ R ^A2 , –NR ^A2 S(O) _r R ^B2 , –NR ^A2 S(O)(=NR ^E2 )R ^B2 , –S(O) _r NR ^A2 R ^B2 , –S(O)(=NR ^E2 )NR ^A2 R ^B2 , –NR ^A2 S(O) ₂ NR ^A2 R ^B2 , –NR ^A2 S(O)(=NR ^E2 )NR ^A2 R ^B2 , –P(O)R ^A2 R ^B2 and –P(O)(OR ^A2 )(OR ^B2 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

each R ³ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A3 R ^B3 , –OR ^A3 , –C(O)R ^A3 , – C(=NR ^E3 )R ^A3 , –C(=N–OR ^B3 )R ^A3 , –C(O)OR ^A3 , –OC(O)R ^A3 , –C(O)NR ^A3 R ^B3 , –NR ^A3 C(O)R ^B3 , –C(=NR ^E3 )NR ^A3 R ^B3 , –NR ^A3 C(=NR ^E3 )R ^B3 , –OC(O)NR ^A3 R ^B3 , –NR ^A3 C(O)OR ^B3 , –NR ^A3 C(O)NR ^A3 R ^B3 , –NR ^A3 C(S)NR ^A3 R ^B3 , –NR ^A3 C(=NR ^E3 )NR ^A3 R ^B3 , –S(O) _r R ^A3 , –S (O)(=NR ^E3 )R ^B3 , –N=S(O)R ^A3 R ^B3 , –S(O) ₂ OR ^A3 , –OS(O) ₂ R ^A3 , –NR ^A3 S(O) _r R ^B3 , –NR ^A3 S(O)(=NR ^E3 )R ^B3 , –S(O) _r NR ^A3 R ^B3 , –S(O)(=NR ^E3 )NR ^A3 R ^B3 , –NR ^A3 S(O) ₂ NR ^A3 R ^B3 , –NR ^A3 S(O)(=NR ^E3 )NR ^A3 R ^B3 , –P(O)R ^A3 R ^B3 and –P(O)(OR ^A3 )(OR ^B3 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent , such as one, two, three or four substituents independently selected from R ^X ;

R ^4a , R ^4b , R ^4c and R ^4d are independently selected from hydrogen, halogen, C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _{1 –4} alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A4 R ^B4 , –OR ^A4 , – C(O)R ^A4 , –C(=NR ^E4 )R ^A4 , –C(=N–OR ^B4 )R ^A4 , –C(O)OR ^A4 , –OC(O)R ^A4 , –C(O) NR ^A4 R ^B4 , –NR ^A4 C(O)R ^B4 , –C(=NR ^E4 )NR ^A4 R ^B4 , –NR ^A4 C(=NR ^E4 )R ^B4 , –OC(O)NR ^A4 R ^B4 , – NR ^A4 C(O)OR ^B4 , –NR ^A4 C(O)NR ^A4 R ^B4 , –NR ^A4 C(S)NR ^A4 R ^B4 , –NR ^A4 C(=NR ^E4 )NR ^A4 R ^B4 , –S( O) _r R ^A4 , –S(O)(=NR ^E4 )R ^B4 , –N=S(O)R ^A4 R ^B4 , –S(O) ₂ OR ^A4 , –OS(O) ₂ R ^A4 , – NR ^A4 S(O) _r R ^B4 , –NR ^A4 S(O)(=NR ^E4 )R ^B4 , –S(O) _r NR ^A4 R ^B4 , –S(O)(=NR ^E4 )NR ^A4 R ^B4 , –NR ^A4 S(O) ₂ NR ^A4 R ^B4 , –NR ^A4 S(O)(=NR ^E4 )NR ^A4 R ^B4 , –P(O)R ^A4 R ^B4 and –P(O)(OR ^A4 ) (OR ^B4 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one with a substituent such as one, two, three or four substituents independently selected from R ^X ;

or "R ^4a and R ^4b " or "R ^4c and R ^4d " 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 ^X groups;

each R ^5a is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one , two, three or four substituents independently selected from R ^X ;

R ^5b is selected from hydrogen, halogen, C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _{1 –4} alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A5 R ^B5 , –OR ^A5 , –C(O)R ^A5 , –C( =NR ^E5 )R ^A5 , –C(=N–OR ^B5 )R ^A5 , –C(O)OR ^A5 , –OC(O)R ^A5 , –C(O)NR ^A5 R ^B5 , –NR ^A5 C( O)R ^B5 , –C(=NR ^E5 )NR ^A5 R ^B5 , –NR ^A5 C(=NR ^E5 )R ^B5 , –OC(O)NR ^A5 R ^B5 , –NR ^A5 C(O)OR ^B5 , – NR ^A5 C(O)NR ^A5 R ^B5 , –NR ^A5 C(S)NR ^A5 R ^B5 , –NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , –S(O) _r R ^A5 , –S(O )(=NR ^E5 )R ^B5 , –N=S(O)R ^A5 R ^B5 , –S(O) ₂ OR ^A5 , –OS(O) ₂ R ^A5 , –NR ^A5 S(O) _r R ^B5 , –NR ^A5 S(O)(=NR ^E5 )R ^B5 , –S(O) _r NR ^A5 R ^B5 , –S(O)(=NR ^E5 )NR ^A5 R ^B5 , –NR ^A5 S(O) ₂ NR ^A5 R ^B5 , –NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , –P(O)R ^A5 R ^B5 and –P(O)(ORA5)(ORB5), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent such as one, two , three or four substituents independently selected from R ^X ;

each R ^6a and R ^6b is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl , heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , –NR ^A6 R ^B6 , –OR ^A6 , –C(O)R ^A6 , –C(=NR ^E6 )R ^A6 , –C(=N–OR ^B6 )R ^A6 , –C(O)OR ^A6 , –OC(O)R ^A6 , –C(O)NR ^A6 R ^B6 , –NR ^A6 C(O)R ^B6 , –C(=NR ^E6 )NR ^A6 R ^B6 , –NR ^A6 C(=NR ^E6 )R ^B6 , –OC(O)NR ^A6 R ^B6 , –NR ^A6 C(O )OR ^B6 , –NR ^A6 C(O)NR ^A6 R ^B6 , –NR ^A6 C(S)NR ^A6 R ^B6 , –NR ^A6 C(=NR ^E6 )NR ^A6 R ^B6 , –S(O) _r R ^A6 , –S(O)(=NR ^E6 )R ^B6 , –N=S(O)R ^A6 R ^B6 , –S(O) ₂ OR ^A6 , –OS(O) ₂ R ^A6 , –NR ^A6 S(O ) _r R ^B6 , –NR ^A6 S(O)(=NR ^E6 )R ^B6 , –S(O) _r NR ^A6 R ^B6 , –S(O)(=NR ^E6 )NR ^A6 R ^B6 , –NR ^A6 S (O) ₂ NR ^A6 R ^B6 , –NR ^A6 S(O)(=NR ^E6 )NR ^A6 R ^B6 , –P(O)R ^A6 R ^B6 and –P(O)(OR ^A6 )(OR ^B6 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substitution a parent such as one, two, three or four substituents independently selected from R ^X ;

or R ^6a and R ^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 ^X groups;

each R ^A , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^B , R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 and R ^B6 independently selected from hydrogen, C _{1– 10} alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _{1– 4} alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R ^X ;

or each "R ^A and R ^B ", "R ^A1 and R ^B1 ", "R ^A2 and R ^B2 ", "R ^A3 and R ^B3 ", "R ^A4 and R ^B4 ", "R ^A5 and R ^B5 " and "R ^A6 and R ^B6 " together with the atom(s) to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus , and optionally substituted with 1, 2 or 3 R ^X groups;

each RC and ^RD is independently selected from hydrogen, halogen, ^C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl , heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least at least one substituent, such as one, two, three or four substituents independently selected from R ^X ;

or ^RC and ^RD together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1, 2 or 3 R ^X groups;

each R ^E , R ^E1 , R ^E2 , R ^E3 , R ^E4 , R ^E5 and R ^E6 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, heterocyclyl, heterocyclyl–C _1–4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , –S(O) _r R ^a1 , –C(O)R ^a1 , C(O)OR ^a1 , –C(O)NR ^a1 R ^b1 and –S(O) _r NR ^a1 R ^b1 , where alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^Y ;

each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 –4} alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, halogen, CN, NO ₂ , –(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t OR ^b1 , –(CR ^c1 R ^d1 ) _t C(O)R ^a1 , –(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , –(CR ^c1 R ^d1 ) _t C(=N– OR ^b1 )R ^a1 , –(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , –(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , –(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , –(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C (=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , –(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t N=S(O )R ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , –(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , –(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , –(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and –(CR ^c1 R ^d1 ) _t P(O)( OR ^a1 )(OR ^b1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^Y ;

each R ^a1 and each R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent such as one, two, three or four substituents independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a 4-12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted at at least one substituent such as one, two, three or four substituents independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1, 2 or 3 groups R ^Y ;

each ^Re1 is independently selected from hydrogen, C _1–10 alkyl, C _3–10 cycloalkyl, C _3–10 cycloalkyl–C _1–4 alkyl, CN, NO ₂ , –OR ^a2 , –SR ^a2 , –S(O) _r R ^a2 , –C(O)R ^a2 , –C(O)OR ^a2 , –S(O) _r NR ^a2 R ^b2 and –C(O)NR ^a2 R ^b2 ;

each R ^{Y is} independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl–C _1–4 alkyl, heteroaryl, heteroaryl–C _1–4 alkyl, halogen, CN, NO ₂ , –(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t OR ^b2 , –(CR ^c2 R ^d2 ) _t C(O)R ^a2 , –(CR ^c2 R ^d2 ) _t C(=NR ^e2 )R ^a1 , –(CR ^c2 R ^d2 ) _t C(=N–OR ^b2 )R ^a2 , –(CR ^c2 R ^d2 ) _t C(O)OR ^b2 , –(CR ^c2 R ^d2 ) _t OC(O)R ^b2 , –(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , –(CR ^c2 R ^d2 ) _t C(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(= NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)OR ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(S)NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , – (CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , –(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t N=S(O)R ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t S(O) ₂ OR ^b2 , –(CR ^c2 R ^d2 ) _t OS(O) ₂ R ^b2 , –(CR ^c2 R ^d2 ) _t N R ^a2 S(O) _r R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )R ^b2 , –(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , –(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 and –(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )( OR ^b2 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from OH, CN, amino, halogen , C _1–10 alkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 cycloalkyl, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^a2 and each R ^b2 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _{1 –10} alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1–10 alkylamino, C _3–10 cycloalkylamino, di(C _1–10 alkyl)amino, heterocyclyl, heterocyclyl–C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl each is unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl )amino;

or R ^a2 and R ^b2 together with the atom(s) to which they are attached form a 4-12-membered heterocyclic ring 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 halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _{3- 10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, C _1–10 alkylamino, C _3–10 cycloalkylamino, di(C _1–10 alkyl)amino, heterocyclyl, heterocyclyl– C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is each unsubstituted or substituted with at least one substituent such as one, two, three or four substituents independently selected from halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3–10 cycloalkyl, OH, C _1–10 alkoxy, C _3–10 cycloalkoxy, C _1–10 alkylthio, C _3–10 cycloalkylthio, amino, C _1–10 alkylamino, C _3–10 cycloalkylamino, and di(C _{1– 10} alkyl)amino;

or R ^c2 and R ^d2 together with the carbon atom(s) to which they are attached form a 3-12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted 1 or 2 substituents independently selected from halo, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each ^Re2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, - C(O)C _1–4 alkyl, –C(O)C _3–10 cycloalkyl, –C(O)OC _1–4 alkyl, –C(O)OC _3–10 cycloalkyl, –C(O)N( C _1–4 alkyl) ₂ , –C(O)N(C _3–10 cycloalkyl) ₂ , –S(O) ₂ C _1–4 alkyl, –S(O) ₂ C _3–10 cycloalkyl, –S( O) ₂ N(C _1–4 alkyl) ₂ and –S(O) ₂ N(C _3–10 cycloalkyl) ₂ ;;

m is selected from 0, 1, 2 and 3;

n is selected from 0, 1, 2 and 3;

o is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is chosen from 0 and 1;

each r is independently selected from 0, 1, and 2;

each t is independently selected from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3 and 4.

[72] In another embodiment (2), the invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Q ¹ is aryl, where aryl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[73] In another embodiment (3), the invention provides the compound of embodiment (2) or a pharmaceutically acceptable salt thereof, wherein Q ¹ is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[74] In another embodiment (4), the invention provides the compound of embodiment (3), or a pharmaceutically acceptable salt thereof, wherein Q ¹ is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from C _{1– 4} alkyl C _3-6 cycloalkyl, halogen, CN, CF ₃ and OCF ₃ where alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y .

[75] In another embodiment (5), the invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q ¹ is phenyl, wherein phenyl is substituted with halogen.

.[76] In another embodiment (6), the invention provides the compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein Q ¹ is

.

[77] In another embodiment (7), the invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Q ¹ is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[78] In another embodiment (8), the invention provides a compound according to any one of embodiments (1)-(7) or a pharmaceutically acceptable salt thereof, wherein Q ² is aryl, wherein aryl is unsubstituted or substituted with at least one substituent, independently selected from R ^X .

[79] In another embodiment (9), the invention provides a compound according to any one of embodiments (1)-(7) or a pharmaceutically acceptable salt thereof, wherein Q ² is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent, independently selected from R ^X .

и

, который является незамещенным или замещен по меньшей мере одним заместителем, независимо выбранным из R^X.[80] In another embodiment (10), the invention provides the compound of embodiment (9) or a pharmaceutically acceptable salt thereof, wherein Q ² is selected from

and

, which is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[81] In another embodiment (11), the invention provides a compound according to any one of embodiments (1)-(10) or a pharmaceutically acceptable salt thereof, wherein L ¹ is -(CR ^C R ^D ) _u -.

[82] In another embodiment (12), the invention provides the compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -.

[83] In another embodiment (13), the invention provides a compound according to any one of embodiments (1)-(12) or a pharmaceutically acceptable salt thereof, wherein L ² is selected from -(CR ^C R ^D ) _u -, -(CR ^C R ^D ) _u O(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u S(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u S(O) _r (CR ^C R ^D ) _t –.

[84] In another embodiment (14), the invention provides the compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein L ² is selected from -O-, -S- and -S(O) _r -.

[85] In another embodiment (15), the invention provides the compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein L ² is –O–.

[86] In another embodiment (16), the invention provides the compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein L ² is –S–.

[87] In another embodiment (17), the invention provides the compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein L ² is -(CR ^C R ^D ) _u - and u is 0.

[88] In another embodiment (18), the invention provides a compound according to any one of embodiments (1) to (17) or a pharmaceutically acceptable salt thereof, wherein X ¹ is C.

[89] In another embodiment (19), the invention provides a compound according to any one of embodiments (1) to (17) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N.

[90] In another embodiment (20), the invention provides a compound according to any one of embodiments (1) to (19) or a pharmaceutically acceptable salt thereof, wherein X ² is C.

[91] In another embodiment (21), the invention provides a compound according to any one of embodiments (1) to (19) or a pharmaceutically acceptable salt thereof, wherein X ² is N.

[92] In another embodiment (22), the invention provides a compound according to any one of embodiments (1)-(21) or a pharmaceutically acceptable salt thereof, wherein X ³ is CR ^4a R ^4b .

[93] In another embodiment (23), the invention provides the compound of embodiment (22) or a pharmaceutically acceptable salt thereof, wherein X ³ is selected from CH ₂ and C(CH ₃ ) ₂ .

[94] In another embodiment (24), the invention provides a compound according to any one of embodiments (1) to (21) or a pharmaceutically acceptable salt thereof, wherein X ³ is O.

[95] In another embodiment (25), the invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein

Q ¹ is aryl, where aryl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

Q ² is heteroaryl, where heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L ¹ is -(CR ^C R ^D ) _u -; L ² is selected from –(CR ^C R ^D ) _u –, –(CR ^C R ^D ) _u O(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u S(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u S(O) _r (CR ^C R ^D ) _t –;

X ¹ represents N; X ² is N; X ³ is -CR ^4c R ^4d ; Z is C;

R ¹ is NO ₂ or SO ₂ CF ₃ ; R ² is hydrogen; R ³ is hydrogen; m is 1; n is 1; p is equal to 1;

R ^4a and R ^4b are independently selected from hydrogen and C _1-10 alkyl, where alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[96] In another embodiment (26), the invention provides the compound of embodiment (25) or a pharmaceutically acceptable salt thereof, wherein

Q ¹ is phenyl, where phenyl is unsubstituted or substituted with at least one substituent independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, halogen, CN, CF ₃ and OCF ₃ ;

и

, каждый из которых независимо является незамещенным или замещен по меньшей мере одним заместителем, независимо выбранным из R^X;Q ² selected from

and

, each of which is independently unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L ¹ is -(CH ₂ ) _u -; L ² is selected from the bond, –O–, –S– and –S(O) _r –;

X ¹ represents N; X ² is N; X ³ is selected from -CH ₂ - and -C(CH ₃ ) ₂ ;

R ¹ is NO ₂ ;

R ^4a and R ^4b are independently selected from hydrogen and C _1-10 alkyl.

[97] In another embodiment (27), the invention provides the compound of embodiment (26) or a pharmaceutically acceptable salt thereof, wherein

; Q² выбран из

и

;Q ¹ is

; Q ² selected from

and

;

L ¹ is -CH ₂ -; L ² is a bond or –O–;

X ¹ represents N; X ² is N; X ³ is -CH ₂ -;

R ^4a and R ^4b are independently selected from hydrogen and methyl.

[98] In another embodiment (28), the invention provides a compound according to any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q ³ is heterocyclyl.

[99] In another embodiment (29), the invention provides the compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NR ^E9 .

[100] In another embodiment (30), the invention provides the compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NH.

[101] In another embodiment (31), the invention provides the compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is O.

[102] In another embodiment (32), the invention provides the compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein Y ¹ is S.

[103] In another embodiment (33), the invention provides a compound according to any one of embodiments (28)-(32) or a pharmaceutically acceptable salt thereof, wherein Y ² is CR ^6a R ^6b .

[104] In another embodiment (34), the invention provides the compound of embodiment (33), or a pharmaceutically acceptable salt thereof, wherein Y ² is CH ₂ .

[105] In another embodiment (35), the invention provides a compound according to any of embodiments (28)-(32) or a pharmaceutically acceptable salt thereof, wherein Y ² is NH.

[106] In another embodiment (36), the invention provides a compound according to any one of embodiments (28) to (32), wherein Y ² is O.

[107] In another embodiment (37), the invention provides a compound according to any one of embodiments (28) to (32), wherein Y ² is S.

[108] In another embodiment (38), the invention provides a compound according to any of embodiments (28)-(37) or a pharmaceutically acceptable salt thereof, wherein Y ³ is selected from (CR ^6a R ^6b ) _o and o is selected from 0 and one.

[109] In another embodiment (39), the invention provides the compound of embodiment (38), or a pharmaceutically acceptable salt thereof, wherein Y ³ is CR ^6a R ^6b .

[110] In another embodiment (40), the invention provides the compound of embodiment (39), or a pharmaceutically acceptable salt thereof, wherein R ^6a and R ^6b are independently selected from hydrogen and C _1-10 alkyl.

[111] In another embodiment (41), the invention provides a compound according to any one of embodiments (28)-(40), wherein Y ⁴ is C.

[112] In another embodiment (42), the invention provides a compound according to any one of embodiments (28)-(40), wherein Y ⁴ is N.

[113] In another embodiment (43), the invention provides a compound according to any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q ³ is aryl.

[114] In another embodiment (44), the invention provides a compound according to any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q ³ is heteroaryl.

.[115] In another embodiment (45), the invention provides the compound of embodiment (44), or a pharmaceutically acceptable salt thereof, wherein Q ³ is

.

,

,

,

и

.[116] In another embodiment (46), the invention provides a compound according to any of embodiments (28)-(42) or a pharmaceutically acceptable salt thereof, wherein Q ³ is selected from

,

,

,

and

.

[117] In another embodiment (47), the invention provides a compound according to any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q ³ is C _3-10 cycloalkyl.

[118] In another embodiment (48), the invention provides a compound according to any one of embodiments (1) to (47) or a pharmaceutically acceptable salt thereof, wherein Z is C.

[119] In another embodiment (49), the invention provides a compound according to any one of embodiments (1) to (47) or a pharmaceutically acceptable salt thereof, wherein Z is N.

[120] In another embodiment (50), the invention provides a compound according to any one of embodiments (1)-(49) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from NO ₂ and SO ₂ CF ₃ and m is 1.

[121] In another embodiment (51), the invention provides a compound according to any one of embodiments (1)-(50) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN alkoxy, CN, –NR ^A2 R ^B2 and –OR ^A2 .

[122] In another embodiment (52), the invention provides the compound of embodiment (51), or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen.

[123] In another embodiment (53), the invention provides a compound according to any one of embodiments (1)-(52) or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, –NR ^A3 R ^B3 and –OR ^A3 .

[124] In another embodiment (54), the invention provides the compound of embodiment (53), or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

[125] In another embodiment (55), the invention provides a compound according to any one of embodiments (1)-(54) or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are independently selected from hydrogen and C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[126] In another embodiment (56), the invention provides the compound of embodiment (55), or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are independently selected from hydrogen and methyl.

[127] In another embodiment (57), the invention provides a compound according to any one of embodiments (1)-(56) or a pharmaceutically acceptable salt thereof, wherein L ³ is selected from -(CR ^C R ^D ) _u -, -(CR ^C R ^D ) _u O(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u C(O)(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u OC(O)(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u C(O)O(CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u NR ^A C(O)(CR ^C R ^D ) _t – , –(CR ^C R ^D ) _u C(O)NR ^A (CR ^C R ^D ) _t –, –(CR ^C R ^D ) _u NR ^A C(O)O(CR ^C R ^D ) _t –, –( CR ^C R ^D ) _u S(O) _r (CR ^C R ^D ) _t – and –(CR ^C5 R ^D5 ) _u NR ^A S(O) _r (CR ^C R ^D ) _t –.

[128] In another embodiment (58), the invention provides the compound of embodiment (57), or a pharmaceutically acceptable salt thereof, wherein u is selected from 0, 1 and 2 and t is selected from 0 and 1.

[129] In another embodiment (59), the invention provides the compound of embodiment (58), or a pharmaceutically acceptable salt thereof, wherein L ³ is selected from the bond, –CH ₂ –, –(CH ₂ ) ₂ –, –CH ₂ O– , –(CH ₂ ) ₂ O–, –(CH ₂ ) ₂ OC(O)–, –C(O)–, –C(O)O–, –CH ₂ C(O)–, –CH ₂ C (O)O–, –CH ₂ OC(O)–, –C(O)NCH ₃ –, –CH ₂ NHC(O)–, –CH ₂ NHC(O)O–, –(CH ₂ ) ₂ NHC (O)–, –(CH ₂ ) ₂ NHC(O)O–, –(CH ₂ ) ₂ SO ₂ –, and –CH ₂ NHSO ₂ –.

[130] In another embodiment (60), the invention provides a compound according to any one of embodiments (1) to (59) or a pharmaceutically acceptable salt thereof, wherein q is selected from 0 and 1.

[131] In another embodiment (61), the invention provides the compound of embodiment (60), or a pharmaceutically acceptable salt thereof, wherein q is 0.

[132] In another embodiment (62), the invention provides the compound of embodiment (60) or a pharmaceutically acceptable salt thereof, wherein q is 1.

[133] In another embodiment (63), the invention provides a compound according to any one of embodiments (1)-(62) or a pharmaceutically acceptable salt thereof, wherein each R ^5a is independently selected from C _1-10 alkyl, C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, where alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

, которые являются незамещенными или замещены по меньшей мере одним заместителем, независимо выбранным из R^X.[134] In another embodiment (64), the invention provides the compound of embodiment (63), or a pharmaceutically acceptable salt thereof, wherein R ^5a is selected from phenyl, pyridinyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

that are unsubstituted or substituted with at least one substituent independently selected from R ^X .

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

, где фенил и пиридинил являются незамещенными или замещены по меньшей мере одним заместителем, независимо выбранным из галогена, CN, OR^A5 и –S(O)_rR^A5.[135] In another embodiment (65), the invention provides the compound of embodiment (64), or a pharmaceutically acceptable salt thereof, wherein R ^5a is selected from phenyl, pyridinyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

where phenyl and pyridinyl are unsubstituted or substituted with at least one substituent independently selected from halo, CN, OR ^A5 and -S(O) _r R ^A5 .

[136] In another embodiment (66), the invention provides a compound according to any one of embodiments (1)-(65) or a pharmaceutically acceptable salt thereof, wherein L ⁴ is selected from -(CR ^C R ^D ) _u - and u is selected from 0, 1 and 2.

[137] In another embodiment (67), the invention provides a compound according to any one of embodiments (1)-(66) or a pharmaceutically acceptable salt thereof, wherein R ^5b is selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3–10 heterocyclyl, CN, –OR ^A5 , –NR ^A5 R ^B5 , –NR ^A5 C(O)OR ^B5 , –N=S(O)R ^A5 R ^B5 , –C(O)R ^A5 , –C(O)OR ^A5 , –C(O)NR ^A5 R ^B5 and –S(O) _r R ^A5 .

[138] In another embodiment (68), the invention provides the compound of embodiment (67), or a pharmaceutically acceptable salt thereof, wherein R ^5b is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, –OCH ₃ , –N(CH ₃ ) ₂ , –N=S(O)(CH ₃ ) ₂ , –NHC(O)OCH ₃ , –C(O)CH ₃ , –C(O)C ₂ H ₅ , – C(O)–c–C ₃ H ₇ , –C(O)OCH ₃ , –C(O)OC(CH ₃ ) ₃ , –C(O)N(CH ₃ ) ₂ , –SOCH ₃ and –S ₍ O) _2CH3 .

[139] In another embodiment (69), the invention provides the compound of embodiment (67), or a pharmaceutically acceptable salt thereof, wherein R ^5b is selected from -NR ^A5 R ^B5 , -N=S(O)R ^A5 R ^B5 , where R ^A5 and R ^B5 together with the atom to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 groups R ^X .

и

.[140] In another embodiment (70), the invention provides the compound of embodiment (69), or a pharmaceutically acceptable salt thereof, wherein R ^5b is selected from

and

.

[141] In another embodiment (71), the invention provides a compound selected from

,

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,

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,

,

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,

,

and its pharmaceutically acceptable salts.

[142] In another embodiment (71), the invention provides a pharmaceutical composition comprising a compound according to any one of embodiments (1) to (70) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[143] In another embodiment (72), the invention provides a method of treating, alleviating, or preventing a condition that responds to Bcl-2 inhibition, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments (1)-( 70) or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[144] In another embodiment (73), the invention provides the use of a compound according to any one of embodiments (1) to (70), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a hyperproliferative disorder.

[145] In yet another aspect, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and instructions that contain one or more forms of information selected from the group consisting of an indication of the disease state for which the composition is to be administered, storage information for the composition, dosage information, and instructions on how to administer the composition. In one particular embodiment, the kit contains the compound in multiple dose form.

[146] In yet another of its aspects, a product is provided that contains a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and packaging materials. In one embodiment, the packaging material includes a container for housing the connection. In one particular embodiment, the container contains a label indicating one or more members of the disease state for which the compound is to be administered, storage information, dosage information, and/or instructions on how to administer the compound. In another embodiment, the article of manufacture contains the compound in multiple dose form.

[147] In a further aspect thereof, a therapeutic method is provided, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[148] In another of its aspects, a method for inhibiting Bcl-2 is provided, comprising contacting Bcl-2 with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[149] In yet another aspect, a method for inhibiting Bcl-2 is provided, comprising providing for the presence of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the body of a subject to inhibit Bcl-2 in vivo .

[150] In a further aspect thereof, a method for inhibiting Bcl-2 is provided, comprising administering a first compound to a subject that is converted in vivo to a second compound, wherein the second compound inhibits Bcl-2 in vivo , wherein the second compound is a compound according to any of the above. embodiments and options.

[151] In another of its aspects, a method for treating a disease state is provided, for which Bcl-2 has an activity that contributes to the pathology and/or symptoms of the disease state, and the method includes providing the presence of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in a subject in a therapeutically effective amount for the disease state.

[152] In a further aspect thereof, a method for treating a disease state is provided, wherein Bcl-2 has an activity that contributes to the pathology and/or symptomatology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound, wherein the second compound inhibits Bcl-2 in vivo . It is noted that the compounds of the present invention may be the first or second compounds.

[153] In one embodiment of each of the above methods, the disease state is selected from the group consisting of cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, gastrointestinal, pancreatic, breast, head, neck, renal cancer, kidney cancer, ovarian cancer, prostate cancer, colorectal cancer, epidermoid cancer, esophageal cancer, testicular cancer, gynecological cancer, or thyroid cancer); noncancerous hyperproliferative disorders (eg, benign skin hyperplasia (eg, psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing implantation of blastocytes; treatment of diseases associated with vasculogenesis or angiogenesis (for example, tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer); asthma; neutrophil chemotaxis (eg, reperfusion injury in myocardial infarction and stroke and inflammatory arthritis); septic shock; T cell-mediated diseases in which immune suppression would be of value (eg, prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocyte responses to cocktails of growth factors; chronic obstructive pulmonary disease (COPD) and other diseases.

[154] In another of its aspects, a method is provided for treating a disease state for which a mutation in the Bcl-2 gene contributes to the pathology and/or symptoms of the disease state, including, for example, melanomas, lung cancer, colon cancer, and other types of tumors.

[155] In another of its aspects, the present invention provides the use of a compound according to any of the above embodiments and variants as a medicine. In yet another of its aspects, the present invention provides the use of a compound of any of the above embodiments and embodiments in the manufacture of a medicament for inhibiting Bcl-2.

[156] In another of its aspects, the present invention provides the use of a compound of any of the above embodiments and embodiments in the manufacture of a medicament for the treatment of a disease state for which Bcl-2 has an activity that contributes to the pathology and/or symptoms of the disease state.

Introduction and pharmaceutical compositions

[157] In general, the compounds of the present disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable regimens known in the art, either alone or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the activity of the compound used, and other factors known to those skilled in the art. For example, for the treatment of neoplastic diseases and disorders of the immune system, the required dosage will also vary depending on the mode of administration, the particular condition being treated, and the desired effect.

[158] In general, it has been shown that satisfactory results are obtained with systemic exposure at daily doses of from about 0.001 to about 100 mg/kg of body weight, or, in particular, from about 0.03 to 2.5 mg/kg of body weight. The indicated daily dose for a larger mammal, such as humans, may be in the range of from about 0.5 mg to about 2000 mg, or more specifically from about 0.5 mg to about 1000 mg, for convenience, administered, for example, in in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration contain from about 1 to 50 mg of the active ingredient.

[159] The compounds of the invention may be administered as pharmaceutical compositions by any conventional route; eg enterally, eg orally, eg in the form of tablets or capsules; parenterally, for example in the form of injectable solutions or suspensions; or topically, for example in the form of lotions, gels, ointments or creams, or in intranasal or suppository form.

[160] Pharmaceutical compositions containing a compound of the present invention in free form or in the form of a pharmaceutically acceptable salt in combination with at least one pharmaceutically acceptable carrier or diluent can be manufactured in the usual way by mixing, granulating, coating, dissolving or lyophilizing processes. . For example, pharmaceutical compositions containing a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in the usual way by mixing with a pharmaceutically acceptable carrier or diluent. Standard dosage forms for oral administration contain, for example, from about 0.1 to about 500 mg of the active substance.

[161] In one embodiment, the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. In the case of lyophilized compositions containing the active ingredient alone or together with a carrier such as mannitol, dispersions or suspensions may be prepared prior to use. Pharmaceutical compositions may be sterilized and/or contain adjuvants such as preservative, stabilizing, wetting or emulsifying agents, solution promoters, salts for adjusting osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid or bactericides such as sorbic acid or benzoic acid. Solutions or suspensions may additionally contain thickeners, including but not limited to sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers such as Tween 80 (polyoxyethylene(20)sorbitan monooleate).

[162] Suspensions in oil may contain as an oil component vegetable, synthetic or semi-synthetic oils, typical for injection purposes. Examples include liquid fatty acid esters that contain as an acidic component a long chain fatty acid having 8 to 22 carbon atoms or, in some embodiments, 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, e.g., oleic acid, elaidic acid. acid, erucic acid, brassidic acid and linoleic acid and, if desired, may contain antioxidants such as vitamin E, 3-carotene or 3,5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be a monovalent or polyvalent, eg mono, di or trivalent, alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol, or isomers thereof; glycol and glycerin.

[163] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M 2375 (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturated polyglycolized glycerides obtained by alcoholysis of apricot kernel oil and containing glycerides and polyethylene glycol ester), LABRASOL™ (saturated polyglycolized glycerides obtained by alcoholysis of TCM and containing glycerides and polyethylene glycol ester; all available from GaKefosse, France) and/or MIGLYOL® 812 (saturated fatty acid triglyceride with a chain length of C8 to C12 from Hüls AG, Germany) and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

[164] Pharmaceutical compositions for oral administration can be prepared, for example, by combining the active ingredient with one or more solid carriers and, if desired, granulating the resulting mixture and processing the mixture or granules by incorporating additional excipients to form tablets or tablet cores.

[165] Suitable carriers include, but are not limited to, bulking agents such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starches, e.g. corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants such as the aforementioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof such as alginate sodium. Additional excipients include conditioning agents and lubricants, for example, silicic acid, talc, stearic acid, or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

[166] Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, among other things, concentrated sugar solutions, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for enteric coatings, solutions of suitable cellulose preparations such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to tablets or tablet coatings, for example for identification purposes or to indicate different dosages of the active ingredient.

[167] Pharmaceutical compositions for oral administration may also include hard capsules containing gelatin or soft capsules containing gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example mixed with excipients such as cornstarch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents may also be added, for example of the fatty acid ester and polyoxyethylene sorbitan.

[168] Pharmaceutical compositions suitable for rectal administration are, for example, suppositories containing a combination of an active ingredient and a suppository base. Suitable bases for suppositories are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

[169] Pharmaceutical compositions suitable for parenteral administration may contain aqueous solutions of the active ingredient in water-soluble form, such as a water-soluble salt, or aqueous injection suspensions that contain thickeners, such as sodium carboxymethylcellulose, sorbitol, and/or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, may also be in the form of a lyophilisate and may be made into a solution prior to parenteral administration by the addition of suitable solvents. Solutions that are used, for example, for parenteral administration, can also be used as infusion solutions. The manufacture of injectable preparations is usually carried out under sterile conditions, as well as filling, for example, filling ampoules or vials, and sealing containers.

[170] The disclosure also provides pharmaceutical combinations, for example, a kit containing a) the first agent, which is the compound of the invention disclosed herein, in free form or in the form of a pharmaceutically acceptable salt, and b) at least one co-agent. The kit may contain instructions for its introduction.

Combination therapies

[171] The compounds or pharmaceutically acceptable salts of the disclosure may be administered as monotherapy or together with another therapeutic agent or agents.

[172] For example, the therapeutic efficacy of one of the compounds described herein can be enhanced by the administration of an adjuvant (i.e., the adjuvant alone may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit for the individual rises). Or, by way of example only, the benefit experienced by an individual can be increased by administering one of the compounds described herein with another therapeutic agent that also has a therapeutic benefit. By way of example only, in the treatment of gout involving the administration of one of the compounds described herein, increased therapeutic benefit can also be achieved by providing the subject with another therapeutic agent for gout. Or, by way of example only, if one of the side effects experienced by an individual when taking one of the compounds described herein is nausea, then it may be appropriate to administer an antiemetic in combination with the compound. Or additional therapy or therapies include, but are not limited to, physical therapy, psychotherapy, radiation therapy, application of compresses to the area of the body affected by the disease, rest, dietary changes, and the like. Regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the individual may be additive from the two therapies, or the individual may experience a synergistic benefit.

[173] In cases where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein may be administered in the same pharmaceutical composition as the other therapeutic agents or due to different physical and chemical characteristics, be introduced through a different route. For example, the compounds described herein may be administered orally to generate and maintain good blood levels, while another therapeutic agent may be administered intravenously. Thus, the compounds described herein may be administered simultaneously, sequentially, or dosed separately from other therapeutic agents.

[174] Compounds of formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurorakinase inhibitors, other inhibitors of apoptosis promoters (e.g., Bcl-xL, Bcl –w and Bfl–1), death receptor pathway activators, Bcr–Abl kinase inhibitors, BiTE antibodies (bispecific T cell response enhancer), drug-antibody conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVD, leukemia viral oncogene homologue receptor (ErbB2) inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormone therapy, immunological agents, inhibitors of inhibitors of apoptosis proteins (IAP) , intercalating antibiotics, inhibitors kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, miRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors ), platinum-containing chemotherapeutic agents, polo-like kinase (Plk) inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid/deltoid plant alkaloids, small inhibitory ribonucleic acids (siRNA), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with one or more of these agents.

EXAMPLES

[175] Various methods can 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. However, it should be noted that the compound of formula (I), or a pharmaceutically acceptable salt thereof, can also be synthesized by other synthetic methods which may be developed by others.

[176] It will be easy to understand that some compounds of formula (I) have atoms with bonds to other atoms, which give the connection a particular stereochemistry (for example, chiral centers). It should be noted that the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof can lead to the formation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a specific stereochemistry is indicated, the disclosure of a compound is intended to cover all possible stereoisomers.

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

[178] The free acid or free base forms of the compounds of formula (I) can be obtained from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in acid addition salt form can be converted to the corresponding free base by treatment with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, and the like). The compound of formula (I) in base addition salt form can be converted to the corresponding free acid, for example by treatment with a suitable acid (eg hydrochloric acid, etc.).

[179] N-oxides of a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared by methods known to those skilled in the art. For example, N-oxides can be prepared by treating the unoxidized form of a 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 a temperature of approximately 0 to 80°C. Alternatively, N-oxides of compounds of formula (I) can be obtained from the N-oxide of the appropriate starting material.

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

[181] Protected derivatives of the compounds of formula (I) can be obtained by methods known to specialists in this field of technology. A detailed description of 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.

[182] In the context of the present description, the symbols and conventions used in these processes, schemes, and examples correspond to those used in modern scientific literature, for example, in the Journal of the American Chemical Society (The Journal of the American Chemical Society) or in the Journal biological chemistry (The Journal of Biological Chemistry). Standard one-letter or three-letter abbreviations are commonly used to denote amino acid residues that are assumed to be in the L-configuration, unless otherwise noted. Unless otherwise indicated, 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 this specification: g (grams); mg (milligrams); l (liters); ml (milliliters); µl (microliters); psi inch (pounds per square inch); M (molar); mM (millimolar); c.c. (intravenously); Hz (hertz); MHz (megahertz); mole(s); mmol (millimoles); k.t. (room temperature); min (minutes); h (hours); m.p. (melting point); TLC (thin layer chromatography); R _beats (retention time); OF (reversed 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'-dimethylpropylene urea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et ₂ O (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); TBS (tert-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphine chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (metachloroperbenzoic acid).

[183] References to ether or Et ₂ O refer to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise noted, all temperatures are in °C (degrees Celsius). All reactions were carried out under an inert atmosphere at room temperature unless otherwise noted.

[184] ¹ H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts were expressed in parts per million (ppm). The coupling constants are expressed in hertz (Hz). The splitting spectra describe apparent multiplicities and are denoted as s (singlet), q (doublet), t (triplet), q (quartet), m (multiplet), and br (broadened).

[185] Low resolution mass spectra (MS) and compound purity data were obtained on a Shimadzu single quadrupole LC/MS system equipped with an electrospray ionization source (IES), a UV detector (220 and 254 nm), and an 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 solution of phosphomolybdic acid, ninhydrin, or p-anisaldehyde. Flash column chromatography was performed on silica gel (200–300 mesh, a branch of Qingdao Haiyang Chemical Co., Ltd).

Synthetic Circuits

[186] Synthetic methods for preparing the compounds of the present invention are illustrated in the following schemes and examples. Starting materials are commercially available or can be obtained in accordance with procedures known in the art or as shown in this document.

[187] The intermediates shown in the following schemes are either known in the literature or can be prepared by various methods well known to those skilled in the art.

[188] By way of illustration, one synthetic approach to compounds of formula I of the present disclosure is set forth in Scheme 1. As shown in Scheme, compounds of formula I can be disassembled into 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.

Scheme 1

[189] As an illustration of the preparation of intermediates of formula III, the preparation of compound IIIa in Scheme 2 is shown. Nitration of IIIa–B under conditions such as HNO ₃ /H ₂ SO ₄ gives IIIa–C, which can then be converted to the sulfonamide IIIa–D by reacting IIIa–C with NH ₃ . Intermediate IIIa can be prepared by combining IIIa-D with IIIa-E via a substitution reaction.

Scheme 2

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

Scheme 3

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

Scheme 4

[192] In some cases, the order of implementation of the above reaction schemes may vary to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for a more complete understanding of the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

Obtaining Intermediates

Intermediate connection A

[193] (S)–2–(iodomethyl)–7–nitroindoline–5–sulfonamide ( intermediate compound A )

[194] (S)-indoline-2-ylmethanol ( A-1 )

[195] ( S )-indoline-2-ylmethanol ( A-1 ) was obtained according to the method described in WO2009/109364 .

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

[197] A mixture of ( S )-indoline-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 hours. The mixture was concentrated and extracted with EtOAc, the extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated, the residue was purified by silica gel column chromatography eluting with PE/EtOAc (8:1~6:1) to give the title compound ( S ) –9,9a–dihydro–1 H ,3 H –oxazolo[3,4– a ]indol–3–one ( A–2 ). MS–IES (m/h): 176 [M+1] ⁺ .

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

[199] To chlorosulfonic acid (1 ml) was added ( S )-9,9a-dihydro-1 H ,3 H -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 hour and quenched with ice water (20 ml) at 0°C. The mixture was extracted with EtOAc (2×50 ml), the extracts were washed with brine (50 ml), dried over Na ₂ SO ₄ and evaporated to give the crude product ( S )-3-oxo-9,9a-dihydro- 1H ,3 H -oxazolo[3,4- a ]indole-7-sulfonyl chloride ( A-3 ), which was directly used for the next step.

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

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

[202] (S)–(7–nitro–5–sulfamoylindolin–2–yl)methylcarbamate ( A–5 )

[203] 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 ₃ in MeOH (3 ml) was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product ( S )-(7-nitro-5-sulfamoylindolin-2-yl)methylcarbamate ( A-5 ), which was used directly for the next step. MS–IES (m/z): 315 [M – 1] ^– .

[204] (S)–2–(hydroxymethyl)–7–nitroindoline–5–sulfonamide ( A–6 )

[205] Mixture of ( S )–(7-nitro-5-sulfamoylindolin-2-yl)methylcarbamate ( A–5 ) (21 mg, 0.068 mmol) and NaOH (2N, 0.2 ml) in MeOH (1 ml) stirred at 50°C for 3.5 hours. The mixture was extracted with DCM and the aqueous 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 ₂ SO ₄ and concentrated to give the crude product ( S )-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide ( A–6 ), which was directly used for the next step. MS–IES (m/z): 272 [M – 1] ^– .

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

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

Intermediate B

[208] (R)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate B)

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

Intermediate C

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

[211] 3-bromo-4-chloro-5-nitrobenzenesulfonamide ( C-1 )

[212] A mixture of 4-chloro-3-nitrobenzenesulfonamide (10 g, 42.5 mmol) in conc. H ₂ SO ₄ (30 ml) was stirred at 50°C and added in portions of NBS (11 g, 61.8 mmol). The mixture was heated to 60°C and stirred at 60°C for 2 hours. The mixture was then poured into ice (200 g), after which it was stirred for 10 minutes and filtered. The filter cake was washed with water (30 ml) and evaporated to give the crude product 3-bromo-4-chloro-5-nitrobenzenesulfonamide ( C-1 ), which was used directly for the next step. MS–IES (m/z): 313 [M – 1] ^– .

[213] methyl-O–(tert-butyldimethylsilyl)–L-serinate ( C–2 )

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

[215] (R)–2–amino–3–((tert–butyldimethylsilyl)oxy)propan–1–ol ( C–3 )

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

[217] (R)–3–bromo–4–((1–((tert–butyldimethylsilyl)oxy)–3–hydroxypropan–2–yl)amino)–5–nitrobenzenesulfonamide ( C–4 )

[218] Mixture of 3-bromo-4-chloro-5-nitrobenzenesulfonamide ( С-1 ) (2.9 g, 9.26 mmol) and ( R )-2-amino-3-(( tert -butyldimethylsilyl)oxy) propan-1-ol ( С-3 ) (1.73 g, 8.44 mmol) and DIPEA (5.5 g, 42.6 mmol) in CH ₃ CN (25 ml) were stirred at 80°C for night. Concentrated, the residue was purified by silica gel column chromatography, eluting to give the title compound ( R )-3-bromo-4-((1-(( tert -butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)- 5-nitrobenzenesulfonamide ( C-4 ). MS–IES (m/h): 484 [M+1] ⁺ .

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

[220] 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 ₄ phen (2.5 mg, 0.010 mmol), CuI (4.0 mg, 0.021 mmol) and Cs ₂ CO ₃ (10 mg, 0.032 mmol) in toluene (1.5 ml) were stirred at 105 °C for 5 hours under N ₂ atmosphere. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography, 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–IES (m/h): 404 [M+1] ⁺ .

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

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

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

[224] To a solution of ( S )–3–(hydroxymethyl)–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( C–6 ) (10, 0 mg, 0.0346 mmol) in DCM/CH ₃ CN (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 minutes. The reaction was quenched with saturated aqueous NaHCO ₃ and the mixture was extracted with DCM. The organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product ( R )–(5–nitro–7–sulfamoyl–3,4–dihydro–2 H –benzo[ b ][1, 4]oxazin-3-yl)methylmethanesulfonate ( intermediate C ), which was directly used for the next step. MS–IES (m/h): 368 [M+1] ⁺ .

Intermediate D

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

[226] Title compound ( S )-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate D ) was prepared according to the method for the synthesis of ( R )-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) by replacement of methyl- O– ( tert -butyldimethylsilyl)– L -serinate ( C–2 ) by methyl- O– ( tert -butyldimethylsilyl)– D -serinate. MS–IES (m/h): 368 [M+1] ⁺ .

Intermediate E

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

[228] methyl-D-homoserinate hydrochloride ( E–1 )

[229] To a solution of D -homoserine (4.76 g, 40.0 mmol) in MeOH (100 ml) was added SOCl ₂ (3.5 ml, 40.0 mmol) in an ice-water bath. The mixture was then stirred at 50° C. for 1 hour. Concentrated to give the crude product methyl D -homoserinate hydrochloride ( E–1 ), which was used directly for the next step. MS–IES (m/z): 170 [M+1] ⁺ .

[230] (R)–3–bromo–4–((4–((tert–butyldimethylsilyl)oxy)–1–hydroxybutan–2–yl)amino)–5–nitrobenzenesulfonamide ( E–2 )

[231] The title compound ( R )-3-bromo-4-((4-(( tert -butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesulfonamide ( E-2 ) was obtained in accordance with the method of synthesis of ( R )-3-bromo-4-((1-(( tert -butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide ( C-4 ) by replacing methyl - L -serinate hydrochloride to methyl- D -homoserinate hydrochloride ( E–1 ). MS–IES (m/h): 418 [M+1] ⁺ .

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

[233] 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 obtained according to the synthesis method ( R )–3–((( tert -butyldimethylsilyl)oxy)methyl)–5–nitro–3,4–dihydro–2 H –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 ) on ( R )–3–bromo–4–((4–(( tert -butyldimethylsilyl)oxy)–1–hydroxybutan–2–yl)amino)–5–nitrobenzenesulfonamide ( E– 2 ). MS–IES (m/h): 418 [M+1] ⁺ .

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

[235] The title compound ( R )-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]oxazine-7-sulfonamide ( E-4 ) was obtained according to the method of synthesis of ( S )-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine-7-sulfonamide ( C-6 ) by substitutions ( R )–3–((( tert -butyldimethylsilyl)oxy)methyl)–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( C–5 ) on ( R )–3–(2–(( tert -butyldimethylsilyl)oxy)ethyl)–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( E-3 ). MS–IES (m/z): 304 [M+1] ⁺ .

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

[237] The title compound ( R )-3-(2- iodoethyl )-5-nitro-3,4-dihydro-2H-benzo[ b ][1,4]oxazine-7-sulfonamide ( intermediate E ) was obtained according to the method of synthesis of ( S )-2-(iodomethyl)-7-nitroindoline-5-sulfonamide ( Intermediate A ) by replacing ( S )-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide ( A –6 ) to ( R )–3–(2–hydroxyethyl)–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( E–4 ). MS–IES (m/h): 414 [M+1] ⁺ .

Intermediate F

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

[239] The title compound ( S )-3-(2- iodoethyl )-5-nitro-3,4-dihydro-2H-benzo[ b ][1,4]-oxazine-7-sulfonamide ( intermediate F ) was obtained according to the synthesis of ( S )-2-(iodomethyl)-7-nitroindoline-5-sulfonamide ( intermediate E ) by replacing D -homoserine with L -homoserine. MS–IES (m/h): [M+1] ⁺ .

Intermediate G

[240] (R)-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methylmethanesulfonate ( intermediate G )

[241] (S)–3–bromo–4–((1–((tert–butyldimethylsilyl)oxy)–3–hydroxypropan–2–yl)amino)–5–nitrobenzenesulfonamide ( G–1 )

[242] The title compound ( S )-3-bromo-4-((1-(( tert -butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide ( G-1 ) was obtained in accordance with the method of synthesis of ( R )-3-bromo-4-((1-(( tert -butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide ( C-4 ) by replacing D -serinate hydrochloride on L -serinate hydrochloride. MS–IES (m/h): 484 [M+1] ⁺ .

[243] (R)–2–((2–bromo–6–nitro–4–sulfamoylphenyl)amino)–3–((tert–butyldimethylsilyl)oxy)propyl methanesulfonate ( G–2 )

[244] The title compound ( R )-2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-(( tert -butyldimethylsilyl)oxy)propylmethanesulfonate ( G-2 ) was prepared according to Synthesis 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–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( С–6 ) on ( S )–3–bromo–4– ((1–(( tert -butyldimethylsilyl)oxy)–3–hydroxypropan–2–yl)amino)–5–nitrobenzenesulfonamide ( G–1 ). MS–IES (m/h): 562 [M+1] ⁺ .

[245] (R)–S–(2–((2–bromo–6–nitro–4–sulfamoylphenyl)amino)–3–((tert–butyldimethylsilyl)oxy)propyl)ethanethioate ( G–3 )

[246] To a solution of ( R )-2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-(( tert -butyldimethylsilyl)oxy)propylmethanesulfonate ( 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 room temperature for 1 hour. 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 ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (1:4) to give the title compound ( R )–S–(2–((2–bromo–6–nitro–4–sulfamoylphenyl)amino)– 3–(( tert -butyldimethylsilyl)oxy)propyl)ethanethioate ( G–3 ). MS–IES (m/h): 542 [M+1] ⁺ .

[247] (R)–3–bromo–4–((1–((tert–butyldimethylsilyl)oxy)–3–mercaptopropan–2–yl)amino)–5–nitrobenzenesulfonamide ( G–4 )

[248] To a solution of ( R )–S–(2–((2–bromo–6–nitro–4–sulfamoylphenyl)amino)–3–(( tert -butyldimethylsilyl)oxy)propyl) ethanethioate ( G–3 ) ( 0.3 g, 0.55 mmol) in MeOH (15 ml) was added K ₂ CO ₃ (0.26 g, 1.88 mmol). The mixture was stirred at room temperature for 10 minutes. The reaction was quenched with water and adjusted to pH=6~7 with conc. HCl. The mixture was extracted with DCM (3 x 25 ml). The extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound ( R )-3-bromo-4-((1-(( tert -butyldimethylsilyl)oxy)-3-mercaptopropan-2-yl)amino )-5-nitrobenzenesulfonamide ( G-4 ). MS–IES (m/z): 500 [M+1] ⁺ .

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

[250] 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 obtained according to the synthesis method ( R )–3–((( tert -butyldimethylsilyl)oxy)methyl)–5–nitro–3,4–dihydro–2 H –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 ) on ( R )–3–bromo–4–((1–(( tert -butyldimethylsilyl)oxy)–3–mercaptopropan–2–yl)amino)–5–nitrobenzenesulfonamide ( G–4 ) . MS–IES (m/z): 420 [M+1] ⁺ .

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

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

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

[254] Title compound ( R )-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] thiazin -3-yl)methylmethanesulfonate ( intermediate G ) was prepared according to the method for the synthesis of ( R )-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) by replacement of ( S )–3–(hydroxymethyl)–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazine–7–sulfonamide ( C–6 ) to ( R )–3– (hydroxymethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]thiazine-7-sulfonamide ( G-6 ). MS–IES (m/z): 384 [M+1] ⁺ .

Intermediate H

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

[256] 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 method for the synthesis 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–nitrobenzenesulfonamide ( G–1 ) by ( R )– 3-bromo-4-((4-(( tert -butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesulfonamide ( E-2 ). MS–IES (m/h): 398 [M+1] ⁺ .

Intermediate I

[257] (S)-(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate ( intermediate I )

[258] (S)–4–((1–azido–3–((tert–butyldimethylsilyl)oxy)propan–2–yl)amino)–3–bromo–5–nitrobenzenesulfonamide ( I–1 )

[259] To a solution of ( R )-2-((2-bromo-6-nitro-4-sulfamoylphenyl)amino)-3-(( tert -butyldimethylsilyl)oxy)propylmethanesulfonate ( G-2 ) (30 mg, 0, 0534 mmol) in DMF (1.5 ml) was added NaN 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 ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (1:5~1:3) to give the title compound ( S )-4-((1-azido-3-(( tert -butyldimethylsilyl)oxy) propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide ( I-1 ). MS–IES (m/h): 509 [M+1] ⁺ .

[260] (S)–4–((1–amino–3–((tert–butyldimethylsilyl)oxy)propan–2–yl)amino)–3–bromo–5–nitrobenzenesulfonamide ( I–2 )

[261] 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 ₂ O/THF (0.125 ml/5 ml) was added PPh ₃ (0.346 g, 1.388 mmol) under N ₂ atmosphere. The mixture was stirred at 35° C. overnight under N ₂ . 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 ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with PE/DCM (50:1~20:1) to give the title compound ( S )-4-((1-amino-3-(( tert -butyldimethylsilyl)oxy) propan-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide ( I-2 ). MS–IES (m/h): 483 [M+1] ⁺ .

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

[263] 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 ₄ phen (10 mg, 0.0415 mmol), CuI (12 mg, 0.0622 mmol) and Cs ₂ CO ₃ (20 mg, 0.0622 mmol) in dioxane (1.5 ml) was stirred at 100°C for 5 hours in an atmosphere of N ₂ . atmosphere. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography 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–IES (m/h): 403 [M+1] ⁺ .

[264] (S)–2–(hydroxymethyl)–8–nitro–1,2,3,4–tetrahydroquinoxaline–6–sulfonamide ( I–4 )

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

[266] (S)–(8–nitro–6–sulfamoyl–1,2,3,4–tetrahydroquinoxalin–2–yl)methyl methanesulfonate ( intermediate I )

[267] The title compound ( S )–(8-nitro-6-sulfamoyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate ( intermediate I ) was prepared according to the synthesis method ( R )– (5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) by replacing ( S )-3-(hydroxymethyl) -5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine-7-sulfonamide ( С-6 ) on ( S )-2-(hydroxymethyl)-8-nitro-1, 2,3,4-tetrahydroquinoxaline-6-sulfonamide ( I-4 ). MS–IES (m/h): 367 [M+1] ⁺ .

Example 1–1

[268] (S)–2–((1Н–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 )

[269] (S)–2–(morpholinomethyl)–7–nitroindoline–5–sulfonamide ( 1–1a )

[270] Mixture of ( S )-2-(iodomethyl)-7-nitroindoline-5-sulfonamide ( intermediate A ) (15.3 mg, 0.04 mmol), K ₂ CO ₃ (6.0 mg, 0, 04 mmol) and morpholine (0.1 ml) in CH ₃ CN (1.5 ml) were stirred at 60°C for 4 hours. The mixture was extracted with EtOAc (2×30 ml), the extracts were washed with brine (100 ml), dried with Na ₂ SO ₄ and concentrated. 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–IES (m/h): 343 [M+1] ⁺ .

[271] 2–((1Н–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 )

[272] Title compound 2-((1 H -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 obtained according to the method described in US 2014/0275540 , ( A1 ). MS–IES (m/h): 571 [M+1] ⁺ .

[273] (S)–2–((1Н–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 )

[274] A mixture of 2–((1 H –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 ₃ N (6.0 mg, 0, 06 mmol) and DMAP (8.0 mg, 0.06 mmol) in DCM (4 ml) were stirred at 30°C for 20 hours. The mixture was extracted with DCM (25 ml), washed with brine (15 ml), dried with Na ₂ SO 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–IES (m/h): 895 [M+1] ⁺ .

Example 1-2

[275] (S)–2–((1Н–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 )

[276] (S)–2–(cyanomethyl)–7–nitroindoline–5–sulfonamide ( 1–2a )

[277] 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 hours. The mixture was extracted with EtOAc, washed with brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (60:1~15:1) to give the title compound ( S )-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide ( 1-2a ) , MS–IES (m/h): 283 [M+1] ⁺ .

[278] (S)–2–(7–nitro–5–sulfamoylindolin–2–yl)acetic acid ( 1–2b )

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

[280] (S)–2–(2–morpholino–2–oxoethyl)–7–nitroindoline–5–sulfonamide ( 1–2с )

[281] 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 ₃ N (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) were added. The resulting mixture was stirred at 30°C for 6 hours. The mixture was extracted with EtOAc, washed with brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give the title compound ( S )-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide ( 1-2c ). MS–IES (m/h): 371 [M+1] ⁺ .

[282] (S)–2–(2–morpholinoethyl)–7–nitroindoline–5–sulfonamide ( 1–2d )

[ 283 ] BH ₃ (150 ml, 0.144 mmol) in THF at room temperature. The mixture was stirred at room temperature overnight and then MeOH solution (0.5 ml) was added and conc. HCl (0.1 ml). Stirred at 80°C for 3 hours. The mixture was cooled to room temperature and adjusted to pH=10 with 4N Na ₂ CO ₃ . The mixture was extracted with EtOAc. The extracts were washed with brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give the title compound ( S )-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide ( 1-2d ). MS–IES (m/h): 357 [M+1] ⁺ .

[284] (S)–2–((1Н–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 )

[285] The title compound ( S )–2–((1 H –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–nitroindoline -5-yl)sulfonyl)benzamide ( 1-2 ) was obtained in accordance with the synthesis method 1-1 by replacing ( S )-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide ( 1-1a ) by ( S ) –2–(2–morpholinoethyl)–7–nitroindoline–5–sulfonamide ( 1–2d ). MS–IES (m/h): 909 [M+1] ⁺ .

[286] Following essentially the same procedures as 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. Structure and Names Examples 1–3 ~ 1–27 are shown in Table 1.

Table 1

EXAMPLE STRUCTURE TITLE DATA 1–3

( S )–2–((1 H –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)-7-nitroindoline -5-yl)sulfonyl)benzamide MS–IES (m/z): 908 [M+1] ⁺ 1–4

( S )–2–((1 H –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-hydroxy-4-methylpiperidin-1-yl)methyl) -7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 1–5

( S )–2–((1 H –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-((dimethylamino)methyl)-7-nitroindolin-5-yl)sulfonyl )benzamide MS–IES (m/z): 853 [M+1] ⁺ 1–6

( S )–2–((1 H –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-(hydroxymethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 1–7

( R )–2–((1 H –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)-7-nitroindoline -5-yl)sulfonyl)benzamide MS–IES (m/z): 908 [M+1] ⁺ 1–8

( R )–2–((1 H –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 MS–IES (m/z): 895 [M+1] ⁺ 1–9

( R )–2–((1 H –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-hydroxy-4-methylpiperidin-1-yl)methyl) -7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 1–10

( R )–2–((1 H –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-((dimethylamino)methyl)-7-nitroindolin-5-yl)sulfonyl )benzamide MS–IES (m/z): 853 [M+1] ⁺ 1–11

( R )–2–((1 H –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-(hydroxymethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 1–12

( S )–2–((1 H –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–IES (m/z): 922 [M+1] ⁺ 1–13

( S )–2–((1 H –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-hydroxy-4-methylpiperidin-1-yl) ethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 937 [M+1] ⁺ 1–14

( S )–2–((1 H –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-(dimethylamino)ethyl)-7-nitroindolin-5-yl )sulfonyl)benzamide MS–IES (m/z): 867 [M+1] ⁺ 1–15

( R )–2–((1 H –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–IES (m/z): 922 [M+1] ⁺ 1–16

( R )–2–((1 H –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 MS–IES (m/z): 909 [M+1] ⁺ 1–17

( R )–2–((1 H –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-hydroxy-4-methylpiperidin-1-yl) ethyl)-7-nitroindolin-5-yl)sulfonyl)benzamide MS–IES (m/z): 937 [M+1] ⁺ 1–18

( R )–2–((1 H –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-(dimethylamino)ethyl)-7-nitroindolin-5-yl )sulfonyl)benzamide MS–IES (m/z): 867 [M+1] ⁺ 1–19

( R )–2–((1 H –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-hydroxyethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS–IES (m/z): 840 [M+1] ⁺ 1–20

( S )–2–((1 H –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-hydroxyethyl)-7-nitroindolin-5-yl)sulfonyl) benzamide MS–IES (m/z): 840 [M+1] ⁺ 1–21

2–((1 H –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-1 H -indol-5-yl)sulfonyl)benzamide MS–IES (m/z): 893 [M+1] ⁺ 1–22

methyl-( S )–2–(5–( N –(2–((1 H –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-nitroindolin-2-yl )acetate MS–IES (m/z): 868 [M+1] ⁺ 1–23

( S )–2–((1 H –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-(dimethylamino)-2-oxoethyl)-7-nitroindoline- 5-yl)sulfonyl)benzamide MS–IES (m/z): 881 [M+1] ⁺ 1–24

( S )–2–((1 H –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-morpholino-2-oxoethyl)-7-nitroindoline-5- yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 1–25

( R )–2–((1 H –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)-2-oxoethyl )–7–nitroindolin–5–yl)sulfonyl)benzamide MS–IES (m/z): 936 [M+1] ⁺ 1–26

( R )–2–((1 H –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-morpholino-2-oxoethyl)-7-nitroindoline-5- yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 1–27

2–((1 H –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–1 H –benzo[ d ]imidazol–6–yl )sulfonyl)benzamide MS–IES (m/z): 894 [M+1] ⁺

Example 2-1

[287] (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)

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

[289] A mixture of ( R )-(5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) (11, 0 mg, 0.03 mmol), 1-methylpiperazine (12.0 mg, 0.12 mmol) and K ₂ CO ₃ (20.7 mg, 0.15 mmol) in CH ₃ CN (4 ml) were stirred at 80 °C for 1.5 hours. The reaction was quenched with water and extracted with EtOAc (2×30 ml). The extracts were washed with brine (30 ml), dried with Na ₂ SO ₄ and concentrated. The residue was purified by flash silica gel column chromatography 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–IES (m/h): 372 [M+1] ⁺ .

[290] (S)–2–((1Н–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–2Н–benzo[b][1,4]oxazin–7–yl)sulfonyl)benzamide ( 2–1 )

[291] 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 obtained in accordance with the synthesis method 1-1 by replacing ( S )–2–(morpholinomethyl)–7–nitroindoline–5–sulfonamide ( 1–1a ) on ( S )–3–((4–methylpiperazin–1–yl)methyl)–5–nitro–3,4–dihydro –2 H -benzo[ b ][1,4]oxazine-7-sulfonamide ( 2-1a ). MS–IES (m/h): 924 [M+1] ⁺ .

Example 2-2

[292] (R)–2–((1Н–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 )

[293] The title compound ( R )–2–((1 H -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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide ( 2-2 ) was obtained in accordance with the method of synthesis 1-1 by replacing ( S )-2- (iodomethyl)-7-nitroindoline-5-sulfonamide ( intermediate A ) on ( R )-3-(2- iodoethyl )-5-nitro-3,4-dihydro-2H-benzo[ b ][1,4 ]oxazine-7-sulfonamide ( intermediate E ). MS–IES (m/h): 925 [M+1] ⁺ .

Example 2-3

[294] (R)–2–((1Н–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 )

[295] methyl-(R)–2–amino–2–(4–hydroxyphenyl)acetate ( 2–3а )

[296] SOCl ₂ (1.3 ml, 18.0 mmol). The mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated to give the crude product of the title compound methyl-( R )-2-amino-2-(4-hydroxyphenyl)acetate ( 2-3a ). MS–IES (m/z): 182 [M+1] ⁺ .

[297] methyl-(R)–2–((tert–butoxycarbonyl)amino)–2–(4–hydroxyphenyl)acetate ( 2–3b )

[298] 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 ₂ CO ₃ (1.2 g, 8.8 mmol) and (Boc) ₂ O (1.3 g, 6.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by recrystallization from PE/EtOAc to give the title compound methyl-( R )-2-(( tert -butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate ( 2-3b ). MS–IES (m/h): 282 [M+1] ⁺ .

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

[300] 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 in portions LAH (445 mg, 11.7 mmol) and the mixture was stirred at 0°C for 1 hour. Na ₂ SO ₄ ∙10∙H ₂ O was added to the reaction mixture at 0°C. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting to give the title compound tert -butyl-( R )-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate ( 2-3c ). MS–IES (m/z): 254 [M+1] ⁺ .

[301] tert-butyl-(R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2-3d )

[302] 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 ₃ .Et ₂ O (40 μl, 0.33 mmol) in acetone (3 ml) were stirred at room temperature for 4 h. The reaction was quenched with ice water and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (6:1) to give the title compound tert -butyl-( R )-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2–3d ). MS–IES (m/h): 294 [M+1] ⁺ .

[303] tert-butyl-(R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate ( 2-3f )

[304] A mixture of tert -butyl-( R )-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate ( 2-3d ) (760 mg, 2.55 mmol) and PtO ₂ (100 mg) in IPA (60 ml) and HOAc (4 ml) was stirred at room temperature in an atmosphere of H ₂ for 48 hours. The reaction mixture was filtered through celite and concentrated to give the crude product of the title compound tert -butyl-( R )-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2-3e ), which was used directly for next stage. MS–IES (m/z): 300 [M+1] ⁺ .

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

[306] A mixture of tert -butyl-( R )-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2-3e ) (233 mg, 0.773 mmol) and DMP (424 mg, 2.18 mmol) in DCM (10 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was washed with saturated aqueous NaHCO ₃ (30 ml). The organic layer was concentrated. The residue was purified by silica gel column chromatography, eluting to give the title compound tert -butyl-( R )-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidin-3-carboxylate ( 2-3f ). MS–IES (m/h): 298 [M+1] ⁺ .

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

[308] 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 hour. The reaction was quenched with saturated aqueous NH ₄ Cl and the mixture was extracted with EtOAc. The extracts were washed with brine (30 ml), dried over Na ₂ SO ₄ and evaporated to give the crude product tert -butyl-( R )-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2–3g ), which was directly used for the next step. MS–IES (m/z): 314 [M+1] ⁺ .

[309] (R)–4–(1–amino–2–hydroxyethyl)–1–methylcyclohexane–1–oltrifluoroacetate ( 2–3h )

[310] A mixture of tert -butyl-( R )-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidin-3-carboxylate ( 2-3g ) (200 mg, 0.63 mmol) and TFA ( 0.5 ml, 5 mmol) in DCM (5 ml) was stirred at room temperature for 45 minutes. The reaction mixture was evaporated to give the crude product (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexane-1-oltrifluoroacetate ( 2-3h ), which was directly used for the next step. MS–IES (m/z): 174 [M+1] ⁺ .

[311] (R)–3–bromo–4–((2–hydroxy–1–(4–hydroxy–4–methylcyclohexyl)ethyl)amino)–5–nitrobenzenesulfonamide ( 2–3i–A and 2–3i–B )

[312] A mixture of ( R )-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexane-1-oltrifluoroacetate ( 2-3h ) (250 mg, 0.81 mmol), 3-bromo-4-chloro- 5-nitrobenzenesulfonamide ( С-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 room temperature and concentrated. The residue was purified by preparative TLC - top spot - to give the 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 - bottom spot - to give the title compound ( R )-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5- nitrobenzenesulfonamide ( 2–3i–B ) MS–IES (m/h): 452 [M+1] ⁺ .

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

[314] 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 ₂ (dba) ₃ (15 mg, 0.016 mmol), Xanthophos (16 mg, 0.028 mmol) and Cs ₂ CO ₃ (71 mg, 0.22 mmol) in dioxane (5 ml) were stirred at 100°C for 1.5 hours. The mixture was cooled to room temperature. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1) to give the 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–IES (m/h): 372 [M+1] ⁺ .

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

[316] 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 obtained in accordance with the synthesis method 2-3j-A by replacing ( R )-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino )-5-nitrobenzenesulfonamide ( 2-3i-A ) on (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide ( 2 -3i-B ). MS–IES (m/h): 372 [M+1] ⁺ .

[317] (R)–2–((1Н–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 )

[318] The title compound ( R )-2-((1 H -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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide ( 2-3А and 2-3В ) was obtained in accordance with the synthesis method 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 -2 H -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–IES (m/h): 924 [M+1] ⁺ .

[319] Following essentially the same procedures as 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. Structures and Names Examples 2–4 ~ 2–252 are shown in Table 2.

table 2

EXAMPLE STRUCTURE TITLE DATA 2–4

( 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]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–5

( R )–2–((1 H –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-(morpholinomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–6

( R )–2–((1 H –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-methylpiperidin-1-yl)methyl) -5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–7

( R )–2–((1 H –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-((dimethylamino)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 869 [M+1] ⁺ 2–8

( R )–2–((1 H –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-(hydroxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 842 [M+1] ⁺ 2–9

( S )–2–((1 H –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-(4-methylpiperazin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–10

( S )–2–((1 H –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- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–11

( S )–2–((1 H –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-(4-hydroxy-4-methylpiperidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 953 [M+1] ⁺ 2–12

( S )–2–((1 H –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-(dimethylamino)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 883 [M+1] ⁺ 2–13

( S )–2–((1 H –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-hydroxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–14

( R )–2–((1 H –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-(4-methylpiperazin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–15

( R )–2–((1 H –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-(4-hydroxy-4-methylpiperidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 953 [M+1] ⁺ 2–16

( R )–2–((1 H –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-(dimethylamino)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 883 [M+1] ⁺ 2–17

( R )–2–((1 H –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-hydroxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 856 [M+1] ⁺ 2–18

( S )–2–((1 H –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-(morpholinomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–19

( S )–2–((1 H –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-methylpiperidin-1-yl)methyl) -5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–20

( S )–2–((1 H –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-((dimethylamino)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 869 [M+1] ⁺ 2–21

( R )–2–((1 H –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-((3-hydroxy-3-methylazetidin-1-yl)methyl) -5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–22

2–((1 H –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–IES (m/z): 980 [M+1] ⁺ 2–23

2–((1 H –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)methyl)-5-nitro -3,4-dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–24

( S )–2–((1 H –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-((3-hydroxyazetidin-1-yl)methyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 897 [M+1] ⁺ 2–25

( S )–2–((1 H –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-((3-hydroxy-3-methylazetidin-1-yl)methyl) -5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–26

2–((1 H –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–IES (m/z): 938 [M+1] ⁺ 2–27

2–((1 H –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 )-3,4-dimethylpiperazin-1-yl) methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–28

( S )–2–((1 H –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-((4-(oxetan-3-yl)piperazin -1-yl)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 966 [M+1] ⁺ 2–29

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 980 [M+1] ⁺ 2–30

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 980 [M+1] ⁺ 2–31

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–32

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–33

( R )–2–((1 H –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-((dimethyl(oxo)-l6-sulfanylidene)amino) ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 931 [M+1] ⁺ 2–34

( R )–2–((1 H –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-(3-hydroxyazetidin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–35

( R )–2–((1 H –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-(3-hydroxy-3-methylazetidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–36

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 952 [M+1] ⁺ 2–37

2–((1 H –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 )–3,4–dimethylpiperazin–1– yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 952 [M+1] ⁺ 2–38

( R )–2–((1 H –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-(2-(4-(oxetan-3-yl) )piperazin-1-yl)ethyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 980 [M+1] ⁺ 2–39

2–((1 H –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–(oxetane -3-yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 994 [M+1] ⁺ 2–40

2–((1 H –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–(oxetane -3-yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 994 [M+1] ⁺ 2–41

2–((1 H –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 )–2–methylmorpholino)ethyl)–5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–42

2–((1 H –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 )–2–methylmorpholino)ethyl)–5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–43

( S )–2–((1 H –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-((dimethyl(oxo)-l6-sulfanylidene)amino) ethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 931 [M+1] ⁺ 2–44

( S )–2–((1 H –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-(3-hydroxyazetidin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–45

( S )–2–((1 H –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-(3-hydroxy-3-methylazetidin-1-yl) ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–46

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 952 [M+1] ⁺ 2–47

2–((1 H –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–(( S )–3,4–dimethylpiperazin–1– yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 952 [M+1] ⁺ 2–48

( S )–2–((1 H –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-(2-(4-(oxetan-3-yl) )piperazin-1-yl)ethyl)-3,4-dihydro- 2H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 980 [M+1] ⁺ 2–49

2–((1 H –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–(oxetane -3-yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 994 [M+1] ⁺ 2–50

2–((1 H –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–(( S )–3–methyl–4–(oxetane -3-yl)piperazin-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 994 [M+1] ⁺ 2–51

2–((1 H –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–(( S )–2–methylmorpholino)ethyl)–5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–52

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–53

( S )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–(acetamidomethyl)–5–nitro–3,4–dihydro–2 H -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–IES (m/z): 883 [M+1] ⁺ 2–54

( S )– N –((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4] oxazin -3-yl)methyl)tetrahydro-2H-pyran-4-carboxamide MS–IES (m/z): 953 [M+1] ⁺ 2–55

( S )– N –((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)morpholine-4-carboxamide MS–IES (m/z): 954 [M+1] ⁺ 2–56

( S )– N –(2–(7–( N –(2–((1 H –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–IES (m/z): 967 [M+1] ⁺ 2–57

( R )– N –(2–(7–( N –(2–((1 H –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–IES (m/z): 967 [M+1] ⁺ 2–58

( S )– N –(2–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)ethyl)morpholine-4-carboxamide MS–IES (m/z): 968 [M+1] ⁺ 2–59

( R )– N –(2–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)ethyl)morpholine-4-carboxamide MS–IES (m/z): 968 [M+1] ⁺ 2–60

methyl-( S )–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)carbamate MS–IES (m/z): 899 [M+1] ⁺ 2–61

tetrahydro–2 H –pyran–4–yl-( S )–((7–( N –(2–((1 H –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–2 H –benzo[ b ][1,4]oxazin–3–yl)methyl)carbamate MS–IES (m/z): 969 [M+1] ⁺ 2–62

( R )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–(2–acetamidoethyl)–5–nitro–3,4–dihydro– 2 H -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–IES (m/z): 897 [M+1] ⁺ 2–63

methyl-( R )–(2–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)ethyl)carbamate MS–IES (m/z): 913 [M+1] ⁺ 2–64

( R )–2–((1 H –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-(methylsulfonyl)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 918 [M+1] ⁺ 2–65

( R )–2–((1 H –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-methoxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 870 [M+1] ⁺ 2–66

( S )–2–((1 H –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-(methylsulfonamidomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 919 [M+1] ⁺ 2–67

( S )–2–((1 H –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-((morpholine-4-sulfonamido)methyl)-5-nitro-3 ,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 990 [M+1] ⁺ 2–68

( R )–2–((1 H –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-(methylsulfonamido)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 933 [M+1] ⁺ 2–69

( R )–2–((1 H –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-(morpholine-4-sulfonamido)ethyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1004
[M+1] ⁺ 2–70

( R )–2–((1 H –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–(((dimethyl(oxo)–λ ⁶ –sulfanylidene)amino)methyl )–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 917 [M+1] ⁺ 2–71

( R )–2–((1 H –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–(((1–oxidotetrahydro–1λ ⁶ –thiophene– 1-ylidene)amino)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 943 [M+1] ⁺ 2–72

( R )–2–((1 H –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-(((4-oxido-1,4λ ⁶ - oxatian-4-ylidene)amino)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 959 [M+1] ⁺ 2–73

( R )–2–((1 H –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-(2-((1-oxidotetrahydro-1λ ⁶ - thiophene-1-ylidene)amino)ethyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 957 [M+1] ⁺ 2–74

( R )–2–((1 H –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-(2-((4-oxido-1,4λ ⁶ -oxatian-4-ylidene)amino)ethyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–75

( S )–2–((1 H –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–(((dimethyl(oxo)–λ ⁶ –sulfanylidene)amino)methyl )–5–nitro–3,4–dihydro–2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 917 [M+1] ⁺ 2–76

( S )–2–((1 H –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–(((1–oxidotetrahydro–1λ ⁶ –thiophene– 1-ylidene)amino)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 943 [M+1] ⁺ 2–77

( S )–2–((1 H –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-(((4-oxido-1,4λ ⁶ - oxatian-4-ylidene)amino)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 959 [M+1] ⁺ 2–78

( S )–2–((1 H –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-(2-((4-oxido-1,4λ ⁶ -oxatian-4-ylidene)amino)ethyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–79

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–80

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–81

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–82

2–((1 H –pyrrolo[2,3–b]pyridin–5–yl)oxy)– N –((( R )–3–(((1 S ,4 S )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 923 [M+1] ⁺ 2–83

2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((( R )–3–(((1 R ,4 R )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 923 [M+1] ⁺ 2–84

( R )–2–((1 H –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-(piperidin-1-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–85

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–86

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–87

2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((( S )–3–(((1 S ,4 S )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 923 [M+1] ⁺ 2–88

2–((1 H –pyrrolo[2,3–b]pyridin–5–yl)oxy)– N –((( S )–3–(((1 R ,4 R )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 923 [M+1] ⁺ 2–89

( S )–2–((1 H –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-(piperidin-1-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–90

( R )–2–((1 H –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-(methylsulfonyl)piperazin-1-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 988 [M+1] ⁺ 2–91

( R )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–((4–acetylpiperazin–1–yl)methyl)–5–nitro -3,4-dihydro-2 H -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–IES (m/z): 952 [M+1] ⁺ 2–92

( R )–2–((1 H –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-((4-propionylpiperazin-1-yl)methyl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 966 [M+1] ⁺ 2–93

methyl-( R )–4–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)piperazine-1-carboxylate MS–IES (m/z): 968 [M+1] ⁺ 2–94

( R )–2–((1 H –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-(cyclopropanecarbonyl)piperazin-1-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 978 [M+1] ⁺ 2–95

( S )–2–((1 H –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-(methylsulfonyl)piperazin-1-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 988 [M+1] ⁺ 2–96

( S )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–((4–acetylpiperazin–1–yl)methyl)–5–nitro -3,4-dihydro-2 H -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–IES (m/z): 952 [M+1] ⁺ 2–97

( S )–2–((1 H –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-((4-propionylpiperazin-1-yl)methyl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 966 [M+1] ⁺ 2–98

methyl-( S )–4–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)piperazine-1-carboxylate MS–IES (m/z): 968 [M+1] ⁺ 2–99

( S )–2–((1 H –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-(cyclopropanecarbonyl)piperazin-1-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 978 [M+1] ⁺ 2–100

( R )–2–((1 H –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-methyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 2–101

methyl-( R )–7–( N –(2–((1 H –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- 2 H -benzo[ b ][1,4]oxazine-3-carboxylate MS–IES (m/z): 870 [M+1] ⁺ 2–102

( R )–7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazine-3-carboxamide MS–IES (m/z): 883 [M+1] ⁺ 2–103

( R )–2–((1 H –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-(morpholine-4-carbonyl)-5-nitro-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–104

( R )–2–((1 H –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-carbonyl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–105

( S )–2–((1 H –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-methyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 2–106

( R )–2–((1 H –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-methyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 2–107

( R )–2–((1 H –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-ethyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 840 [M+1] ⁺ 2–108

( R )–2–((1 H –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-isopropyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 854 [M+1] ⁺ 2–109

( R )–2–((1 H –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-cyclopropyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 852 [M+1] ⁺ 2–110

( R )–2–((1 H –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-(methoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 856 [M+1] ⁺ 2–111

( S )–2–((1 H –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-methyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 826 [M+1] ⁺ 2–112

( S )–2–((1 H –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-ethyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 840 [M+1] ⁺ 2–113

( S )–2–((1 H –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-isopropyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 854 [M+1] ⁺ 2–114

( S )–2–((1 H –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-cyclopropyl-5-nitro-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 852 [M+1] ⁺ 2–115

( S )–2–((1 H –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-(cyanomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 851 [M+1] ⁺ 2–116

( S )–2–((1 H –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-(methoxymethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 856 [M+1] ⁺ 2–117

( R )–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methylmorpholine-4-carboxylate MS–IES (m/z): 955 [M+1] ⁺ 2–118

( S )–2–((1 H –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-methoxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 870 [M+1] ⁺ 2–119

methyl-( S )–2–(7–( N –(2–((1 H –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–2 H –benzo[ b ][1,4]oxazin–3–yl)acetate MS–IES (m/z): 884 [M+1] ⁺ 2–120

( S )–2–((1 H –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-(methylsulfonyl)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 918 [M+1] ⁺ 2–121

( S )–2–((1 H –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-((1,1-dioxidothiomorpholino)methyl)-5-nitro-3 ,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 959 [M+1] ⁺ 2–122

( S )–2–((1 H –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–((1–(methylimino)–1–oxido–1λ ⁶ –thiomorpholino )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 972 [M+1] ⁺ 2–123

( S )–2–((1 H –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–((1–(ethylimino)–1–oxido–1λ ⁶ –thiomorpholino )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 986 [M+1] ⁺ 2–124

( S )–2–((1 H –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–((1–(cyclopropylimino)–1–oxido–1λ ⁶ –thiomorpholino )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 998 [M+1] ⁺ 2–125

( S )–2–((1 H –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–((dimethyl(oxo)–λ ⁶ –sulfanylidene) amino)piperidin-1-yl)methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1000
[M+1] ⁺ 2–126

( R )–2–((1 H –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-(1,1-dioxidothiomorpholino)ethyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–127

( R )–2–((1 H –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-(1-(methylimino)-1-oxido-1λ ⁶ -thiomorpholino)ethyl)-5-nitro-3,4-dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 986 [M+1] ⁺ 2–128

( R )–2–((1 H –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–(1–(ethylimino)–1–oxido–1λ ⁶ -thiomorpholino)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1000
[M+1] ⁺ 2–129

( R )–2–((1 H –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-(1-(cyclopropylimino)-1-oxido-1λ ⁶ -thiomorpholino)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1012
[M+1] ⁺ 2–130

methyl-( R )–(4–(2–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)ethyl)-1-oxido-1λ ⁶ -thiomorpholine-1-ylidene)carbamate MS–IES (m/z): 1030
[M+1] ⁺ 2–131

( R )–2–((1 H –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–(4–((dimethyl(oxo)–λ ⁶ – sulfanylidene)amino)piperidin-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1014
[M+1] ⁺ 2–132

( S )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–benzyl–5–nitro–3,4–dihydro–2 H –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–IES (m/z): 902 [M+1] ⁺ 2–133

( S )–2–((1 H –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-(pyridin-2-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 903 [M+1] ⁺ 2–134

methyl-( R )–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)carbamate MS–IES (m/z): 899 [M+1] ⁺ 2–135

( S )–2–(7–( N –(2–((1 H –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 –2 H –benzo[ b ][1,4]oxazin–3–yl)ethylmorpholine–4–carboxylate MS–IES (m/z): 969 [M+1] ⁺ 2–136

( R )–2–((1 H –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-(methylsulfonamidomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 919 [M+1] ⁺ 2–137

( R )–2–((1 H –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-(ethylsulfonamidomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 933 [M+1] ⁺ 2–138

( R )–2–((1 H –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-(cyclopropanesulfonamidomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 945 [M+1] ⁺ 2–139

( R )–2–((1 H –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-2 H -pyran)-4 -sulfonamido)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 989 [M+1] ⁺ 2–140

( R )–2–((1 H –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 -((4-methyl-3-(morpholinomethyl)-5-nitro-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 2–141

2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((( R )–3–(((1 S ,4 S )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-4-methyl-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 937 [M+1] ⁺ 2–142

( S )–2–((1 H –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-morpholino-2-oxoethyl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–143

( R )–2–((1 H –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-morpholino-2-oxoethyl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 939 [M+1] ⁺ 2–144

( R )–2–((1 H –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-(cyanomethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 851 [M+1] ⁺ 2–145

( S )–2–((1 H –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-((methylsulfonyl)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 904 [M+1] ⁺ 2–146

( R )–2–((1 H –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-((2-oxooxazolidin-3-yl)methyl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–147

( R )–2–((1 H –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-((methylsulfonyl)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 904 [M+1] ⁺ 2–148

( S )–2–((1 H –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-((2-oxooxazolidin-3-yl)methyl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 911 [M+1] ⁺ 2–149

( R )–2–((1 H –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-((1,1-dioxidothiomorpholino)methyl)-5-nitro-3 ,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 959 [M+1] ⁺ 2–150

( R )–2–((1 H –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-((dimethyl(oxo)-l6-sulfanylidene)amino )piperidin-1-yl)methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1000 [M+1] ⁺ 2–151

( R )–2–((1 H –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-(methylsulfonamido)piperidin-1-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 1002 [M+1] ⁺ 2–152

methyl-( R )–(1–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)piperidin-4-yl)carbamate MS–IES (m/z): 982 [M+1] ⁺ 2–153

( S )–2–((1 H –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-(1,1-dioxidothiomorpholino)ethyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–154

( R )–2–((1 H –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-methyl-4-oxido-1,4-azaphosphinan- 1-yl)methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 957 [M+1] ⁺ 2–155

( R )–2–((1 H –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-(4-methyl-4-oxido-1,4- azaphosphinan-1-yl)ethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 971 [M+1] ⁺ 2–156

( R )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–benzyl–5–nitro–3,4–dihydro–2 H –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–IES (m/z): 902 [M+1] ⁺ 2–157

( R )–2–((1 H –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-fluorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 920 [M+1] ⁺ 2–158

( R )–2–((1 H –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-fluorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 920 [M+1] ⁺ 2–159

( R )–2–((1 H –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-chlorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 936 [M+1] ⁺ 2–160

( R )–2–((1 H –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-chlorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 936 [M+1] ⁺ 2–161

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 933 [M+1] ⁺ 2–162

( S )–2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 933 [M+1] ⁺ 2–163

( S )–2–((1 H –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-(pyridin-3-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 903 [M+1] ⁺ 2–164

( S )–2–((1 H –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-(pyridin-4-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 903 [M+1] ⁺ 2–165

( R )–2–((1 H –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-phenyl-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 888 [M+1] ⁺ 2–166

( R )–2–((1 H –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-fluorophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 906 [M+1] ⁺ 2–167

( R )–2–((1 H –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-chlorophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 922 [M+1] ⁺ 2–168

( S )–2–((1 H –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-(methylsulfonyl)phenyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 966 [M+1] ⁺ 2–169

( R )–2–((1 H –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-methoxyphenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 918 [M+1] ⁺ 2–170

( R )–2–((1 H –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-cyanophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 913 [M+1] ⁺ 2–171

( S )–2–((1 H –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-(pyridin-2-yl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 889 [M+1] ⁺ 2–172

( S )–2–((1 H –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-phenyl-3,4-dihydro- 2H -benzo [ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 888 [M+1] ⁺ 2–173

( S )–2–((1 H –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-fluorophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 906 [M+1] ⁺ 2–174

( S )–2–((1 H –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-chlorophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 922 [M+1] ⁺ 2–175

( R )–2–((1 H –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-(methylsulfonyl)phenyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 966 [M+1] ⁺ 2–176

( S )–2–((1 H –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-methoxyphenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 918 [M+1] ⁺ 2–177

( R )–2–((1 H –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-(pyridin-2-yl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 889 [M+1] ⁺ 2–178

( R )–2–((1 H –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-fluoropyridin-2-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 907 [M+1] ⁺ 2–179

( R )–2–((1 H –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)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 919 [M+1] ⁺ 2–180

2–((1 H –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–2 H –pyran–4–yl)methyl)– 3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–181

( R )–2–((1 H –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-2 H -pyran-4-yl )methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–182

( S )–2–((1 H –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-2 H -pyran-4-yl )methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–183

( S )–2–((1 H –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-2 H -pyran-4- yl)oxy)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 926 [M+1] ⁺ 2–184

( R )–2–((1 H –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-2 H -pyran-4- yl)oxy)methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 926 [M+1] ⁺ 2–185

2–((1 H –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–2 H –pyran–4–yl)–3.4 -dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 896 [M+1] ⁺ 2–186

( R )–2–((1 H –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-2 H -pyran-4-yl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 896 [M+1] ⁺ 2–187

( S )–2–((1 H –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-2 H -pyran-4-yl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 896 [M+1] ⁺ 2–188

2–((1 H –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–IES (m/z): 910 [M+1] ⁺ 2–189

( S )–2–((1 H –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-fluorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 920 [M+1] ⁺ 2–190

( S )–2–((1 H –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-fluorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 920 [M+1] ⁺ 2–191

( S )–2–((1 H –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-chlorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 936 [M+1] ⁺ 2–192

( S )–2–((1 H –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-(methylsulfonyl)pyridin-2-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 981 [M+1] ⁺ 2–193

( S )–2–((1 H –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-((1-methylpiperidin-4-yl)methyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–194

( S )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–((1–acetylpiperidin–4–yl)methyl)–5–nitro -3,4-dihydro-2 H -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–IES (m/z): 951 [M+1] ⁺ 2–195

methyl-( S )–4–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)piperidine-1-carboxylate MS–IES (m/z): 967 [M+1] ⁺ 2–196

( S )–2–((1 H –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-((1-(methylsulfonyl)piperidin-4-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 987 [M+1] ⁺ 2–197

( S )–2–((1 H –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-fluoropyridin-2-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 907 [M+1] ⁺ 2–198–A

( S )–2–((1 H –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-chloropyridin-2-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–198–B

( S )–2–((1 H –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-chloropyridin-2-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–199

( R )–2–((1 H –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-(pyridin-2-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 903 [M+1] ⁺ 2–200

( R )–2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 933 [M+1] ⁺ 2–201

( R )–2–((1 H –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-((1-methylpiperidin-4-yl)methyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–202

methyl-( R )–4–((7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)methyl)piperidine-1-carboxylate MS–IES (m/z): 967 [M+1] ⁺ 2–203

( R )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–((1–acetylpiperidin–4–yl)methyl)–5–nitro -3,4-dihydro-2 H -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–IES (m/z): 951 [M+1] ⁺ 2–204

( R )–2–((1 H –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-((1-(methylsulfonyl)piperidin-4-yl)methyl)- 5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 987 [M+1] ⁺ 2–205

(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-(5-cyanopyridin-2-yl)-5-nitro-3,4 -dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 914 [M+1] ⁺ 2–206

( S )–2–((1 H –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-cyanophenyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 913 [M+1] ⁺ 2–207

( S )–2–((1 H –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-chlorobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 936 [M+1] ⁺ 2–208

( S )–2–((1 H –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-cyanobenzyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 927 [M+1] ⁺ 2–209

2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((( R )–3–(((1 S ,4 S )–2–oxa–5– azabicyclo[2.2.1]heptan-5-yl)methyl)-5-nitro-3,4-dihydro-2 H -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–IES (m/z): 923 [M+1] ⁺ 2–210

2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 980 [M+1] ⁺ 2–211

( S )–2–((1 H –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 -((5-nitro-3-(pyridin-2-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 903 [M+1] ⁺ 2–212

( S )–2–((1 H –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 -((5-nitro-3-(tetrahydro-2 H -pyran-4-yl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 896 [M+1] ⁺ 2–213

( R )–2–((1 H –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 -((5-nitro-3-(tetrahydro-2 H -pyran-4-yl) -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 896 [M+1] ⁺ 2–214

( R )–2–((1 H –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-(piperidin-4-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–215

( S )–2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–216

( S )–2–((1 H –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)methyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–217

( R )–2–((1 H –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-chloropyridin-2-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–218

( S )–2–((1 H –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-(5-chloropyridin-2-yl)-8-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl)sulfonyl)benzamide MS–IES (m/z): 923 [M+1] ⁺ 2–219

( R )–2–((1 H –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)methyl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–220

( S )–2–((1 H –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-(hydroxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 842 [M+1] ⁺ 2–221

( S )–2–((1 H –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-(piperidin-4-ylmethyl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–222

tert-butyl -( R )–4–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)piperidine-1-carboxylate MS–IES (m/z): 995 [M+1] ⁺ 2–223

methyl-( R )–4–(7–( N –(2–((1 H –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–2 H –benzo[ b ][1,4]oxazin–3–yl)piperidine–1–carboxylate MS–IES (m/z): 953 [M+1] ⁺ 2–224

( R )–2–((1 H –pyrrolo[2,3– b ]pyridin–5–yl)oxy)– N –((3–(1–acetylpiperidin–4–yl)–5–nitro–3, 4-dihydro-2 H -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–IES (m/z): 937 [M+1] ⁺ 2–225

( R )–2–((1 H –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-(1-(methylsulfonyl)piperidin-4-yl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–226

( R )–2–((1 H –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-(piperidin-4-yl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 895 [M+1] ⁺ 2–227

( R )–2–((1 H –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-(1-methylpiperidin-4-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–228

( S )–2–((1 H –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-(piperidin-4-yl)-3,4- dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 895 [M+1] ⁺ 2–229

tert-butyl -( S )–4–(7–( N –(2–((1 H –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-2 H -benzo[ b ][1,4]oxazin-3-yl)piperidine-1-carboxylate MS–IES (m/z): 995 [M+1] ⁺ 2–230

methyl-( S )–4–(7–( N –(2–((1 H –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–2 H –benzo[ b ][1,4]oxazin–3–yl)piperidine–1–carboxylate MS–IES (m/z): 953 [M+1] ⁺ 2–231

( S )–2–((1 H –pyrrolo[2,3–b]pyridin–5–yl)oxy)– N –((3–(1–acetylpiperidin–4–yl)–5–nitro–3, 4-dihydro-2 H -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–IES (m/z): 937 [M+1] ⁺ 2–232

( S )–2–((1 H –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-(1-(methylsulfonyl)piperidin-4-yl)-5-nitro -3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 973 [M+1] ⁺ 2–233

( S )–2–((1 H –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-(1-methylpiperidin-4-yl)-5-nitro-3, 4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 909 [M+1] ⁺ 2–234

( R )–2–((1 H –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 -((5-nitro-3-(((tetrahydro-2 H -pyran-4- yl)oxy)methyl)-3,4-dihydro-2 H -benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 926 [M+1] ⁺ 2–235

( S )–2–((1 H –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 -((5-nitro-3-((tetrahydro-2 H -pyran-4-yl )methyl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–236

( R )–2–((1 H –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-(isopropoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 884 [M+1] ⁺ 2–237

( S )–2–((1 H –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-(isopropoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 884 [M+1] ⁺ 2–238

( R )–2–((1 H –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-cyclohexyl-5-nitro-3,4-dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 894 [M+1] ⁺ 2-239A

( R )–2–((1 H –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)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–239B

(R )–2–((1 H –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)methyl)-5-nitro-3,4 -dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2-240A

( R )–2–((1 H –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- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–240B

( R )–2–((1 H –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- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–241

( S )–2–((1 H –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-(cyclopropoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 882 [M+1] ⁺ 2–242

( R )–2–((1 H –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-(cyclopropoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 882 [M+1] ⁺ 2–243

2–((1 H –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–((((1 r ,4 R )–4–hydroxycyclohexyl)oxy )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 940 [M+1] ⁺ 2-244A

( S )–2–((1 H –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)methyl)-5-nitro-3,4 -dihydro-2H-benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–244B

( S )–2–((1 H –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)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2-245A

( S )–2–((1 H –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- 2 H -benzo[ b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2–245B

( S )–2–((1 H –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- 2 H -benzo[ b] [1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 2-246A

( S )–2–((1 H –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-methoxycyclohexyl)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–246B

( S )–2–((1 H –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-methoxycyclohexyl)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–247A

( S )–2–((1 H –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-methoxycyclohexyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–247B

( S )–2–((1 H –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-methoxycyclohexyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2-248A

( R )–2–((1 H –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-methoxycyclohexyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–248B

( R )–2–((1 H –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-methoxycyclohexyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 924 [M+1] ⁺ 2–249A

( R )–2–((1 H –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-methoxycyclohexyl)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–249B

( R )–2–((1 H –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-methoxycyclohexyl)methyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 938 [M+1] ⁺ 2–250

2–((1 H –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–((((1 r ,4 R )–4–hydroxycyclohexyl)oxy )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 940 [M+1] ⁺ 2–251

2–((1 H –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–((((1 r ,4 R )–4–methoxycyclohexyl)oxy )methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 954 [M+1] ⁺ 2–252

2–((1 H –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,4 R )–4–methoxycyclohexyl)oxy) methyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 954 [M+1] ⁺

Example 3-1

[320] (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)

[321] The title compound ( R )-2-((1 H -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 obtained in accordance with the synthesis method 2-1 by replacement of ( S )–2–(iodomethyl)–7–nitroindoline–5–sulfonamide ( intermediate C ) by ( R )–(5–nitro–7–sulfamoyl–3,4–dihydro– 2H –benzo[ b ] [1,4]thiazin-3-yl)methylmethanesulfonate ( intermediate G ). MS–IES (m/h): 940 [M+1] ⁺ .

Example 3-2

[322] (R)–2–((1Н–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 )

[323] The title compound ( R )-2-((1 H -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-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide ( 3-2 ) was obtained in accordance with the synthesis method 2-1 by replacing 1-methylpiperazine and ( R )–(5–nitro–7–sulfamoyl–3,4–dihydro–2 H –benzo[ b ][1,4]oxazin–3–yl)methylmethanesulfonate ( intermediate C ) to morpholine and ( R )–2– (5-nitro-7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] thiazin -3-yl)ethylmethanesulfonate ( intermediate H ). MS–IES (m/h): 941 [M+1] ⁺ .

[324] Following essentially the same procedures as described for examples 3-1~3-2, or or using similar synthetic methods or strategies, the examples 3-3~3-20 listed in Table 3 were prepared. Structure and the names of examples 3–3 ~ 3–20 are shown in Table 3.

Table 3

EXAMPLE STRUCTURE TITLE DATA 3–3

( R )–2–((1 H –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-(morpholinomethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 927 [M+1] ⁺ 3–4

( R )–2–((1 H –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-((dimethylamino)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]thiazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 885 [M+1] ⁺ 3–5

( R )–2–((1 H –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-(hydroxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 858 [M+1] ⁺ 3–6

( R )–2–((1 H –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-(methoxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 872 [M+1] ⁺ 3–7

( S )–2–((1 H –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-(hydroxymethyl)-5-nitro-3,4-dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 858 [M+1] ⁺ 3–8

( S )–2–((1 H –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-((dimethylamino)methyl)-5-nitro-3,4-dihydro –2 H –benzo[ b ][1,4]thiazin–7–yl)sulfonyl)benzamide MS–IES (m/z): 885 [M+1] ⁺ 3–9

( S )–2–((1 H –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-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 940 [M+1] ⁺ 3–10

( S )–2–((1 H –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-(morpholinomethyl)-5-nitro-3,4-dihydro- 2H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 927 [M+1] ⁺ 3–11

( R )–2–((1 H –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-hydroxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 872 [M+1] ⁺ 3–12

( R )–2–((1 H –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-methoxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 886 [M+1] ⁺ 3–13

( R )–2–((1 H –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-(dimethylamino)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 899 [M+1] ⁺ 3–14

( R )–2–((1 H –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-(4-methylpiperazin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 954 [M+1] ⁺ 3–15

( S )–2–((1 H –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-hydroxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 872 [M+1] ⁺ 3–16

( S )–2–((1 H –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-methoxyethyl)-5-nitro-3,4-dihydro- 2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 886 [M+1] ⁺ 3–17

2–(( S )–7–( N –(2–((1 H –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 –2 H –benzo[ b ][1,4]thiazin–3–yl)ethylmethanesulfinate MS–IES (m/z): 934 [M+1] ⁺ 3–18

( S )–2–((1 H –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-(methylsulfonyl)ethyl)-5-nitro-3,4 -dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 934 [M+1] ⁺ 3–19

( S )–2–((1 H –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-(4-methylpiperazin-1-yl)ethyl)-5 -nitro-3,4-dihydro-2 H -benzo[ b ][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 954 [M+1] ⁺ 3–20

( S )–2–((1 H –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- 2 H -benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 941 [M+1] ⁺

Example 4-1

[325] (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)

[326] The title compound ( S )–2–((1 H -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 ) 7-sulfamoyl-3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) on ( S )-(8-nitro-6-sulfamoyl-1, 2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate ( intermediate I ). MS–IES (m/z): 923 [M+1] ⁺ .

[327] Following essentially the same procedures as described for Example 4-1, or using similar synthetic strategies or methods, Examples 4-2 ~ 4-5, listed in Table 4, were prepared. Structures and titles of Examples 4-2 ~ 4–5 are shown in Table 4.

Table 4

EXAMPLE STRUCTURE TITLE DATA 4–2

( S )–2–((1 H –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-1,2,3,4- tetrahydroquinoxalin-6-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 4–3

( R )–2–((1 H –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 MS–IES (m/z): 923 [M+1] ⁺ 4–4

( R )–2–((1 H –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-1,2,3,4- tetrahydroquinoxalin-6-yl)sulfonyl)benzamide MS–IES (m/z): 910 [M+1] ⁺ 4–5

( R )–2–((1 H –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)-8 -nitro-1,2,3,4-tetrahydroquinoxalin-6-yl)sulfonyl)benzamide MS–IES (m/z): 937 [M+1] ⁺

Example 5-1

[328] (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)

[329] 3-nitrobenzene-1,2-diol ( 5-1a )

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

[331] (R)–(2,2–dimethyl–1,3–dioxolan–4–yl)methyl methanesulfonate ( 5–1b )

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

[333] (S)–2–((2,2–dimethyl–1,3–dioxolan–4–yl)methoxy)–6–nitrophenol ( 5–1c )

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

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

[336] 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 hours. Then EtOH (3.0 ml) and NaOH (50% in H ₂ O, 1.4 ml) were added to the mixture at 25°C and stirred at 25°C for 12 hours. Then, conc. HCl (1.4 ml) at 25°C. The mixture was extracted with EtOAc, washed with brine (15 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (1:4) to give the title compound ( S )–(8–nitro–2,3–dihydrobenzo[ b ][1,4]dioxin–2– yl)methanol ( 5–1d ).

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

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

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

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

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

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

[343] (S)–2–((1Н–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 )

[344] The title compound ( S )–2–((1 H –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 obtained in accordance with the method of synthesis 2-1 by replacing ( R ) 3,4-dihydro-2H-benzo[ b ][1,4] oxazin -3-yl)methylmethanesulfonate ( intermediate C ) on ( R )-(8-nitro-6-sulfamoyl-2,3-dihydrobenzo[ b ][1,4]dioxin-2-yl)methylmethanesulfonate ( 5-1g ). MS–IES (m/z): 912 [M+1] ⁺ .

[345] Following essentially the same procedures as described for Example 5-1, or using similar synthetic methods or strategies, Examples 5-2 ~ 5-4 listed in Table 5 were prepared. Structure and titles of Examples 5-2 ~ 5–4 are shown in Table 5.

Table 5

EXAMPLE STRUCTURE TITLE DATA 5–2

( R )–2–((1 H –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- 2 H -benzo[ b ][1,4]oxazin-7-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺ 5–3

( R )–2–((1 H –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 MS–IES (m/z): 912 [M+1] ⁺ 5–4

( R )–2–((1 H –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 -2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)sulfonyl)benzamide MS–IES (m/z): 925 [M+1] ⁺

Example 6-1

[346] 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)

[347] 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–е]pyridin–1(5H)–yl)benzoic acid ( 6–1a )

[348] 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(5 H )–yl)benzoic acid (6–1a) was obtained according to the method described in WO2017/132474 .

[349] (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 )

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

[351] 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 )

[352] The title compound N –((( R )–3–(((1 S ,4 S )–2–oxa–5–azabicyclo[2.2.1]heptan–5–yl)methyl)–5– nitro–3,4–dihydro–2 H –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 ]pyridine– 1(5 H )–yl)benzamide ( 6–1 ) was obtained in accordance with the synthesis method 1–1 by replacing ( S )–2–(morpholinomethyl)–7–nitroindoline–5–sulfonamide ( 1–1a ) and 2– ((1 H -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 ) on ( R )-3-(((1 S ,4 S )-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(5 H )–yl)benzoic acid ( 6–1a ). MS–IES (m/h): 947 [M+1] ⁺ .

[353] Following essentially the same procedures as described for Example 6-1, or using similar synthetic methods or strategies, Examples 6-2 ~ 6-3, listed in Table 6, were prepared. Structure and titles of Examples 6-2 ~ 6–3 are shown in Table 6.

Table 6

EXAMPLE STRUCTURE TITLE DATA 6–2

( S )–4–(4–((4'–chloro–5,5–dimethyl–3,4,5,6–tetrahydro–[1,1'–biphenyl]–2–yl)methyl)piperazine–1 -yl) - N - ((3-cyclopropyl-5-nitro-3,4-dihydro-2 H -benzo[ b ] [1,4]oxazin-7-yl)sulfonyl) -2- (pyrazolo[4, 3– b ]pyrrolo[3,2– e ]pyridin–1(5 H )–yl)benzamide MS–IES (m/z): 876 [M+1] ⁺ 6–3

( S )–4–(4–((4'–chloro–5,5–dimethyl–3,4,5,6–tetrahydro–[1,1'–biphenyl]–2–yl)methyl)piperazine–1 –yl)– N –((5–nitro–3–(pyridin–2–ylmethyl)–3,4–dihydro–2 H –benzo[ b ][1,4]oxazin–7–yl)sulfonyl)–2 –(pyrazolo[4,3– b ]pyrrolo[3,2– e ]pyridin–1(5 H )–yl)benzamide MS–IES (m/z): 927 [M+1] ⁺

Cell Proliferation Assays

[354] The MTS test kit was purchased from Promega. RPMI-1640, fetal bovine serum, and penicillin-streptomycin were purchased from Gibco. Dimethyl sulfoxide (DMSO) was purchased from Sigma.

[355] To investigate whether a compound is able to inhibit BCL-2 activity in cells, a mechanism-based assay was developed using DOHH2 cells (DSMZ No.® ACC 47) and RS4;11 (ATCC® CRL-1873™). In this assay, Bcl-2 inhibition was detected by inhibition of DOHH2 cell proliferation. DOHH2 cells were cultured in culture flasks to 40–80% confluency in RPMI–1640 plus 10% fetal bovine serum. Cells were harvested and plated in 96-well plates at the desired cell density (5000 cells/well). The plates were incubated overnight at 37°C with 5% CO ₂ for adherence. Compounds were added to the plates and final compound concentrations were 10,000, 3333, 1111, 270, 124, 41, 14, 4.6, and 1.5 nM. Plates coated with DOHH2 or RS4;11 cells were placed at 37° C. with 5% CO ₂ for 120 hours (DOHH2) or 72 hours (RS4;11), respectively. A mixed solution of 20 μl MTS/100 μl medium was added to each well and the plates were incubated for exactly 2 hours. The reaction was stopped by adding 25 μl of 10% SDS per well. The absorbance was measured at 490 nm and 650 nm (reference wavelength). IC50 was calculated using GraphPad Prism 5.0.

[356] Selected compounds obtained as described above were analyzed in accordance with the biological procedures described herein. The results are shown in table 7.

Table 7

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

Claims (40)

1. Connection selected from

,

,

,

and its pharmaceutically acceptable salts. 2. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, where the compound is

or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition having Bcl-2 inhibitory activity, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.