Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases. There is therefore an existing need in the therapeutic arts for compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, and the like is described in commonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCT US 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases is described in Current Allergy and Asthma Reports 2003, 3, 378-384; British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418. Involvement of Bcl-2 proteins in arthritis is disclosed in commonly-owned United States Provisional Patent Application Serial No. 60/988,479. Involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in commonly-owned United States Patent Application Serial No. 11/941,196.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds or therapeutical acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors anti-apoptotic Bcl-2 proteins, the compounds having Formula I

201

6001925

<img file="MY179077A_D0001.tif" />

P1TERIMA

OCT 2016

<img file="MY179077A_D0002.tif" />

(D, wherein

A¹ isNorC(A²);

A² is H, R¹, OR¹, SR¹, S(O)R‘, SO2R¹, C(O)R', CfOJOR¹, OC(O)R\ NKR¹, NfR¹)*

C(O)NHR', C(O)N(R')_2i NHC(O)R', NR’CtOJR¹, NHCtOJOR¹, NR'C(O)OR', NHC(O)NH2, NHC(O)NHR‘, NHCfO)N(R'j2j NR'CtOJNHR', NR’C(0)N(R^,)2, SO2NH2, SO.XHR¹, SO2N(R¹)3) NHSO2R’, NR'SOiR¹, NHSO2NHR¹, NHSO2N(R')2, NR’SOiNHR¹, NR¹SO2N(R¹)2) C(OJNHNOH, C(OJNHNOR’, C(O)NHSO₂R', C(NHJNH₂₁ C(NH)NHR', C(NH)N(R’)2

NHSO2NHR¹, NHSOjNCCHjJR¹, N(CH₃)SO2N(CH₃)R', F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H,

CHNOH, CH(N0CH₃), CF₃, C(O)OH, C(O)NH₂ or C(OJOR^,A;

B¹ is H, R¹, OR¹, SR¹, S(O)R\ SO2R¹, C(O)R', C(O)OR‘, OC(O)R', NHR¹, N(R')2j C(O)NHR‘, C(O)N(R')2, NHC(O)R', NR’CtOJR¹, NHC(O)OR', NR'CtOJOR¹, NHC(O)NH2, NHC(O)NHR', NHC(0)N(R‘)2, NR'CtOJNHR¹, NR'CiOJNtR¹),, SO2NH2, SOiNHR¹, 15 SO2N(R¹J2, NHSO2R¹, NR’SOjR’.NHSOiNHR¹, NHSOzNtR'jj, NR'SOiNHR¹, NR’SOjNtR^, C(O)NHNOH, CCOJNHNOR¹, QOJNHSOjR¹, C(NHJNH2, C(NH)NHR’, C(NH)N(R')₂NHSO2NHR¹, NHSO2N(CH3JR¹, N(CH3)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^lA;

D¹ is H, R¹, OR¹, SR¹, S(O)R^l, SO2R^l, C(O)R’, C(O)OR', OC(O)R’, NHR¹, NfR^, 20 C(O)NHR’&gt; C(O)N(R^l)2, NHCfOJR¹, NR^lC(O)R’&gt; NHC(O)OR^!, NR'CtOJOR¹, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R‘)2, NR'C(O)NHR^l, NR^[C(O)N(R¹)2, SO2NH2, SOzNHR¹, SO2N(R')2, NHSO2R¹, NR'SO/, NHSO2NHR¹, NHSOiNtR’jj, NR'SOjNHR¹, NR^NfR'h, C(O)NHNOH, CfOJNHNOR¹, CtO)NHSO2R^,J C(NH)NH2, CfNHJNHR¹, C(NH)N(R^l)2 NHSO2NHR¹, NHSO2N(CH3)R^l, N(CH3)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃, OH, C(O)H, 25 CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A;

E¹ is H, R^l, OR¹, SR¹, S(O)R', SOjR¹, CtOJR¹, C(O)OR', OC(O)R’, NHR¹, N(R^l)21 C(O)NHR^l, C(O)N(R‘)2, NHCtOJR¹, NR^!C(O)R’, NHC(O)OR', NR’CCOJOR¹, NHC(O)NH2, NHC(O)NHR‘, NHC(O)N(R’):, NR’CtOJNHR¹, NR’C(O)N(R^:)2, SO₂NH₂, SO2NHR¹, SO2N(RⁱJ2, NHSO2R¹, NR'SOjR¹, NHSOiNHR¹, NHSO2NtR'j21 NR^lSO2NHR¹, NR’SOjNfR’ja, 30 C(OJNHNOH, CtOJNHNOR¹, CtOJNHSOjR¹, CtNH)NH2, CtNHJNHR¹, CtNHJN(R^,J2 NHSO₂NHR’, NHSO₂NtCH₃JR¹,_NtCH3JSO2N(CH3JR^l, F, Cl, Br, I, CN, NO2.N₃, OH, C(OJH, CHNOH, CH(NOCH₃J, CF₃₁ C(O)OH, C(O)NH₂ or CtOJOR^1A; and '201 600 1 9 25

Y¹ is Η, CN, Ν02, C(O)OH, F, Cl, Br, I, CF3, OCF3, CF2CF3, OCF2CF3, R¹⁷, OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO2R¹⁷, NH2j NHR¹⁷, N(R^!7)2j NHC(O)R¹⁷, C(O)NH2, C(O)NHR¹⁷, C(O)N(R¹⁷)2j NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y^l, together with the atoms to which they are attached, are benzene, naphthylene, 5 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A³, B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R^l, SO2R^l, C(O)R^l, C(O)OR’, OC(O)R’, NHR¹, N(R’)2, C(O)NHR', CtOMR'h, NHC(O)R', NR'C(O)R^!, NHC(O)OR^!, NR’CtOJOR¹, NHC(O)NH2, NHC(O)NHR‘, NHC(O)N(R')2, NR^lC(O)NHR', NR'CCOJNtR'h, SO2NH₂, SO₂NHR’, SO₂N(R')₂, NHSO₂R', NR'SOjR¹, NHSO^HR¹, 10 NHSO2N(R’)2, NR^!SO2NHR', NR^!S02N(R’)2i C(O)NHNOH, C(O)NHNOR’, C(O)NHSO2R‘, C(NH)NH2j C(NH)NHR’, C(NH)N(R')2 NHSO2NHR‘, NHSO2N(CH3)R’, N(CH3)SO2N(CH3)R¹, F, CI, Br, I, CN, NO2 N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^,a; or

Y^l and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 15 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A³, D¹, and E^l are independently selected H, R¹, OR¹, SR^!, S(O)R^!, SO2R', C(0)R', C(O)OR', OC(O)R’, NHR¹, N(R')2, C(O)NHR’, CiOJNCR'K NHC(O)R’, nr'ccojr¹, NHC(O)OR‘, NR'CtOJOR¹, NHC(O)NH2, NHC(O)NHR', NHCtOiNfR¹)^ NR'CiOJNHR¹, NR'CtOJNtR¹)^ SO2NH₂, SO^HR¹, SO2N(R^l)2, NHSO₂R', NR'SOjR¹, NHSOzNHR¹, 20 NHSO2N(R')2, NR'SOjNHR¹, NR’SO^CR’K C(O)NHNOH, C(O)NHNOR', CtOiNHSOiR¹, C(NH)NH2j C(NH)NHR', C(NH)N(R^l)2 NHSO2NHR¹, NHSO2N(CH₃)R¹, N(CH₃)SO₃N(CH₃)R', F, Cl, Br, I, CN, NO₂.N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^IA; or

A³ and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 25 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

D¹, E^!, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SO2R’, QOIR¹, C(O)OR’, OC(O)R', NHR¹, N(R'):, C(O)NHR', CCOiNtR¹^, NHC(O)R^l, ΝΚ’^ΟίΚ¹, NHC(O)OR^!, NR'QOJOR’, NHC(O)NH2, NHC(O)NHR’, NHC(O)N(R’)3, NR'CCOJNHR¹, NR’CiOJNiR’K SO2NH₂, SO₂NHR', SO₂N(R')_2j NHSOiR¹, NR'SOiR¹, NHSO2NHR', 30 NHSO^R’h, NR’SOjNHR¹, NR’SO^R’h, C(O)NHNOH, C(O)NHNOR', C(O)NHSO-R’, C(NH)NH2, C(NH)NHR', CfNHJNtR¹^ NHSO2NHR’, ^50^(^3^, NiCHOSO^tCHslR¹, F, Cl, Br, I, CN, NO2, Nj, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^lA; or

A³ and D^l, together with the atoms to which they are attached, are benzene, naphthalene, 35 heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

1 600 1 9 25'

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SOjR¹, C(O)R\ 0(0)010 00(0)10 NHR¹, N(R’)2, C(0)NHR’, C(O)N(R^!)2, NHC^R¹, NR'C(O)R^:, NHC(0)0R', ΝΈ'ίχΟίΟΚ¹, NHC(0)NH2, NHC(O)M110 NHC(0)N(R’)2j NR’C(O)XHI0 NR’CCOJNiR¹)* SO2NH₂, S0₂NHR’, SCbNfR¹^ NHSO2I0 NR'SOjR¹, nhso2nhr¹, 5 NHSO2N(R')2j NR'SOiNHR¹, NR'SO2N(R^l)2, C(0)NHN0H, C(0)NHN0R^l, C(O)NHSO2R', C(NH)NH_2i C(NH)NHR', C(NH)N(R')₂ NHSO^NHR¹, NHSC^NfCH^R¹, N(CH3)SO2N(CH3)R^,i F, Cl, Br, I, CN, NO₂.N₃, OH, C(0)H, CHNOH, CH(N0CH₃), CF₃, C(O)OH, C(0)NH₂ or C(0)0R^1A;

R¹ is R², R³, R⁴ or R⁵;

R^,a is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene or R^iA; R^2A is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^3A; R^3A is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^4A; R^4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected 10 NC(R^6A)(R^6B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO2R⁷, NHR⁷, 20 N(R⁷)2, C(O)R⁷, C(O)NH2, C(O)NHI0 C(O)N(R⁷)2, NHC(0)R⁷, NR^TC(0)R⁷, NHSO₂R⁷,

NHC(O)OR⁷, SO2NH2, SO2NHR⁷, SO2N(R⁷)2, NHC(0)NH2i NHC(0)NHR⁷, NHC(O)CH(CH3)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR^l, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N₃, 25 CN, CF₃, CF₂CF_3j F, Cl, Br, I, NH₂, NH(CH₃) or NfCH^;

R^sa and R^6B are independently selected alkyl or, together with the N to which they are attached, R^6C;

R^fiC is azirtdin-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(0), CN0H, CN0CH₃, S, S(0), SO₂ or NH;

R⁷isR⁸, R⁹, R^l0orRⁿ;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^8A; R^8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^9A; R^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

2016001925

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloaikyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^1QA; R^1QA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 5 two or three of independently selected R¹², OR¹², SR¹², S(O)R¹², SO2R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹², NH2, NHR¹², N(Rⁱ²)2, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)2R¹², NR¹²S(O)2R¹², NHC(O)OR'², NRⁱ²C(O)OR¹², NHC(O)NH2j NHC(O)NHR¹², NHC(O)N(R^,2)2, NR^l2C(O)NHR¹², NRⁱ²C(O)N(R¹²)2, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)2, C(O)NHOH, C(O)NHOR¹², C(O)NHSO2R^,:!, C(O)NR¹²SO2R¹², SO2NH&gt;, SO₂NHR¹², SO2N(R^l2)2) C(O)H, 10 C(O)OH, C(N)NH_2j C(N)NHR¹², C(N)N(R^I2)₂, CNOH, CNOCH₃, OH, (O), CN, n₃, no₂, cf₃, CF₂CFj, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R¹² is R¹³, R'\ R¹³ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene or R^I3A; R^13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^UA; R^!4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R^I5A; R^I5A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R^I7isR¹⁸, R¹⁹, R²⁰ or R²¹;

R^IS is phenyl, which is unfused or fused with benzene, heteroarene or R^ISA; R^IGA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^I9A; R^l9A is 25 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloaikyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^20A; R^20A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 30 two or three of independently selected R²², OR²², SR³², S(O)R³², SO2R²², C(O)R²², CO(O)R²². OC(O)R²², OC(O)OR²², NH2, NHR²³, N(R²²)2j NHC(O)R²², NR²²C(O)R²², NHS(O)2R²², NR³²S(O)2R²², NHC(O)OR²², NR²²C(O)OR²³, NHC(O)NH2i NHC(O)NHR²², NHC(O)N(R²²)2, NR³²C(O)NHR²², NR²²C(O)N(R²²)2, C(O)NH_:, C(O)NHR²², C(O)N(R²²)2, C(O)NHOH, CtOJNHOR²², C(O)NHSO2R²², C(O)NR²²SO2R²², SO2NH_2j SO₂NHR²², SO2N(R²²)2j C(O)H, 35 C(O)OH, C(N)NH_2j C(N)NHR²², C(N)N(R²²)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, bJO₂, CF₃, CF₂CF₃, OCF₃₎ OCF₂CF₃, F, Cl, Br or I;

R²¹ is R²³, R^?J or R²ⁱ;

R³³ is phenyl, which is unfused or fused with benzene, heteroarene or R^23A; R^23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroarene or R^24A; R^24A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²ⁱ is cycloalkyl, cycloalkenyl, heterocycloalky I or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^35A; R^35A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R³⁷;

Z³ is R³⁸, R²⁹ or R³⁰;

Z^1A and Z^2A are both absent or are taken together to form CH₂, CH₂CH₂ or Z^12A;

Z^I2A is C_rC₆-alkylene having one or two CH₂ moieties replaced by NH. N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO2R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷, OC(O)OR³⁷, 15 NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO2R³⁷, SO₂NH, SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R^3&lt;&gt; is phenylene, which is unfused or fused with benzene or heteroarene or R^36A; R^36A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene or heteroarene or R^37A; R^27A20 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene or R^28A; R^28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁹ is heteroarylene, which is unfused or fused with benzene or heteroarene or R^29A; R^29Ais cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;

R³⁰ is eyeloalkylene, cycloalkenylene, heterocycloalkylene or heterocycloalkenylene, each of which is unfused or fused with benzene, heteroarene or R^30A; R^30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^37A·

R^37Ais alkylene, alkenylene, or alkynylene, each of which is unsubstituted or substituted 30 with one or two or three independently selected R^37B, OR³⁷⁸, SR^37B, S(O)R^37B, SO2R^37B, C(O)R^37B, CO(O)R^37B, OC(O)R^37B, OC(O)OR^37B, NH2, NHR³⁷⁰, N(R^37B)a, NHC(O)R^37B, NR^37BC(O)R^37B, NHS(O)2R^37B, NR^37BS(O)2R^37B, NHC(O)OR^37B, NR^37BC(O)OR³⁷⁰, NHC(O)NH2i NHC(O)NHR³⁷⁰, NHC(O)N(R^37B)2, NR^37BC(O)NHR^37B, NR³⁷⁸C(O)N(R^37B)2, C(O)NH2, C(O)NHR³⁷⁰, C(O)N(R^37BK C(O)NHOH, C(O)NHOR^37B, C(O)NHSO2R^37B, C(O)NR^37BSO2R^37B, 35 SO2NH₂, SOjNHR³⁷⁸, SO2N(R^37B)21 C(O)H, C(O)OH, C(N)NH_2i C(N)NHR^37S, C(N)N(R³⁷⁰)₂,

CNOH, CNOCH₃,OH, (O), CN, N_3s NO_:, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃₁ F, Cl, Br and I substituents;

R^37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R^3a, R³⁹ or R^4tJ;

R is phenyl, which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^39A; R^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^40A; R^40A is cycloalkane, cycloalkene.

heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷are substituted (i.e,, if Z^1A and Z^2A are absent) or further substituted (i.e., if Z^1A and Z^2A are present) with one or two or three or four of 15 independently selected R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO2R⁴¹, C(O)R⁴¹, CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴', NH3, NHR⁴¹, N(R^4[)2, NHC(O)R⁴¹, NR⁴¹C(O)R^4!, NHS(O)2R⁴¹, NR⁴ⁱS(O)2R⁴¹, NHC(O)OR⁴¹, NR^4IC(O)OR⁴¹, NHC(O)NH2, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)3, NR^4IC(O)NHR⁴¹, NR^4lC(O)N(R^4,)21 C(O)NH_2j C(O)NHR⁴¹, Ο(Ο)Ν(Κ^4ι)2, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO2R⁴', C(O)NR^4,SO2R⁴¹s SO2NH2j SO2NHR⁴¹? SO₂N(R⁴¹)_2j C(O)H, C(O)OH,

C(N)NH₃, C(N)NHR⁴', C(N)N(R^4,)2, CNOH, CNOCH₃, OH, (O), CN, Nj, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴¹ is R⁴²,R⁴³, R⁴⁴ orR⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene or R^42A; R^42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^43A; R^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^44A; R^ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁴⁶, OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, SO2R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH:, NHR⁴⁶, N(R⁴⁶)2, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHSfO^R⁴⁶, NR⁴⁶S(O)2R⁴⁶, NHC(O)OR⁴⁶, NR⁴⁶C(O)OR⁴⁶, NHC(O)NH3j NHC(O)NHR⁴⁶, NHCiOjNfR⁴⁶^, NR⁴⁶C(O)NHR⁴⁶, NR⁴⁶C(O)N(R⁴⁶)2, C(O)NH_2j C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH,

C(O)NHOR⁴⁶, C(O)NHSO:R⁴⁶, C(O)NR⁴⁶SO3R⁴⁶, SO2NH3, SO3NHR⁴⁶, SO2N(R⁴⁶)₃, C(O)H,

C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOClk OH, (O), CN, n₃, no₂₎ CFj, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R^47A; R^47A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁸ is heteroaryl, which is unftised or fused with benzene, heteroarene or R^48A; R^48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkeny], each of which is unfused or fused with benzene, heteroarene or R^49A_} R^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R⁴², R^42A, R0 R^43A, R⁴⁴, R^44A, R⁴⁷, R^47A, R⁴⁸, R^48A, R⁴⁹, and R^49A are independently substituted with one or two or three or four of independently selected R³⁰, OR⁵⁰, SR³⁰, S(O)R⁵⁰, SO2R³⁰, C(O)R³⁰, CO(O)R³⁰, OC(O)R³⁰, OC(O)OR³⁰, NH2, NHR³⁰, N(R³°)2, NHC(O)R³⁰, NRⁱ⁰C(O)R³⁰, NHS(O)2R⁵⁰, NR^3t,S(O)₂R^5t), NHC(O)ORⁱ⁰,

NR³⁰C(O)OR³⁰, NHC(O)NH2, NHC(O)NHR³⁰, NHC(O)N(R^s°)2, NR³⁰C(O)NHR³⁰,

NR⁵⁰C(O)N(R³⁰)2, C(O)NH2, C(O)NHR^S°, C(O)N(R⁵⁰)2, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO2R³⁰, C(0)NR⁵⁰S02R³⁰, SO2NH₂, SO₂NHR^s0, SO2N(R³⁰)2j C(O)H, C(O)OH, C(N)NH₂, C(N)NHR³⁰, C(N)N(R³⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N₃₎ NO_2: CF₃, CF₂CF₃, OCF₃, OCF₂CF_3j F, Cl, Br or I;

R³⁰ is R³¹, R³², R³³ or R³⁴;

R³' is phenyl, which is unfused or fused with benzene, heteroarene or R^3,A; R^S,A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³² is heteroaryl, which is unfused or fused with benzene, heteroarene or R^S2A; R^32A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^33A; R^33A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R³³, OR³³, SR³³, S(O)R³³, SO_;R0 C(O)R³³, CO(O)R³³,

OC(O)R³³, OC(O)OR³³, NH2, NHR³³, N(R⁵0, NHC(O)R³³, NR³³C(O)R³³, NHS(O)2R³³,

NR³⁵S(O)2R³⁵, NHC(O)OR⁵³, NR⁵³C(O)OR³ⁱ, NHC(O)NH:, NHC(O)NHR³⁵, NHC(O)N(R³³)2, NR³³C(O)NHR^i!, NR⁵ⁱC(O)N(R⁵³)2, C(O)NH₂, C(O)NHR⁵³, C(O)N(R³³)2, C(O)NHOH, C(O)NHOR³³, C(O)NHSO2R⁵³, C(O)NR³³SO2R⁵³, SO2NH_2j SO₂NHR³³, SO?N(R⁵⁵)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵³, C(N)N(R⁵⁵)_2: CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,

CF₂CF₃, 0CF_3j OCF₂CF₃, F, Cl, Br or I;

R⁵ⁱ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R^57A, Rⁱ⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO2R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)Rⁱ⁷, OC(O)OR⁵⁷, NH2, NHRⁱ⁷, N(Rⁱ⁷)2, NHC(O)Rⁱ⁷, NRⁱ⁷C(O)Rⁱ⁷, NHS(O)2R⁵⁷, NR⁵⁷S(O)2R⁵⁷, NHC(O)ORⁱ⁷, NR⁵⁷C(O)ORⁱ⁷f NHC(O)NH₂, NHC(O)NHR^S7, NHC(O)N(R⁵⁷)2, NR⁵⁷C(O)NHR⁵⁷, NR^S7C(O)N(R⁵⁷)2, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(Rⁱ⁷)2, C(O)NHOH, C(O)NHOR^S7, C(O)NHSO2R⁵⁷, C(O)NR⁵⁷SO2R^S7, SO2NH₂₎ SO₂NHRⁱ⁷, SO2N(R^S7)2j C(O)H, C(O)OH,

C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R^J7)_2j CNOH, CNOCH₃, OH, (O), CN, n_3i no₂, cf₃, cf₂cf₃, OCF₃, OCF₂CF_3j F, Cl, Br or I;

C R^S7A is spirocyclyl;

R⁵⁷ is Rⁱ⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfiised or fused with benzene, heteroarene or R^58A; R^iSA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Rⁱ⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^S9A; R^i9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^60A; R^60A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶², OR⁶², SR⁶², S(O)R⁶², SO2R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶², NH2, NHR⁶², N(R⁶²)2, NHC(O)Rⁱ², NR⁶²C(O)Rⁱ², NHS(O)2R⁶³, i NR^wS(O)2R⁶², NHC(O)OR⁶², NR⁸²C(O)OR⁶², NHC(O)NH2j NHC(O)NHR⁶², NHC(O)N(R⁶²)_2t

NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R^S2)2, C(O)NH2, C(O)NHR⁶², C(O)N(Rⁱ²)2, C(O)NHOH, C(O)NHOR⁶², C(O)NHSO2R⁶², C(O)NR⁶²SO2R⁶², SO2NH2, SO2NHR⁶², SO2N(R⁶²)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR⁶², C(N)N(R⁶²)2j CNOH, CNOCH₃, OH, (O), CN, N₃, NO_:, CF₃, CF₂CF₃, OCFj, OCF₂CF₃, F, Cl, Br or I;

R⁶² is R^m, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene or R^63A; R^63a is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^S4A; R^MA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶ⁱ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^MA; R^MA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶⁷, OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO2R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷ NHj, NHR⁶⁷, N^Y NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)2R⁶⁷, NR⁶⁷S(O)2R⁶⁷, NHC(O)OR⁵⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH2, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)2, 5 NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)2i C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)2, C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO2R⁶⁷, C(O)NR⁶⁷SO2R⁶⁷, SO2NH₂, SO₂NHR⁶⁷, SO2N(R⁶⁷)2j C(O)H, C(O)OH, C(N)NH₃, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH, CNOCH₃,OH, (O), CN, n₃, no₂, cf₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or 1 substituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, 10 heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^57A, R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, and R⁶⁷are unsubstituted or substituted with one or two or three or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO2R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH2j NHR⁶⁸, N(R⁶⁸)2, NHC(O)R^fiS, NR^6SC(O)R⁶⁸, NHS(O)iR⁶⁸, NR^StO^R⁶⁸, NHC(O)OR⁶⁸, NR^6SC(O)OR⁶⁸, 15 NHC(O)NH:, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)2, NR⁶⁸C(O)NHR^6S, NR^6SC(O)N(R⁶⁸)2, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)2, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO2R⁶⁸, CiOJNR^SOjR⁶⁸, SO2NH2} SO.NHR^ SO2N(R⁶⁸)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, Nj, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene or R^69A; R^69A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl, which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is 25 unfused or fused with benzene, heteroarene or R^71A; R^7IA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁷³, OR⁷³, SR⁷³, S(O)R⁷³, SO2R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH2, NHR⁷³, N(R⁷³)2, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)2R⁷³, 30 NR⁷³S(O)2R⁷³, NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH2, NHC(O)NHR⁷³, NHC(O)N(R⁷³)2,

NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)2, C(O)NH2, C(O)NHR⁷³, C(O)N(R⁷³)2, C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO2R⁷³, C(O)NR⁷³SO2R⁷³, SO2NH2, SO2NHR⁷³, SO2N(R⁷³)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR⁷³, C(N)N(R⁷³)2, CNOH, CNOCH₃, OH, (O), CN, N₃, NO_2s CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted or substituted with one or two or three or four of independently selected NH₂, C(O)NH_2s C(0)NH0H, SO₂NH₂, CF₃, CF₂CF_3t C(O)H, C(0)0H, C(N)NH₂, OH, (O), CN, N₃, N0_:, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I.

Another embodiment pertains to a compound having Formula (II)

<img file="MY179077A_D0003.tif" />

(II), or a therapeutically acceptable salt thereof, wherein

R¹⁰⁰ is as described for substituents on R²⁶;

nisO, l,2,or3;

R¹⁰¹ is as described for substituents on R⁴²;

m is 1,2, 3, 4, or 5;

A¹ isNorC(A²);

A² is H, R¹, OR¹, SR¹, S(O)R’&gt; SO2R^!, CtOiR¹, CiOJOR¹, OC(O)R', NHR¹, N(R^!)2,

C(O)NHR’, C(O)N(R⁵)2, NHC(O)R', NR^!C(O)R’, NHC(O)OR‘, NR’CtOjOR¹, NHC(O)NH2,

NHC(O)NHR^l, NHC(O)N(R’)2, NR^lC(O)NHR’, NR’C^NiR’h, SO2NH₂, SOaNHR¹, SO2N(R’)2i NHSO^¹, ^^0-,^, NHSOzNHR¹, NHSO2N(R^l)2, NR’SOjNHR¹, NR'SO.NiR¹);. C(O)NHNOH, CtOJNHNOR¹, C(O)NHSO2R’, C(NH)NH_:, C(NH)NHR’, C(NH)N(R^!)2 NHSO2NHR’, NHSO2N(CH3)R^l, N(CH3)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂₎ N₃, OH, C(O)H,

CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^ia;

B¹ is H, R¹, OR¹, SR¹, S(O)R’, SO2R’, CtOIR¹, C(O)OR^!, OC(O)R^!, NHR¹, N(R')2, C(O)NHR^!, C(O)N(R^l)2, NHC(O)R’, NR’C(O)R’, NHC(O)OR’, NR'C(O)OR’, NHC(O)NH:, NHC(O)NHR’, NHQOJNtR’h, NR'CtOJNHR¹, NR^lC(O)N(R’)2, SO2NH_2i SOiNHR¹, SO2N(R’)2j NHSO2R’, NR’SOiR¹, NHSOjNHR¹, NHSO;N(R'E NR’SOjNHR¹, NR'SO2N(R')₂, 25 C(O)NHNOH, C(O)NHNOR^l, C(O)NHSO₂R', C(NH)NH_2j C(NH)NHR’, C(NH)N(R’)₂

NHSOzNHR¹, NHSO2N(CH3)R', NtCHjJSOzNtCHzJR¹, F, Cl, Br, 1, CN, N0;. Nj, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₃ or C(O)OR^1A;

D¹ is H, R¹, OR¹, SR¹, S(O)R^l, SO3R^f, C(O)R', C(O)OR’, OC(O)R^j, NHR¹, N(R‘)3j C(O)NHR’, QOJNfR'h, NHC(O)R’, NR'C^R¹, NHC(O)OR', NR'C^OR¹, NHC(O)NH_3:

NHC(O)NHR‘, NHC(O)N(R’)2₅ NR’CtOJNHR’, NR'CtOJNtR'K SO_:NH_2j SO₂NHR^!, SOjNfR¹)^ NHSOzR¹, NR’SOzR¹, NHSOjNHR¹, NHSOiNfR^, NR'SOzNHR¹, NR'SO2N(R’)2, C(O)NHNOH, C(O)NHNOR', CCOJNHSOzR¹, C(NH)NH2, C(NH)NHR^[, C(NH)N(R’)z NHSOzNHR¹, NHSO_?N(CH_;)R', 1^(013)80214(0¾^^ F, Cl, Br, I, CN, NO₂.N₃, OH, C(O)H, CHNOH, CH(N0CH₃), CF_3j C(O)OH, C(O)NH₃ or C(O)OR^IA;

E¹ is H, R¹, OR¹, SR¹, S(O)R’, SOzR¹, C(O)R’, C(O)OR’, OC(O)R’, NHR¹, N(R’)₂,

C(O)NHR’, CffW'jj, NHC(O)R’, NR’QOJR¹, NHC(O)OR’,1^0(0)0^, NHC(O)NH2, NHC(O)NHR’, NHC(O)N(R’)2, NR’C(O)NHR^l, NR'C(O)N(R’)2, so₂nh₂, SOzNHR¹, SOzNtR'jz, NHSOzR¹, NR'SOzR¹, NHSOzNHR¹, NHSO^fR'E NR'SOzNHR¹, NR'SOzNfR¹^, C(O)NHNOH, C(O)NHNOR’, C(O)NHSO2R^l, C(NH)NH2, C(NH)NHR', C(NH)N(R'}₂

NHSOzNHR¹, NHSO₂N(CH₃)R’, N(CH₃)SO₂N(CH₃)R’, F, Cl, Br, I, CN, NO₃.N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A; and

Y¹ is H, CN, NO2, C(O)OH, F, Cl, Br, I, CF3, OCF3j CF2CF3j 0CF2CF3j R¹⁷, OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO2R¹⁷, NH2, NHR¹⁷, NfR¹⁷^, NHC(O)R¹⁷, C(O)NH2, C(O)NHR¹⁷, C(O)N(R^I7)2, NHS(O)R¹⁷ or NHSO2R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, are benzene, naphthylene, heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SO2R^!, C(O)R^!, C(O)OR’, OC(O)R‘, NHR¹, N(R’)2, CtOJNHR¹, C(O)N(R’)2, NHC(O)R', NR'CfOJR¹, NHC(O)OR', NR^!C(O)OR', NHC(O)NH2, NHC(O)NHR’, NHC(O)N(R’)₂₁ NR’CtOJNHR’, 25 NR¹C(O)N(R')2, SO,NH2, SO2NHR^], SO2N(R^!)_:, NHSOzR¹, NR’SOzR¹, NHSOzNHR¹,

NHSO_:N(R^l)z, NR'SOzNHR¹, NR’SOiNfR^, C(0)NHN0H, C(O)NHNOR‘, CtOJNHSOiR¹, C(NH)NHz, C(NH)NHR‘, CiNHJNlR^ NHSOzNHR¹, NHSOzNCCHiJR¹, NiCHJSOzNiCHOR¹, F, Cl, Br, I, CN, NO₃ Nj, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₃ or C(O)OR^1A; or

Y¹ and B¹, together with the atoms to which they are attached, are benzene, naphthylene, heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A², D^l, and E¹ are independently selected H, R¹, OR¹, SR¹, StOjR¹, SO^R¹, CfOlR¹, C(O)OR^!, OC(O)R’, NHR¹, N(R^!)2, C(O)NHR’, C(O)N(R’)2, NHC(O)R’, NR’CfOjR¹, NHC(O)OR', NR'CtOlOR¹, NHC(O)NH3, NHC(O)NHR', NHC(O)N(R^!)3, NR’CtOJNHR¹, 35 NR’CiOMR¹^ SO3NH₃, SOzNHR¹, SOzN(R’)z, NHSOzR¹, NR’SOzR¹, NHSOzNHR¹, NHSO3N(R')2, NR'SOzNHR¹, NR’SOzN(R’)3, C(O)NHNOH, C(O)NHNOR', C(0)NHSOzR’,

C(NH)NH₂, C(NH)NHR', C(NH)N(R’)₂ NHSOjNHR¹, NHSO₂N(CHj)R’, ΝίΟΗ^δΟίΝ^Η^’, F, Cl, Br, I, CN, NO₂ Nj, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A; or

A² and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 5 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R’, OR¹, SR¹, S(O)R’, SO2R*, C(O)R', C(O)OR‘, OC(O)R', NHR¹, NtR¹)^ C(O)NHR', C(O)N(R’)j, NHC(O)R\ NR'CfOJR¹, nhc(O)or¹s nr'c(O)OR’, nhc(O)nh₂, nhc(O)nhr', nhc(O)N(r')_2j nr'c(O)nhr', NR'CCOJNfR'h, SO₂NH₂, SOONER¹, SO2N(R’)2, NHSO2R', NR’SOjR¹, NHSO2NHR^j,

NHSO₂N(R’)₂₁ NR'SO_:NHR', NR'SOzNiR'jj, C(O)NHNOH, C(O)NHNOR^], C(O)NHSO2R', C(NH)NH2, C(NH)NHR’, C(NH)N(R')3 NHSOjNHR¹, NHSO2N(CH₃)R', N(CH₃)SO₂N(CHj)R’, F, Cl, Br, 1, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CFj, C(O)OH, C(O)NH₂ or C(O)OR^,A; or

A² and D¹, together with the atoms to which they are attached, are benzene, naphthalene, 15 heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

B'.E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R\ SO2R‘, C(O)R’, CiOjOR¹, OCtOjR¹, NHR¹, N(R’)2, CtOjNHR¹, C(O)N(R')2j NHC(O)R’, NR^tOjR¹, NHC(O)OR^!, NR‘C(O)OR', NHC(O)NH2, NHC(O)NHR', NHC(O)N(R’)₂₁ NR'CCOjNHR¹, NR'CCOJNCR¹^, SO2NH2, SO^HR¹, SO2N(R')_2j NHSO₂R’, NR'SOjR¹, nhso₂nhr’,

NHSO₂N(R’)₂, NR^O^HR¹, NR’SOsNfR¹):, C(O)NHNOH, CtOJNHNOR¹, QOJNHSOjR¹, c(nh)nh2, ccnhjnhr¹, C(NH)N(R'), nhso2nhr', nhso₂n(ch₃)r', n(Ch₃)so₂n(ch₃)r', F, Cl, Br, I, CN, N0₂.N₃, OH, C(0)H, CHNOH, CH(NOCH₃), CF₅, C(0)0H, C(O)NH₂ or C(O)OR^1A;

R¹ is R², R³, R⁴ or R^s;

R^lA is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene or R^2A; R^2A is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^3A; R^3A is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^4A; R^4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R' is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶, NC(R^6A)(R^6B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO2R⁷, NHR⁷, 35 N(R⁷)2, C(O)R⁷, C(O)NH2, C(O)NHR⁷, 0(0)5/(10)-, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO2R⁷,

NHC(O)OR⁷, SO2NH2, SO2NHR⁷, SO2N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,

NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHCtOiCHtCH^NHCtOjCHtCH^NHR¹, OH, (0), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-Cj-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N₃₎CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CHj) or NfCH^;

R^6A and R^6B are independently selected alkyl or, together with the N to which they are attached, R^6C;

R^6C is aziridin-l-yl, azetidin-l-yl, pyrrolidin-1 -yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with 0, C(0), CNOH, CNOCHj, S, S(0), S0₂ or NH;

R⁷ is R⁸, R’, R^worR;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^!A; R^8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^9A; R^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is 15 unfused or fused with benzene, heteroarene or R^,0A; R^,0A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R¹², OR¹², SR¹², S(O)R¹², SO2R¹², C(0)R¹², CO(O)R¹², OC(O)R¹², 0C(0)0R¹², NH2, NHR¹², N(R^I2)2j NHC(0)R¹³, NR^[2C(O)Rⁱ², NHS(O)2R¹²,

NR^t2S(O)2R¹², NHC(O)OR¹², NR^I2C(O)OR¹², NHC(0)NH2, NHC(0)NHR¹², NHC(O)N(R¹²)₂,

NR¹²C(O)NHR¹², NR¹²C(O)N(R^,2)2, C(0)NH2, C(O)NHR^1Z, C(O)N(R^!2)2, C(O)NHOH, C(O)NHOR¹², C(O)NHSO2R¹², C(O)NR¹²SO2R'², SO2NH2, SO2NHR¹², SO2N(R¹²)2j C(O)H, C(O)OH, C(N)NH2, C(N)NHR’², C(N)N(R^I2)2j CNOH, CNOCH₃, OH, (O), CN, Nj, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF_3j F, Cl, Br or I;

R^,2isR¹³, R¹⁴, R^liorRⁱ⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene or R^i3A; R^I3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^I4A; R^14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R^!i is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R^liA; R^liA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷isR¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^18A; R^1BA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^,9A; R^19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^20A; R^20A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R²², OR²², SR²², S(O)R²², SO2R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²², NH2, NHR²², N(R²²)2j NHC(O)R²², NR²²C(O)R²², NHS(O)2R²², NR²²S(O)2R²², NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH2j NHC(O)NHR²², NHC(O)N(R²²)_2j

NR²²C(O)NHR²², NR²²C(O)N(R²²)2, C(O)NH2, C(O)NHR²², C(O)N(R“)2, C(O)NHOH,

C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO2R²², SO2NH₂, SChNHR²², SO_;N(R²²k C(O)H, f C(O)OH, C(N)NH2, C(N)NHR²², C(N)N(R²²)2j CNOH, CNOCHj. OH, (O), CN, Nj, no₂, CFj, ^V CF₂CF₃, OCF₃, OCF₂CF₃₎ F, Cl, Br or I;

R²² is R²³, R²⁴ or R²ⁱ;

R“ is phenyl, which is unfused or fused with benzene, heteroarene or R ; R’ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroarene or R^24A; R^24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R^2S is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is 20 unfused or fused with benzene, heteroarene or R^25A; R^2SA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Z² is R²⁸, R²⁹ or R³⁰;

Z^1A and Z^2A are both absent or are taken together to form CH₂₎ CH₂CH₂ or Z^I2A;

Z^12A is C₃-C₆-alkylene having one or two CH₂ moieties replaced by NH, N(CH₃), S, S(O) 25 or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO2R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷, OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO2R³⁷, SO₂NH, SO_:NHR³⁷, C(N)NH, C(N)NHR³⁷;

R^2S is phenylene, which is unfused or fused with benzene, heteroarene or R^28A; R^28A is 30 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene or heteroarene or R^29A; R^29Ais cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene or heterocycloalkenylene, each of which is unfused or fused with benzene, heteroarene or R^30A; R^30A is cycloalkane, 35 cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^37A'

R^37A is alkylene, alkenylene, or alkynylene, each of which is unsubstituted or substituted with one or two or three independently selected R^37B, OR^37B, SR^37B, S(O)R^37B, SO2R^37B, C(O)R^37B, CO(O)R^37B, OC(O)R^37B, OC(O)OR^37B, NH2, NHR^37B, N(R^37B)2, NHC(O)R^37B, NR^37BC(O)R^37B, NHS(O)2R^37B, NR³⁷³S(O)2R^37B, NHC(O)OR^37B, NR^37BC(O)OR^37B, NHC(O)NH2,

NHC(O)NHR^37B, NHC(O)N(R^37B)2i NR^37BC(O)NHR^37S, NR^37BC(O)N(R^37B)2, C(O)NH₂, C(O)NHR^37B, C(O)N(R^?;Bh, C(O)NHOH, C(O)NHOR^37B, C(O)NHSO2R^37B, C(O)NR^37BSO2R^37B, SO2NH2, SO2NHR^37B, SO2N(R^37B)2j C(O)H, C(O)OH, C(N)NH3, C(N)NHR^37B, C(N)N(R^37B)2, CNOH, CNOCH3,OH, (O), CN, N₃, NO_2: CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R³⁷⁸ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

f Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^38A; R^38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^39A; R^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^40A; R^40A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R⁴² are independently substituted with one or two or three or four of independently selected R³⁰, OR⁵⁰, SR⁵⁰, S(O)Rⁱ⁰, SO?R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R³⁰, OC(O)OR⁵⁰, NH2, NHR⁵⁰, N(R⁵°)2, NHC(O)R³⁰, NRⁱ⁰C(O)R⁵⁰, NHS(O)2R⁵⁰, NR⁵⁰S(O)2R^s“, NHC(O)OR^S0, NR³⁰C(0)OR³⁰, NHC(O)NH2f NHC(O)NHR³⁰, NHC(O)N(R⁵⁰^, f NR^S°C(O)NHR³⁰, NR^S0C(O)N(R³⁰)₃, C(O)NH₃, C(O)NHR⁵⁰, C(O)N(R³⁰)i, C(O)NHOH,

C(O)NHOR⁵°, C(O)NHSO2Rⁱ⁰, C(O)NR⁵⁰SO2Rⁱ⁰, SO2NH2, SO2NHR^s0, SO2N(R^s0)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR⁵⁰, C(N)N(R^!0)3, CNOH, CNOCHj, OH, (O), CN, Nj, NO₂, CF₃, CF₂CF₃, OCF₃, OCFiCFj, F, Cl, Br or I;

R^s0 is R⁵¹, R³², R³³ or R³⁴;

R³¹ is phenyl, which is unfused or fused with benzene, heteroarene or R^51A; R^5,A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³² is heteroaryl, which is unfused or fused with benzene, heteroarene or R^52A; R^32A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^33A; R^53A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloaikene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R^Si, OR³⁵, SR⁵⁵, S(O)R^iS, S02R³³, C(O)R³⁵, CO(O)R^JS, 0C(0)R³³, OC(O)OR^iS, NH;, NHR³³, N(Rⁱ⁵)2, NHC(O)R^5S, NR⁵⁵C(O)R\ NHS(O)2R⁵³, NR³³S(O)2R³³, NHC(0)0R⁵³, NR³ⁱC(O)OR³³, NHC(O)NH2, NHC(O)NHR³³, NHC(O)N(R⁵⁵)j, 5 NRⁱ⁵C(O)NHR^iS, NR³ⁱC(0)N(R³ⁱ)₂, C(O)NH_;. C(O)NHR⁵³, C(O)N(R³³)2, C(O)NHOH, C(O)NHOR³³, C(O)NHSO2R⁵⁵, C(0)NRⁱ³S0₂R³³, S02NH2, SO2NHRⁱ³, SO2N(R^3S)21 C(O)H, C(O)OH, C(N)NH2, C(N)NHR^ss, C(N)N(R³³)2j CNOH, CNOCH₃, OH, (O), CN, N₃, N0₂, CF₃, CF₂CF₃, OCF₃₁ OCF₂CF₃, F, CI, Br or I;

R³³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, 10 heterocycloaikyl or heterocycloalkenyl; and wherein each foregoing cyclic moiety is independently unsubstituted, further ( unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R^57A, R^S7, OR³⁷, SR⁵⁷, S(O)R⁵⁷, SO2R⁵⁷, C(O)R⁵⁷, CO(O)R^V, OC(O)Rⁱ⁷, OC(O)OR⁵⁷, NH;, NHR³⁷, N(R^S7)2, NHC(O)R^S7, NR⁵⁷C(O)R^S7, NHS(O)2R^S7, NR⁵⁷S(O)2Rⁱ⁷, 15 NHC(O)OR⁵⁷, NR⁵⁷C(O)ORT NHC(O)NH2, NHC(0)NHRⁱ⁷, NHC(O)N(R^S7)2, NRⁱ⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(Rⁱ⁷)2, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(K’l C(O)NHOH, C(O)NHORⁱ⁷, CfOJNHSOjR⁵⁷, C(O)NR⁵⁷SO2R⁵⁷, SO2NH₂₎ SO₂NHR³⁷, SO2N(R⁵⁷)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH, CNOCH_3jOH, (O), CN, N₃, N0₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF_3i F, Cl, Br or 1;

R^57A is spirocyclyl;

R⁵⁷ is R⁵⁸, R³⁹, R⁶⁰ orR⁶¹;

R^iS is phenyl, which is unfused or fused with benzene, heteroarene or R^i8A; R^i8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

f R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^59A; R^59A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁰ is cycloalky], cycloalkenyl, heterocycloaikyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^S0A; R^ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 30 two or three of independently selected R⁶², OR⁶², SR⁶², S(O)R⁶², SO2R⁶², C(O)R⁶², CO(O)R^W, OC(O)R⁶², OC(O)OR⁶², NH2, NHR¹⁵², N(R⁶²)2, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)2R⁶², NR⁶²S(O)2R⁶², NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(0)NH2, NHC(O)NHR⁶², NHC(O)N(R^S2)2, NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)2i C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)2, C(O)NHOH, C(O)NHOR⁶², C(O)NHSO:R“, C(O)NR⁶²SO2R⁶², SO2NH₂, SO_;NHR⁶², SO2N(R⁶²)2, C(O)H, 35 C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF_3jCF₂CF₃, 0CF_3i OCF₂CFj, F, Cl, Br or I;

R⁴² is R⁴³, R⁶⁴, R^6S or R⁴⁴;

R⁴³ is phenyl, which is unfiised or fused with benzene, heteroarene or R^63A; R^63A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁴ is heteroaryl, which is unfiised or fused with benzene, heteroarene or R^64A; R^44A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴ⁱ is cycloalky I, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^6iA; R^4SA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or 10 two or three of independently selected R⁴⁷, OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO:R⁶⁷, C(O)R⁴⁷, CO(O)R⁴⁷, OC(O)R⁴⁷, OC(O)OR⁶⁷, NH2, NHR⁶⁷, N(R⁶⁷)2j NHC(O)R⁶⁷, NR^CfOjR⁴⁷, NHS(O)2R⁶⁷, ( ' NR⁴⁷S(O)2R⁶⁷, NHC(O)OR⁴⁷, NR^CfOJOR⁶⁷, NHC(O)NH2, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,

NR⁴⁷C(O)NHR⁶⁷, NR⁴⁷C(O)N(R⁴⁷)2j C(O)NHj, C(O)NHR⁴⁷, C(O)N(R⁶⁷)2, C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO:R⁶⁷, C(O)NR⁴⁷SO2R⁶⁷, SO2NH2, SO2NHR⁶⁷, SO2N(R⁴⁷)2i C(O)H, 15 C(O)OH, C(N)NH2, C(N)NHR⁶⁷, C(N)N(R⁶⁷)2j CNOH, CNOCH_3j OH, (O), CN, Nj, NO_:, CF₃, CF₂CF₃, OCF₃, OCF₂CF_3j F, Cl, Br or I substituents;

R⁴⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^I7A, R⁵⁸, Rⁱ⁹, R⁶⁰, R⁶³, R⁴⁴, R⁴⁵, and R⁴⁷ are 20 unsubstituted or substituted with one or two or three or four of independently selected R^4S, OR⁶⁸, SR⁶⁸, S(O)R⁴⁸, SO2R⁴⁸, C(O)R⁴⁸, CO(O)R⁴⁸, OC(O)R⁴⁸, OC(O)OR⁶⁸, NH2i NHR⁴⁸, N(R⁶⁸)2. NHC(O)R⁴⁸, NR⁴⁸C(O)R⁴⁸, NHS(O):R⁴⁸, NR⁶⁸SfO)2R⁴⁸, NHC(O)OR⁶⁸, NR⁴⁸C(O)OR^4S, NHC(O)NH2, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)2, NR⁶⁸C(O)NHR⁶⁸, NR^tSC(O)N(R^M)2, C(O)NH_2? ( C(O)NHR⁴⁸, QO)N(R^m)2, C(O)NHOH, C(O)NHOR⁴⁸, C(O)NHSO3R⁴⁸, C(O)NR⁶⁸SO₂R⁶⁸,

SO₂NH₂, SO₂NHR⁴⁸, SO2N(R⁶⁸)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R% CNOH, CNOCH₃, OH, (O), CN, Nj, NO₂, CF₃₎ CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁴⁹ is phenyl, which is unfused or fused with benzene, heteroarene or R^49A; R^69A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷⁰ is heteroaryl, which is unfiised or fused with benzene, heteroarene or R^70A; R^7flA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^7lA; R^71A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁷³, OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³,

OC(O)R⁷³, OC(O)OR⁷³, NH_2j NHR⁷³, N(R⁷³)2, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)2R⁷³, NR⁷³S(O)₂R⁷³, NHC(O)OR⁷³, NR^7JC(O)OR” NHC(O)NH2j NHC(O)NHR⁷³, NHC(O)N(R⁷³)2j NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)2j C(O)NH3, C(O)NHR⁷³, C(O)N(R⁷³)2i C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO2R⁷³, C(O)NR⁷³SO2R⁷³, SO2NH2j SO2NHR⁷³, SO2N(R⁷³)₂, C(O)H,

C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)_2j CNOH, CNOCHj, OH, (O), CN, N_3&gt; NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted or substituted with one or 10 two or three or four of independently selected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF_3s OCF₂CF₃, F.

( CljBrorl.

Still another embodiment pertains to a compound of Formula I or Formula II, wherein A¹is C(A²); and A² is H.

Still another embodiment pertains to a compound of Formula I or Formula II, wherein A¹ is C(A²); A² is H; and B¹ is NHR¹.

Still another embodiment pertains to a compound of Formula I or Formula II, wherein A¹is C(A²); A² is Η; B¹ is NHR¹; and D^l is H,

Still another embodiment pertains to a compound of Formula I or Formula II, wherein A¹20 is C(A²); A² is H; B^[ is NHR¹; D¹ is H; and E¹ is H.

Still another embodiment pertains to a compound of Formula I or Formula II, wherein A¹is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO₂.

Still another embodiment pertains to compounds having Formula I, which are f 4-(4-((4'-chloro-l, 1 '-biphenyl-2-y I )methyl)piperazin-l-y 1)-2-(325 ((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l_jr-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-(methylamino)phenoxy)-N-((3nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-l-yl)methyI)piperazin-I-yl)-2-((2-methyl3 0 1 H-indo 1-5 -yl)oxy)-N-((4-(( 1 -methy I p i perid in-4-y I )am ino)-3 -nitrophenyl )sulfony 1 )benzamide;

4-(4-((2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -y I )methy l)piperazin-1 -yl )-2-((2-methyllH-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyI)sulfonyl)benzamide; 4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-y 1)-2-(2-chlorophenoxy )-N-((3-nitro-4{(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-y 1)-2-(3-chlorophenoxy )-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amtno)phenyl)sulfonyl)benzamide;

4-(4-((4 '-chloro-1,1 '-b ipheny 1 -2-yl)methyl)piperazin-1 -y l)-2-(4-chlorophenoxy )-N-((3 -n itro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)suIfonyl)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-nitrophenoxy )-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su Ifony l)benzamide;

4-(4-( (4'-chloro-l ,1'-bipheny l-2-yl)methyl)piperazin- l-yl)-2-(3-(hydroxymethyl)phenoxy )-N-((4((3-morpholtn-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -yl)-2-(2-chlorophenoxy)-N-( (4-((3morphol in-4-y Ipropy l)am ino)-3 -n itropheny IJsulfony l)benzamide;

4-(4-((4'-chloro-1 ,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-chlorophenoxy )-N-((4-((310 (dimethylamino)propyl)amino)-3-n itropheny l)su Ifony l)benzamide;

4-(4-((4'-chloro-l ,l'-bipheny 1-2-yl)methyl)piperazin-1 -y 1)-2-(3-chlorophenoxy)-N-((4-((3morpholin-4-ylpropyl)amino)-3-nitrophenyI)sulfonyl)benzamide;

4-(4-((4^l-chloro-l,l^,-biphenyI-2-yl)methyl)piperazin-l-yl)-2-(4-chlorophenoxy)-N-((4-((3morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yI)methyl)piperazin-l-yl)-2-(3-chlorophenoxy)-N-((4-((3(d imethy lam ino)propyI)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((4’-c h 1 oro-1,1 '-bipheny 1 -2 -y l)methy l)piperazin-1 -yl)-2-(4-chlorophenoxy)-N-((4-((3(dimethylamino)propyl)amino)-3 -nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-ch 1 oro-1,1 '-biphenyl-2-yl)methy l)piperazin-1 -y l)-N-((4-((3 20 (dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((l -methyl-1 H-indol-4yl)oxy)benzamide;

2-(3-( acetylamino)phenoxy)-4-(4-((4'-chIoro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3n itro-4-((tetrahydro-2 H-pyran-4-y Imethy l)am ino)pheny l)su Ifony i Jbenzam i de;

2-(4-aminophenoxy )-4-(4-((4'-ch loro-1,1 -bipheny 1-2-y IJmethyl )piperazin-1 -y l)-N-((3 -n itro-425 ((tetrahydro-2 H-pyran-4-yl methy l)amino)phenyl)sulfonyl)benzamide;

-(3 -aminophenoxy )-4-(4-( (4'-c h loro-1, l'-bipheny 1-2-y l)methyl )piperazin-1 -yl)-N-((3 -n itro-4((tetrahydro-2 H-py ran-4-y Imethy l)am ino)pheny l)sulfony l)benzam ide;

4-(4-((4'-ch loro-1, Γ-bipheny l-2-yl)methyl)piperazin-l-yl )-2-(3-methoxyphenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-y Imethy 1 Jam ino)phenyl)su Ifony l)benzamide;

0 4-(4-((4'-chloro-1,1 '-bipheny 1-2-y IJmethy IJpiperazin-1 -y 1)-2-(3 -(d i methy lamino)phen oxy )-N -((3nitro-4-((tetrahy dro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzam ide;

4-(4-( (4’-chIoro-l,r-b ipheny 1-2-yl)methyi)piperazin-l-y 1)-2-(3-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran -4-yl methy I )amino)pheny l)su Ifony I )benzam ide;

4-(4-(( 4'-chloro-l, 1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-2-((2-methyl-1,3-benzothiazol-635 yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ammo)phenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-Ι,Γ-bipheny 1-2-yl )methyl)piperazin-1-y 1)-2-((2-methy 1-1,3-benzothiazol-5y l)oxy)-N-((4-((3 -morp hoi in-4-yl propy l)amino )-3 -n itropheny I)su Ifony l)benzamide;

4-(4-((4'-chloro-l₁l’-biphenyl-2-yl)methyl)piperazm-l-yl)-N-((4-((3(di methy lamino)propyl)amino)-3-nitropheny l)sulfony 1)-2-((2-methy 1-1,3-benzothiazo 1-55 yl)oxy)benzamide;

4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin-l-y 1)-2-(2-(3-(dimethylamino )-3oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4'-ch loro-Ι,Γ-bipheny 1-2-y l)methy l)piperazm-1 -y 1)-2-(2-(2-{d imethy lam ino)-210 oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4yl methy I)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4'-chloro-1,1 '-bi pheny l-2-yl)methy l)piperazin-1 -y 1 )-2-(2-(3(dimethylamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -y 1)-2-(2-(2(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

2-(5 -(4-((4'-ch lorobipheny 1-2-y l)methy 1 )piperazi n-1 -y 1 )-2-(3 -nitro-4-((tetrahyd ro-2H-pyran-4yl)methylainino)phenylsulfonylcarbamoyl)phenoxy)-N,’N-dimethylbenzamide;

4-(4-((4'-chloro-l, I '-biphenyl-2-yl)metliyl)piperazin-l-yl)-2-(2((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y I methy l)amino)pheny l)sulfonyl)benzam ide;

4-(4-( (4'-chloro-1,1 '-biphenyl-2-yl)methyI)piperazin- l-yl)-N-((4-((3(d imethy Iamino)propy 1 )am ino)-3 -nitropheny l)sulfony 1 )-2-(3 -morph ο I in-4-y lphenoxy)benzamide; 25 4-(4-( (4'-chloro-l, l’-bipheny 1-2-yl)methyl)pi perazin-1-y 1)-2-(3-(2,4-dimethy 1-1,3-thiazo 1-5yl)phenoxy)-N-( (4-((3 -morpholin-4-y Ipropy I )am ino)-3-nitrophenyl )su Ifony I )benzam ide; 2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-d imethy 1 cyclohex-1-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yI)amino)-3nitrophenyl)sulfonyl)benzamide;

0 4-(4-((2-(4-c h loropheny 1 )-4,4-d imethy Icyclohex-1 -en-1 -y l)methy 1 )piperazin-1 -y 1 )-2-( 3,5 dichlorophenoxy )-N-((4-((1 -methyl pi peridin-4-yl)amino)-3 -nitropheny l)sulfonyl)benzamide; 2-(3 -chlorophenoxy )-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 yl)methyl)piperazin-l-yI)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-( (4'-chloro-4-(2-(dimethylamino)ethoxy )-1, l'-bipheny 1-2-yl)methy l)piperazin-l -yl)-2-(3ch lorophenoxy)-N-((4-(( 1 -methy lpiperidin-4-y l)am i no)-3 -n itropheny I )sulfony l)benzamide;

2-(2-chlorophenoxy )-4-(4-( (4-( 4-chloropheny 1)-6,6-dimethy 1-5,6-dihydro-2 H-pyran-3yl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3n itrophenyl)sul fony l)benzamide;

4-(4-((4'-chloro-l,l'-bipheny 1-2-yl)methyl)piperazin-l-y 1)-2-(3-(25 (dimethyIammo)ethoxy)phenoxy)~N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-lyl)methy l)piperazin-1 -y 1 )-N-((4-(( 1 -methy lpiperidin-4-y 1 )am ino)-3 nitrophenyl)sulfonyl)benzaniide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-eTi-ly l)methy 1 )piperazin-1 -y l)-N-((4-(( 1 -i sopropy 1 piperidin-4-y l)am ino)-3 nitrophenyl)sulfonyl)benzamide;

2-(2-bromophenoxy)-4-(4-((2-(4-chloiOphenyl)-4,4-dimethylcyclohex-l -en-1yl)methyl)pi perazin-1 -y l)-N -((4-(( 1 -methy lpiperidin-4-yl)amino )-315 nitrophenyl)sulfonyl)benzamide;

2-(2-ch lorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1 -en-1 -yl)methyl)piperazin-1 -y l)-N-((4((l-methylpiperidin-4-yl)amino)-3-nitrophenyI)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl)methyl)piperazin-]-yl)-2-((3-methyllH-indazol-4-yl)oxy)-N-((4-((3-marphoIin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chIoropheny 1)-4,4-di methylcyclohex-l-en-l-yl)methy I )piperazin-1-y I )-2-(2,3difluoropheno xy)-N -((4-(( 1-methy Ipi peridin-4 -yl)amino)-3-nitrophenyl)suIfonyl)benzamide; 2-(3-bromophenoxy)-4-(4-((2-(4-chloropheny1)-4,4-dimethylcyclohex-l-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)aniino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-(4-( (2-(4-chloropheny 1)-4,4-dirnethy Icyclohex-1 -en-1 yl)methyl)piperazin-l-yl)-N-((4-((l-ethylpiperidin-4-yl)ammo)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-Iy l)methy I )piperazin-1 -y l)-N-((3 -n itro-4-(( 1,2,2,6,6-pentamethy Ip i pe ridin-430 yl)amino)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-ch loropheny 1 )-4,4-dimethy Icyclohex-1 -en-1 -y l)methy l)p iperazin-1 -y 1)-2-(2,3 d ifluorophenoxy)-N-((3 -n i tro-4-((1 -tetrahydro-2H-pyran-4-yl piperid in-4yl)amino)phenyl)sulfonyl)benzamide;

4-( 4-( (2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y 1 )methy l)piperazin-1 -y 1)-2 -((7-fluoro35 1 H-indol-5-yl)oxy)-N-((4-(( 1 -methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y l)methy l)piperazin-1 -y 1)-2-(2,3 difluorophenoxy )-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyI)benzamide;

2-(4-amino-3-chlorophenoxy )-4-(4-( (2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1-en-lyl)methy l)piperazin-1 -y 1 )-N-« 4-((3 -morphol ίη-4-y Ipropy l)am ino)-3 5 nitrophenyl)sulfonyl)benzamide;

2-(3-chlc)rophenoxy)-4-(4-((4'-chloro-4-(2-pynOlidin-l-yIethyl)-l,r-biphenyI-2yl)methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4yl methy l)am ino)phenyl )sulfonyl)benzamide;

4-(4-((2-(4-ch!oropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl)methyl)piperazin-l-y 1)-2-(2,310 di chlorophenoxy )-N-((4-((l-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzam ide;

4-(4-((2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -yl)methyl)piperazin-1 -yI)-2-((3-methyIIH-indazol-4-yi)oxy)-N((4-((l-methylpiperidin-4-yl)amino)-3-nitrophenyl)suIfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-l-en-l-yl)methyl)piperazin-I-yl)-N-((4((1-methy lpiperidin-4-yI)amino)-3-nitrophenyl)sulfonyl)benzam ide;

4-(4-((2-(4-ch loropheny 1)-4,4-d i methy icyc lohex- 1-en-l -y l)methy l)piperazin-1 -yl)-N-((4-(( 1 methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trif]uoromethyl)phenoxy)benzamide; 4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-l -yl)-N-((4-((3(diTnethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-l,2,3,4-tetrahydroquinolin-5yl)oxy)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yI)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-di methy Icyclohex-l-en-l-yl)methyl)piperazm-l-yl)-2-(2,5dich lorophenoxy)-N-((4-(( 1 -methylpiperidin-4-yl)am i no)-3 -n itropheny l)su 1 fony l)benzam ide;

2-(2-chloro-4-fluorophenoxy )-4-( 4-((2-( 4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3n itropheny l)sulfonyl)benzamide;

2-(2-ch lorophenoxy )-4-(4-( (2-(4 -chlorophenyl )-4,4-d imethy Icyc lopent-1 -en-1 yl)methyl)piperazin-]-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-330 n itropheny l)sul fony l)benzam ide;

4-(4-((2-(4-chloropheny I )-4,4-d imethy Icyclohex-l-en-l-yl)methyl)piperazin-l-y 1)-2-((3-methyllH-indoJ-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en- I-yl)methyl)piperazin-1 -yl)-2-(2-chloro-3(trifluoromethyl)phenoxy)-N-((4-((l-methy lpiperidin-4-y l)amino)-335 nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyI)-4,4-dimethylcycIohex-l-en-lyl)methyl)piperazin- l-yl)-N-( (4-(( 1 -cyclopropylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl)methyl)piperazin-1-y 1)-2-((3-methy 15 lH-indol-4-yl)oxy)-N-( (4-(( l-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-(( 2-(4-ch loropheny 1)-4,4-d i methy Icy c lohex-1 -en-1 -y l)methy l)piperazi η-1 -y 1)-2-(2,5dichlorophenoxy)-N-((4-((3-morpholm-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-l, l’-biphenyl-2-yl}methyl)piperazin-1-y 1)-2-(( I-methyl-lH-indol-4-yl)oxy)-N((4-((3 -morpholin-4-y Ipropy l)amino)-3 -nitropheny I )s u 1 fony l)benzam ide;

4-(4-((4'-chloro-1, r-biphenyl-2-y])methyl)piperazin-l-yl)-2-(3-niorpholin-4-ylphenoxy)-N-((4((3 -morpholin-4-ylpropy 1 )am ino)-3 -n itrophenyl)sulfony l)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3(dimethy lam ino)propy l)am ino)-3-n itropheny I) s u Ifony 1 )-2-((3 -(3 -morpholin-4-y 1-3-oxopropy ΟΙ H-indol-5-yl)oxy)benzam ide;

2-(3-(benzyloxy)phenoxy)-4-(4-((4’-chloro-I,1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3-nitro4-((tetrahydro-2 H-pyran-4-y I methy l)amino)phenyl)sul fony l)benzam ide;

4-(4-((4'-chloro-l, 1 '-biphenyl-2-yl)methyl)piperazin-l-yI)-2-(4-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-yl methyl )amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)20 lH-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -yl)-2-((3-(3-morpholin-4-ylpropyl)-1Hindol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4-chloro-l, 1 '-biphenyl-2-yl)methyl)piperazin-1 -y 1)-2-(4((dimethy 1 am i no)methy l)phenoxy )-N-((3 -nitro-4-((tetrahydro-2H-pyran-4 y!methyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l ,1 '-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(4-(1 H-imidazol-1 -yl)phenoxy)-N((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyI)amino)phenyl)sulfonyl)benzamide;

4-( 4-(( 4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

tert-butyl 4-(5-(4-((4'-chloro-i,l'-biphenyl-2-yl)methyI)piperazin- 1-y 1)-2-((((3-nitro-4((tetrahydro-2H-pyraii-4yl methy l)am!no)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;

tert-butyl 3-(5-(4-((4'-chIoro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin-l-y 1)-2-((((3-nitro-4((tetrabydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;

4-(4-((4'-chloro-1,1 '-biphenyl -2-yl )methy l)piperazin-1 -y 1)-2 - (4 -((ethy lam inojmethy 1 )phenoxy )-N5 ((3 -n itro-4-((tetrahydro-2 H-pyran-4-y Imethy I)am ino)pheny l)sulfony l)benzamide;

4-(4-((4'-chloro-1,) '-biphenyl-2-yl)methyl)piperazin-1 -y 1)-2-(3 -((ethy Iamino)methyl)phenoxy)-N((3 -nitro-4-(( tetrahydro-2 H-pyran-4-y Imethy 1 )am ino)pheny I )sulfony l)benzam ide;

2-(4-( acety lam ino)phenoxy )-4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yljmethy l)piperazin-l-y l)-N-((3n i tro-4-((tetrahy dro-2H-pyran-4-y Imethy l)am ino)pheny l)sulfony I )benzam ide;

tert-butyl 4-(5-(4-( (4'-ch loro-Ι,Γ-bipheny 1-2-yl)methy I )piperazin-l-y 1)-2-((((3-nitro-4((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;

2-(1, r-biphenyl-2-yloxy )-4-(4-( (4'-chloro-1, r-biphenyl-2-yl)methyl)piperazin-i-yl)-N-((3-nitro4-((tetrahy dro-2H-pyran-4 -y Imethy l)am ino)pheny l)su Ifony l)benzam i de;

tert-butyl 3-(5-(4-((4'-ch loro-Ι,Γ-bipheny 1-2-yl)methy l)piperazin-l-y 1)-2-((((3-nitro-4((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;

2-(1,1 '-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1 '-biphenyI-2-yl)methyl)piperazin-1 -yl)-N-((3-nitro4-((tetrahydro-2H-pyran-4-yImethyl)amino)phenyl)suIfonyl)benzamide;

4-(4-((4'-chl oro-1, l'-bipheny 1-2-yl)methyl)piperazin-1-y 1)-2-(4-(2(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfbnyl)benzamide;

2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin-l-yl)-N-((3-nitro4-((tetrahy dro-2 H-pyran-4-y I methy l)am i no)pheny l)sulfony 1 )benzam ide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-y 1)-2-(3-morpholin-4-yl phenoxy )-N-((3n itro-4-((tetrahydro-2H-pyran-4-y lmethyl)amino)pheny I )su I fony l)benzam ide;

4-(4-((4’-ch loro-Ι,Γ-bipheny I-2-y J )methyl)piperazin-1-y))-2-((2-methy 1-1,3-benzothiazol-5y l)oxy&gt;N -((3 -n itro-4 -((tetrahydro-2H-pyran-4-y Imethy l)am ino)phenyl)su Ifony l)benzamide; tert-butyl 4-(3 -(5 -(4-((4'-ch loro-1,1 '-bipheny 1-2-yl)methyl)pi perazin-1 -yl )-2-((((3 -n itro-430 ((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-l-carboxylate;

2-(3 -(benzyloxy )phenoxy )-4-(4-( (4’-ch loro-1,1 '-bi phenyl-2-y I )methy l)piperazin-1 -y 1)-N-((4-((3 (d imethy lamino)propyl)amino)-3-nitrophenyl)su Ifony l)benzamide;

2-(3-(benzyloxy)phenoxy)-4-(4-((4’-chloro-1, r-biphenyl-2-yl)methyl)piperazin-]-yl)-N-( (4-((335 morpholin-4-ylpropyl)amino)-3-nitrophenyI)su Ifony 1) benzamide;

4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin-1-y 1)-2-(4-(2-morpholin-4ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethy l)am ino )pheny 1 )sulfony l)benzamide;

4-(4-((4'-ch loro-Ι,Γ-bipheny 1-2-y 1 )methyl )piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-45 y Imethy l)amino)pheny l)sul fony I)-2-((2-oxo-1,2,3,4-tetrahydroquino lin-5 -y 1 )oxy)benzam ide;

2-(4-(benzy loxy)phenoxy )-4-(4-((4'-chloro-l,i'-bipheny 1-2-yl)methyl)pi perazin-l-yl)-N-((4-((3morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

tert-butyl 4-(4-(5-(4-((4'-chloro-l,l'-bipheny 1-2-yl)methyl)piperazin-l-y 1)-2-((((4-((3-morpholin4-ylpropyl)amino)-3-nitropheny I )sul fony l)amino)carbonyl)phenoxy)phenyl)pi perazine-110 carboxylate;

4-(4-((4'-ch 1 oro-1,1 '-biphenyl -2-yl)methy 1 )p iperazin- i -y l)-N -((4-((3 -morph ol i π-4 ylpropyl)amino )-3-nitrophenyl)sulfony 1)-2-(3-pyridin-4-ylphenoxy)benzam ide;

4-(4-((4'-chloro-l, I '-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3-morpholin-4y 1 propyl )amino)-3 -nitropheny l)su Ifony 1 )-2-(4-pyrid in-4-y lphenoxy)benzamide;

4-(4-((4'-chloro-l, I'-bipheny 1-2-yl)methyl)piperazin-1 -yl)-N-( (4-((3-morpholin-4ylpropyl)amino)-3-nitrophenyI)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamide;

4-(4-(( 4'-ch loro-1,1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-(2-(dimethylamino)-2oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sul fony l)benzam ide;

4-(4-((4'-chloro-l, Γ-b i phenyl-2-yl)methyl)piperazin-l-y 1)-2-((1-methyl-IH-benzimidazo 1-5yI)oxy)-N-((4-( (3-morphoIin-4-ylpropyl)amino)-3 -nitropheny l)sulfonyl)benzam ide;

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3morpholinopropylamino )-3-nitrophenylsulfonyI)benzamide;

4-(4-((4'-chlorDbiphenyl-2-yl)methyl)piperazin-l-yl)-N-(4-(3“(dimethylamino)propylamino)-325 nitropheny Isulfony 1)-2 -(3-(methylcarbamoyl)phenoxy)benzamide;

4-(4-((4'-ch loro-1, l'-bipheny 1-2-yl)methyl)piperazin-l-y 1)-2-(3-(2-(d imethy lam ino)-2oxoethoxy )phenoxy)-N-( (3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4 '-ch loro-1, Γ-b i phenyl-2-y l)methy l)piperazin- i -y 1 )-2-((3 -(3 -(d imethy lam ino)propy 1)-1H30 indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)aniino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chIoro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -yl)-N-((4-((3(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(3(hydroxymethyl)phenoxy)benzamide;

4-(4-((4’-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-((4-methoxybenzyl)oxy)-N-((3-nitro4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

TJ

N-(4-((4-annnotetrahydro-2H-pyran-4-yl)methylarnino)-3-nitropheny Isulfony 1)-2-(3ch!orophenoxy)-4-(4-((2-(4-chlorophenyl )-4,4-dimethylcyclohex-1 -enyl)methyl)piperazin-1 yl)benzamide;

4-(4-( l-(4'-chlorobiphenyl-2-y])ethyl)piperazin-l-yl)-2-(2-chlorophenoxy)-N-(3-nitro-45 ((tetrahydro-2H-pyran-4-y l)methy lamino)phenylsu Ifony l)benzamide;

N- {[4-{4-[(4'-ch loro-1.1 '-bipheny 1-2-y l)methy IJpiperazin-1 -y I} -2-(3,5d ichlorophenoxy)pheny l]sulfony 1} -4 -[(1 -methy Ip iperidin-4-yl)am ino] -3 -nitrobenzam i de;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-1 -en-1 -y 1] methy 1} piperazin-1 -y I )-2-(3fluorophenoxy)-N-({4-[(l-methylpiperidin-4-y!)amino]-3-nitrophenyI}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-di methy lcyclohex-1-en-1-yl] methy I) piperazin-1-yl )-2-(3fluorophenoxy)-N -({3 -n itro-4- [(1 -tetrahy dro-2H-py ran-4-y Ipiperidin-4 yl)amino]phenyl}sulfonyl)benzamide;

4-(4 - {[2-(4 -ch loropheny I)-4,4-d imethy Icyc 1ohex-1-en-1 -yl] methy I} pi perazin-1 -y I )-2 -(3 fluorophenoxy)-'N-({4-[(3-morpholin-4-ylpropy])amino]-3-nitrophenyl}suIfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-1-yI)-N-({3-nitro-4-[( I-tetrahydro-2H-pyran-4-ylpiperidin-4y 1 )ami no] phenyl} sulfonyl )benzam ide;

2-(2-ch lorophenoxy)-4-(4- {[2-(4-chloropheny 1)-4,4-d imethylcyclohex-1 -en-1 y l]methy 1} piperazin-1 -y l)-N-( {4- [(3 -morphol in-4-y Ipropy l)am ino] -3 20 nitrophenyl} sulfony l)benzam ide;

2-(2-ch lorophenoxy)-4-(4-{ [2-(4-ch loropheny l)-4,4-dimethylcycl ohex-1-en-ly 1 ]methy i} piperazin-1 -yl)-N-( {4-[( 1 -cyclopenty Ip iperidin-4-yl Jam ino] -3 nitrophenyl} sulfony l)benzamide;

4-(4- {[2 -(4-chloropheny 1)-4,4-dimethylcycIohex-1 -en-1 -y I] methy 1} piperazin-1 -y I )-2-(42 5 fluorophenoxy )-N-( {4- [(1 -methylpiperidin-4-yl)am ino]-3-n itropheny I} sulfony l)benzam i de;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-chloropheny l)-4,4-d imethy Icycl ohex- 1-en-Iyl]methyl}piperazin-l-yl)-N-({4-[(l-cyclopropylpiperidin-4-yl)amino]-3nitrophenyl} sulfony l)benzamide;

2-(2-chloro-4-fl uorophenoxy)-4 -(4-{ [2-(4 -ch loropheny 1)-4,4-d i methy Icyclohex-1 -e n-1 30 yl]methyl} piperazin-l-yI)-N-( {4-[(3-morphoIin-4-y Ipropy l)amino]-3nitrophenyl} sulfony l)benzamide;

4-( 4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-N-({4-[(lcy clopropy 1 piperidin-4-y I )am ino]-3 -nitropheny I} sulfonyl)-2-(2,3 -d ifluorophenoxy) benzamide; 4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -yl] methyl} piperazin-1 -y I )-2-(235 fluorophenoxy )-N-({4-[(l -methy Ip iperidin-4-yl)amino]-3-nitropheny I [sulfony l)benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y 1 ] methy 1} piperazin- l-yl)-N-({4-[(lcyclopropy Ipiperid in-4-yI)am ino] -3 -nitrophenyl} sulfonyl)-2-(2-fluorophenoxy )benzamide; 4-(4- {[2-(4-chlorophenyl)-4,4-dimethy Icy cloh ex-1 -en-1 -y l]methy 1} piperazin-1 -y 1 )-2-(2fluorophenoxy)-N-( {3-nitro-4-[( 1 -tetrahydro-2H-pyran-4-y lpiperidm-45 yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-( 4-ch loropheny 1)-4,4-di methy Icyc lohex-1 -en-1 -yl]methyl} piperazin-1 -y 1)-2-(2fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyI}sulfonyi)benzamide; 4-(4- {[2-(4 -ch loropheny 1)-4,4-dim ethylcyclohex-1 -en-1 -y l]methy I} p iperazin-1 -y 1)-2-(2fluorophenoxy)-N-( {4- [(2-morphol in-4-y lethy I )amino]-3 -nitrophenyl} sul fony 1 )benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfony!)benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4 -chloropheny])-4,4 -d i methy Icyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-315 nitrophenyl}sulfonyl)benzamide;

4-(4-{ [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-l-en-l-yl]methyl}piperazin-]-yI)-2-(3fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl)sulfonyl)benzamide;

2-(3 -ch lorophenoxy)-4-(4- {[2-(4-chloropheny 1)-4,4-dim ethy Icyc lohex-1 -en-1 yl]methy I} piperazin-l-yl)-N-({4-[( 1-cyclopenty lpiperidin-4-yl)aniino]-320 nitrophenyl} sul fony l)benzam ide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4 -ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-( [4-((1-methy lpiperidin-4-yl)amino]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({4-[( 125 cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(3-fluorophenoxy)benzamide;

4-(4-{[2-(4-chloropheny 1 )-4,4-dimethyIcyclohex-1 -en-1 -y I] methy 1}piperazin-1 -y 1)-N-({4-[(I eye iopenty Ipiperid in-4-y I )amino]-3-nitrophenyl} su Ifony 1)-2-(2,3-difluorophenoxy)benzamide; 4-(4- {[2-(4-ch loropheny I )-4,4-d imethy Icyc lohex-1 -en-1 -y l]methy 1} piperazin-1 -y l)-N-( {4 - [(1 cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}su Ifony] )-2-(2-fluorophenoxy)benzamide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-dimethy Icyclohex-1 -en-1 -y i] methy 1} piperazin-1 -y I )-2-(2,3 di fluorophenoxy )-N -({4-[(2-morpho I in-4-yie thy l)am ino] -3-nitrophenyl} sulfonyl )benzamide; 4-(4-] [2-(4-chloropheny l)-4,4-dimethylcyclohex-l-en-l-yl]niethyl} piperazin-1-y 1)-2-(2,3difluorophenoxy )-N-[(3 -nitro-4- {[ 1 -(th i en-3 -y Imethy I )piperidin-4yl]amino}phenyl)sulfonyl]benzamide;

4-(4- {[2 -(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y l]methy I} piperazin-1 -y I )-N - [(4 - {[3 (dimethyIamino)propyl]amino}-3-nitrophenyI)sulfonyl]-2-(2-fluorophenoxy)benzamide;

4-(4- {[ 2-(4-ch loropheny 1)-4,4-d i methylcyclohex-1 -en-1 -y 1] methy 1} piperazin-1 -yl)-N-((4-{[3(dimethylamino)propyl]amino}-3-n itropheny l)sulfonyl]-2-(3-fluorophenoxy) benzamide;

4-(4- {[2-(4-chloropheny I )-4,4-d imethylcyclohex-1 -en-1 -y] ] methy 1} piperazin-1 -y l)-N-[(4- {[3(dimethy lam ino)propyl] amino}-3-n itropheny l)sulfonyl]-2-(4-fluorophenoxy)benzani ide;

4-(4-{ (2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-1-yl]methyl} piperazin-1-y 1)-2-(2,3difluorophenoxy)-N-[(4-{[l-(2-fluoroethyl)piperidin-4-y!]amino}-3nitrophenyl)suifony I] benzamide;

2-(3-chlorophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4-d imethylcyclohex-1 -en-1 yl]methy I} piperazin-l-yl)-N-( {4-((2-morpholin-4-ylethyI)amino]-310 nitrophenyl} sulfonyl)benzamide;

2-(3 -ch lorophenoxy )-4-(4- {(2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 y l]methy I} piperazin-l-yl)-N-[(4-{ (3-(dimethylamino)propyl] amino}-3n itropheny l)sulfony 1 ]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-l -en-115 yl]methyl} piperazin-]-yl)-N-[(4-{{3-(4-methylpiperazin-l-yl)propyl]amino}-3n itropheny l)sulfony I] benzamide;

2-(3-chlorophenoxy )-4-(4-{[4-(4-chloropheny 1)-6,6-dimethy 1-5,6-dihydro-2H-pyran-3yl]methyl}piperazin-l-yl)-N-({4-f(l-methylpiperidin-4-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

4-(4-{[4-(4-chIorophenyI)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-l-yl)-2(2,3-d ifluorophenoxy)-N-({4-((1-methy lpiperidin-4-yl )amino]-3nitrophenyl} sulfonyl)benzamide;

N-({4-[(l-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(2-(4-chlorophenyl)-4,4dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-2-(2,3-difluorophenoxy)benzamide;

2-(3-chloro-2-fluorophenoxy )-4-(4-{[2-(4-chlorophenyl )-4,4-dimethylcyclohex-l-en-lyljmethy I} piperazin-l-yl)-N-( {4-((1-methy lpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl] methy 1} piperazin-1 -y l)-N-( {4-[(3-morpholin-4-y Ipropy 1 )amino] -3 30 nitrophenyl}sulfbnyl)benzamide;

2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly IJmethy I} piperazin-1-y I )-N-({3-nitro-4-[(3-pyrrol idin-1ylpropyl)amino]phenyl}sulfonyl)benzamide;

2-(3 -ch loro-2-fluorophenoxy)-4-(4 - {[2-(4-ch loropheny 1)-4,4 -d imethy Icy c lohex-1-en-13 5 y l]methy 1} piperazin-1 -y l)-N-( { 4-((2-morphol i n-4-y lethy l)aminoJ-3 n itropheny! }sulfonyl)benzam ide;

2-(2-chloro-6-fluorophenoxy )-4-(4-( [2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-l-en-1yl]methyl}piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(2-chloro-6-fluorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-l-en-l5 y l]methy 1} piperazin-1 -y l)-N-( { 3 -nitro-4-[( 1 -tetrahy dro-2H-pyran-4-y 1 piperid in-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-]-en-l-yl]methyl}piperazin“l-yl)-2-[(6-fluoro1H- indo 1-5 -y l)oxy ]-N -({4-(( 1 -methy lpiperidin-4-y l)am ino]-3 -nitropheny 1} sul fony l)benzam ide; 2-(3-chlorophenoxy )-4-(4-( [2-(4-chlorophcnyl)-4,4-dimcthylcyclohcx-l -cn-1 10 yl]methy]}piperazin-l-yl)-N-[(4-{[(l-methylpiperidin-4-yl)methyl]amino}-3nitrophenyl )su[fonyl (benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethylcyclohex-1 -en-1 -y I] methy I} piperazi n-1 -yl)-2-(2,3d i fluorophenoxy )-N-((4-{[(1-methy lpiperidin-4-yl)methyl] amino}-3nitropheny l)sul fony 1] benzamide;

4-(4-{[2-(4-chlorophenyl )-4,4-di methy lcyclohex-1-en-l-yl] methyl} piperazin-1-y 1)-2-[(4-fluorolH-indoI-5-yl)oxy]-N-((4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; 4-(4-{[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-l-en-l-yl] methyl} piperazi n-l-y 1)-2-(3(methoxymethoxy)-2-methylphenoxy]-N-( {4-(( I-methy lpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {(2-(4-chloropheny 1 )-4,4-d imethylcyclohex-1 -en-1 -yl ] methyl} piperazin-1 -y 1)-2-(3 -hydroxy2-methy lphenoxy)-N-( (4-[(1-methy lpiperidin-4-yl)amino]-3-nitropheny I }sulfonyl)benzamide; 2-(3-bromophenoxy )-4-( 4-{[4-(4-ch loropheny 1 )-6,6-dimethy 1-5,6-dihydro-2H-pyran-3yl]methyl}piperazin-1-yl)-N-( {4-((1-methy lpiperidin-4-y])amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {(4-(4-c h loropheny 1 )-6,6-d i methy 1-5,6-dihy dro-2H-pyran-3 -y I ]methy 1} pi perazin- l-yl)-2-(3iodophenoxy)-N-( (4-(( l-methyIpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(3-chlorophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4-d imethylcyclohex-1 -en-1 y I] methyl} piperazin-1 -y l)-N - [(4- {[ 1 -(2-hydroxyethy l)piperidin-4-y 1 ]am ino} -3 nitropheny l)sul fony 1] benzamide;

0 2-(3 -chlorophenoxy )-4-(4 - {[2-(4 -c hloropheny 1)-4,4-d imethy Icyc lohex- 1-en-ly I ]m ethy 1} p i perazin- ] -y 1 )-N -((3 -n itro-4- {[ 1 -(2-pheny lethy 1 )piperidin -4yl]amino}phenyl)sulfonyl]benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-l-en-l-yl J methy I} piperazin-]-y 1)-2-(3,4dichlorophenoxy)-N-({4-[(I-methylpiperidin-4-yl)amino]-3-nitrophenyI}sulfonyI)benzamide;

2-^-chloro-l^-difluorophenoxy )-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-lyl]methyl} piperazin-1-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl }sulfonyl)benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -y IJmethy 1} pi perazin-1 -y 1)-2 -(35 methoxy phenoxy )-N-( {4- [(1 - methy lpiperidin-4-y I )am ino] -3 -n itropheny 1} su Ifony l)benzam ide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-dimethy Icyclohex-1 -en-1 -yl] methyl} p iperazin-1 -y 1)-2- [3 (hydroxymethyl)phenoxy]-N-((4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl)sulfonyl)benzamide;

2-(2-ch lorophenoxy )-4-(4- {[2-(4-chlorophenyl)-4,4 -dimethy Icyc I ohex-1 -en-1 10 y IJmethyl} piperazin-l-yl)-N-((4-[(l₁4-dimethyIpiperidin-4-yl)amino]-3nitrophenyi}sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2 -(4 -ch 1 oropheny 1)-4,4-d imethy Icy clohex-1 -en-1 yl]methyl) piperazin-l-yl)-N-({4-[(l,4-dimethylpiperidin-4-yl)amino]-3n itropheny 1} su 1 fony 1 )benzam i de;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-y!)-N-{ [4-( {I-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}amino)-3n itropheny 1] sul fony I} benzam ide;

2-(2-chloro-3-hydroxyphenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-d i methy Icyc lohex-1-en-lyl]methyl}piperazin-l-yl)-N-({4-[(l-methy lpiperidin-4-yl)amino]-320 nitrophenyl }su Ifony l)benzam ide;

2-(3-ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex- 1-en-lyl]methyl}piperazin-l-yl)-N-[(3-nitro-4-{[l-(3-phenylpropyl)piperidin-4y I] am ino} ph eny l)sulfony I] benzam ide;

2-(3 -chlorophenoxy)-4-(4- {[2-(4-ch 1 oropheny 1 )-4,4 -d i methy Icyclohex-1 -en-1 25 yl]methyl}piperazin-]-yl)-N-[(4-{[l-(2-methoxyethyl)piperidin-4-yl]amino}-3n itropheny l)sulfony I] benzam ide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icy c lohex-1 -en-1 yl] methy i} piperazin-1 -y l)-N-( {4-[( 1 -ethy lpiperidin-4-y 1 )amino]-3 nitrophenyl} sul fony l)benzam ide;

2-(3-chIorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-[(]-isopropylpiperidin-4-yI)amino]-3nitropheny 1} su Ifony l)benzam ide;

4-(4-{ [2 -(4-ch lorophenyl)-4,4-dimethy Icyclohex-] -en-]-yl]methyl}piperazin-l-yl)-2-(3hydroxyphenoxy)-‘N-({4-[(l-methylpiperidin-4-yI)ammo]-3-nitrophenyl}sulfonyl)benzamide;

2-(2-chloro-3-fluorophenoxy)-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-1-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4_J4-dimethylcyclohex-l-en-l5 y I] methyl} piperazin-1 -y l)-N-( {3 -n itro-4 - [ (1 -tetrahydro-2 H-pyran-4-y Ip i per i d i n-4yl)amino]pheny 1} sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyljmethyl} piperazin-1-yl)-'N-[(4-{[3-(dimethy]amino)propyl]amino}-3n itropheny l)sulfonyl]benzamide;

JO 4-( 4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-(2methoxyphenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyI)benzaniide; 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yI)-2-(2methylphenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1 )-4,4-dimethy Icyclohex-1-en-l-y I] methy 1} pi perazin-1-y 1)-2-(315 methylphenoxy)-N-({4-[(l-methy!piperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(2-cb lorophenoxy )-4-(4- {[6-(4-chloropheny I)-1,3 -benzod ioxol-5 -yljmethy 1} piperazin-1 -y I )-N ({4-[( 1 -methy Ipiperid in-4-yl )am ino] -3 -nitropheny 1} sulfony l)benzam ide;

2-(2-ch lorophenoxy )-4-(4- {[2-(4-ch 1 oropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl) piperazin-1-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-320 nitrophenyl} sulfony l)benzamide;

2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3y 1] methy I} piperazin-1-y 1)-N-({4-[(4-methylpiperazin-1-y l)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[4-(4-chloropheny 1 )-6,6-d imethy 1-5,6-d ihydro-2H-pyran-3-y I ] methy I} piperazin-1 -y 1)-225 (2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-l-yl)amino]-3n itropheny 1} su I fony l)benzam ide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-[(4-{[l-(cyclopropylmethyl)piperidin-4-yl]amino}-3nitropheny l)su I fony I] benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-lyljmethyl} piperazin-1-yl)-N-[(4-{[ 1-( cyclopropylmethyl)piperidin-4-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2 -(4-chloropheny 1)-4,4-dimethy Icyc lohex- 1-en-ly 1 ] methy 1} piperazin-1 -yl)-N- {[4-( {1 - [2-(di methy Iamino)-2-oxoethyl] piperidin-4-y I} amino)-3 3 5 n itropheny 1 ] sulfony 1} benzam ide;

-(3 -chlorophenoxy )-4-(4- {[2-(4 -chloropheny 1)-4,4-d imethy Icyc lohex- 1-en-ly l]methy I} piperazin-l-yl)-N-[(4-{[l-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(25 chi orophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dime thy Icyc 1 ohex-1 -en-1 -y I ]methy 1} piperazin-1 yl)benzamide;

2-(2-ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icycloh ex- l-en-1yl]methyl} piperazin-l-yI)-N-[(4-{[(4-hydroxy-l-methylpiperidin~4-yl)methyl]amino)-3nitrophenyl)sulfonyl]benzamide;

4-(4- {[2-(4-ch loropheny!)-4,4-d ί methy Icyc lohex- l-en-l-yl]methyl}piperazin-I-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl)sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex- 1-en-ly I] methy I} piperazin-1 -y l)-N-[(4- {[(3 S)-1 -methy Ipyrro I idin-3 -y l]amino} -3 15 nitrophenyl)sulfonyl]benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yljmethyl} piperazin-l-yl)-N-[(4-{[(3R)-l-methylpyrrolidin-3-yl]amino}-3nitrophenyl)su I fony I] benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin- l-yl)-N-({4-[(l 20 methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyi)-2-[3-(lH-pyrrol-2-yI)phenoxy]benzamide;

4-(4-{ [2-( 4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl]methyl} piperazin-1-y 1)-2-(3fluorophenoxy)-N-[(4-{[(4-hydroxy-l-methylpiperidin-4-yl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-l25 yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl} sulfonyl) benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-I-en-l-yl]methyl}piperazin-I-yl)-2-[(6,7difluoro-lH-indol-5-yl)oxy]-N-({4-[(l-methylpiperidin-4-yI)amino]-3nitrophenyl} sulfonyi)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1-en-l-yl] methy l}piperazin-l-yl)-2-[(6,7difluoro-1 H-indoI-5-yl)oxy]-N-( {3-nitro-4-[(l -tetrahydro-2 H-pyran-4-ylpiperidin-4yl)amino]phenyi}sulfonyl)benzamide;

tert-butyl 4-(5-(4-{[2-(4-chlorophenyI)-4,4-dimethyIcyclohex- 1-en-l-yl] methy 1}piperazin- 1-y1)2-( [({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)aniino]carbonyl} phenoxy)- 1H3 5 indole-1 -carboxylate;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl)piperazin-l-yl)-N-[(4-{[4-(dimethylaniino)cyclohexyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 5 yI]methyl}piperazin-I-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]arnino}-3nitrophenyl)sulfonyl]benzamide;

Trans-2-(3 -ch lorophenoxy )-4 -(4- {[2-( 4-chloropheny 1)-4,4-di methy Icyc loh ex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3n itrophenyl Jsul fony l)benzam ide;

4-{4-[l-(4’-chloro-],r-biphenyl-2-yl)ethyl]piperazin-l-yl}-2-(2-chlorophenoxy)-N-({4-[(lmethy Ipiperidin-4-y I )amino]-3-nitrophenyl} sulfony l)benzam ide;

2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl) piperazin-l-yI)-N-({4-[(l-methylpiperidin-4-y l)amino]-3nitrophenyl} sulfony l)benzamide;

2-( 2-chloro-4-hydroxyphenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-d imethylcyclohex- l-en-lyl]methyl Ipiperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3n itrophenyl} sui fony l)benzamide;

4-(4- {[2-(4-ch lorophenyl )-4,4-dimethy Icyclohex- l-en-l -y IJmethy 1} piperazi n-1 -y 1 )-2-[(6-fluoro1 H-indol-4-y l)oxy]-N-( {4- [(1 -methyl piperid ΐη-4-y l)am ino]-3 -n itrophenyl} sulfony l)benzam ide;

4-(4-{[2-(4-ch!orophenyl)-4,4-dimethylcyclohex-l-en-l-yl]metliyl} piperazin-l-yl)-2-[(6-fluoro1 H-indol-4-y l)oxy ]-N-({ 3-n itro-4- [(1 -tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-(2-chloro-4-hy droxyphenoxy )-4-(4- {[2-(4-chl orophenyl )-4,4-di methy Icyclohex- 1 -en-1 y l]methy 1} p i perazin-1 -y 1 )-N-( { 4-[(4-methy Ipiperazin-1 -y 1 )amino] -3 25 [(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-( {1,3-bis[(4-methy Ipiperazin-l-yl)methyl]-lH-indol-4-y I} oxy )-4-(4-{[2-(4-chloropheny 1)-4,4dimethylcyclohex-1-en-]-yl]methyl}piperazin-l-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3nitrophenyl)su I fony I] benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex- l-en-l -y IJmethy 1} piperazin-l-yl)-N-[(4-{ [330 (dimethy lam ino)propy I] amino)-3-nitrophenyl )sulfonyl]-2-( {3-[(4-methy Ipiperazin-1-yl)methy I ]1 H-indol-4-yl) oxy)benzamide;

2-( 5-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -enyljmethy I )piperazin-l -y 1)-2-(4-( 1 methy lpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex- l-en-l -y 1] methy 1} piperazin-1 -y l)-N-( {3-n itro-435 [(1 -tetrahydro-2 H-pyran-4-ylpiperidin-4-yl)anii no] phenyl} sulfony 1)-2-{[2-(trifluoromethy I)-1Hindol-4-yl]oxy) benzamide;

2-(2 -ch loro-4-hydroxy phenoxy)-4-(4- {[2 -(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en -1 y l]methy 1} piperazin- ] -y I )-N-( {3-ni tro-4-[(1 -tetrahydro-2 H-pyran-4-yl pi peri din-4yl )amino]phenyl} su Ifony l)benzam ide;

4-(4-( [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-1-yl)-N-( (4-((15 methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-]H-indol-5yl]oxy} benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-l-en-!-yl] methyl} piperazin-1-y 1)-N-({ 3-nitro-4((l-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)ami no] phenyl} sul fony 1)-2-{[6-(trifluoromethy 1)-1Hindo 1-5-yl] oxy} benzamide;

2-[(2-amino-I_i3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc]ohex-l-en-ly 1 ] methyl} pi perazin-1 -y 1 )-N-( {3 -n itro-4- [(1 -tetrahydro-2 H-pyran-4-ylpiperidin-4y 1 )ami no]pheny 1} sul fony I )benzam ide;

4-(4-{[2-(4-chloropheny 1 )-4,4-dimethylcyclohex-l-en-l-yl] methy IJpiperazin-1-y 1)-2-[(6,7difluoro-lH-indol-5-yI)oxy]-N-((4-[(4-methylpiperazin-l-yl)amino]-315 nitrophenyl }su Ifony l)benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methy]} piperazin-1-y ])-2-[(6-fluoro1 H-indo l-5-yI)oxy]-N-( {4-[(4-methy 1 piperazin-l-yl)amino]-3-nitrophenyl} sul fony l)benzam ide; tert-butyl 4-((5-(4-{(2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-]-yl]methyl}piperazin-l-yl)2-{[({4-((1-methy lpiperidin-4-yl)amino]-320 nitrophenyl} sul fony I)amino] carbonyl} phenoxy )methy I]-1, 3-thiazoI-2-ylcarbamate;

2-[(2-amino-l,3-thiazol-4-yl)methoxy]-4-(4-{(2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-lyl] methyl} pi perazin-1 -y 1 )-N-( {4-(( I -methy Ipiperidin-4-yl)amino]-3 nitrophenyl }sulfonyl)benzamide;

2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4_i4-dimethy Icyclohex-1-en-l25 yl]methyl}piperazin-l-yl)-N-( {4-((1-methy lpiperidin-4-yl)amino]-3nitropheny 1} su 1 fony 1 )benzam ide;

2-(3 -(acetyiamino)phenoxy]-4-( 4-( [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 y l]methy 1} piperazin-1 -y l)-N-( {3 -n itro-4-[( 1 -tetrahydro-2H-pyran-4-y J piperi din-4yl)amino]phenyl}sulfonyl)benzamide;

2-[(2-ch loropheny l)am ino]-4-(4- {[2-(4-chloropheny I)-4,4-di methy Icyc lohex-1 -en-1 yl] methyl} piperazin-1-yl)-N-( {3-nitro-4-[(I-tetrahydro-2H-pyran-4-y lpiperidin-4y I )amino]ph eny 1} su Ifony l)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyc!ohex-l-en-l-yl]methy I }piperazin-1-y 1)-2-((6methoxy- lH-indol-5-yl)oxy]-N-( {3-nitro-4-[( I-tetrahydro-2 H-pyran-4-ylpiper id in-435 yl)amino]phenyl}sulfonyl)benzamide;

2-[(2-amino-l,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en-lyI]methyl}piperazin-l-yl)-N-((4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl} su Ifony l)benzamide;

2-[(2-chloropheny l)am i no]-4-(4- {[2-(4-chloropheny 1)-4,4-d i methylcyclohex-1 -en-1 5 yl]methy I} piperazin-l-yl)-N-({ 4-[(l-methylpiperidin-4-yl)amino]-3n itropheny 1} su Ifony l)benzam ide;

tert-butyl 5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-1 -en- 1-yl]methyl}piperazin-1 -yl)2-( {[(4-{[3-(dimethy lam ino)propyl]amino}-3 -n itropheny l)sulfonyl]amino }carbonyl)phenoxy ]1 H-indoIe-1 -carboxylate;

2-[(2-am ino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 yl]methyl} piperazin-l-yI)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-1-yl] methyl} piperazin-1-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-[(3-nitro-4-([3-(3-oxopiperazm-l15 yl)propyl]amino}phenyl)sulfonyl]benzamide;

Trans-4-(4-{[2-(4-chIoropheny 1)-4,4-dimethyl cyclohex-1-en-l-yl] methyl} piperazin-1-y 1)-2-[(6fl uoro-1 H-indoI-5-yl )oxy] -N-( {4-[(4-morpholin-4-ylcycl ohexy l)am ino]-3 nitrophenyl }sulfonyl)benzamide;

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex~l-en-l-yl]methyl}piperazin-I-yl)-2-[(6,720 difluoro-lH-indoI-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]inethyl}piperazin-l-yl)-N-[(4-{[l(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-lH-indol-5yl)oxy]benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yI)-N-[(4-{[](cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyI)suIfonyl]-2-[(6,7-difluoro-lH-indol-5y I )oxy]benzam ide;

4-(4- {[2 -(4-chloropheny 1 )-4,4-d imethy Icyc lohex-1 -en-1 -y 1 ]methy I} pi perazin-1 -y I )-2- [(6-fluorolH-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethyl cyclohex-1 -en-t-y I] methyl} piperazin- 1-y 1)-2-((6,7difluoro-1 H-i ndol-5 -y l)oxy ] -N-[(3-n itro-4- ([3 -(3-oxopiperazin-1 y])propyl]amino}phenyl)su Ifony l]benzam ide;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -y l]methy 1} piperazin-1 -yl )-2-(( 6-fluoro35 1 H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-l-tetrahydro-2H-pyran-4-ylethyl)amino]-3nitrophenyl} su 1 fony 1 )benzamide;

4-(4-( [2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -y IJmethy I} piperazin-1 -y 1)-2- [(6- fl uorolH-indol-5-yl)oxy]-N-([4-(([4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3nitrophenyl] sulfonyl} benzamide;

2- [(6-ch 1 oro-1 H-i ndol-5-y l)oxy ] -4-(4- {[2 -(4-ch loropheny 1)-4,4-d i methy Icyc lohex-1 -en-1 5 y l]methy 1} pi perazin-1 -y 1)- N-( {3 -nitro-4- [(I -tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4- ([2-(4-ch loropheny 1)-4,4-dimethy 1 cycl ohex-1 -en-1 -y I] methy 1} piperazin-1 -y 1)-2-((6,7di fl uoro-1 H-indo 1-5 -y 1 )oxy]-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]pheny I} sulfonyl )benzam ide,

2-[(6-chl oro-1 H-indoI-5-y l)oxy]-4-(4 - {[2-(4-chloropheny 1)-4,4-d i methy Icy c lohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethy lcyclohex-1-en-l-yl] methyl} piperazin-1-y 1)-2-[(6-fl uorolH-indol-5-yl)oxy]-N-[(3-nitro-4-{[l-(l,3-thiazol-4-ylmethyl)piperidin-415 yl]afnino}phenyl)sulfonyl]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-iyl] methy I} piperazin-1 -y l)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl)sulfonyl)benzamide;

2-(4-am ino-3 -ch lorophenoxy)-4-(4- {[2-(4 -chloropheny 1)-4,4 -d imethy Icyc lohex-1 -en-1 20 yl]methyl) piperazin-1 -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy 1 Jam ino] phenyl} su 1 fonyl )benzam ide;

N- [(4- {[(4-aminotetrahydro-2H-pyran-4-y l)methy l]am ino} -3 -n itroph eny I )sulfony l]-4-(4- {[2-(4chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-[(6-fluoro-] H-indol-5yl)oxy] benzamide;

4-(4-{[2-(4-ch!oropheny 1)-4,4-dimethylcyclohex-1-en-1 -yl]methy I} piperazin-1-y 1)-2-((6-fluoro1 H-indol-5-yl)oxy]-N-[(4-{ [(3 S,4 R)-3-hydroxy-1-( 1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}3-nitrophenyl)sulfonyl]benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcycIohex-l-en-lyl]methyl} piperazin-l-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)30 3-nitrophenyl]sulfonyl} benzamide;

4-(4- {[ 2-(4-ch loropheny I )-4,4-dimethy Icyc lohex-1 -en-1 -yl] methy 1} piperazin-1 -yl)-2-[(6-fluoro1 H-indol-5-yl)oxy]-N-{ [3-nitro-4-(tetrahydro-2H-pyran-4-y lam ino)phenyl]su I fonyl} benzamide;

4-(4-{[2-(4-chl oroph eny 1)-4,4-d imethy lcyclohex-l-en-!-y I] methy I} piperazin-1-yl )-2-[(6-fl uoro1 H-in dol-5-y l)oxy ]-N-{[4-(morphQ I in-4-y lam ino)-3-nitrophenyl] sulfonyl} benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-Iyl]methyl}piperazin-l-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;

2-(2-chlorophenoxy )-4-(4-{[2-(4-chlorophenyl)-4₃4-dimethylcyclohex-1 -en-1 y l]methyl} piperazin-1 -y l)-N- [(3-n itro-4- {[3 -(3-oxopiperazin-1 yl)propyl]amino}phenyl)sulfonyl]benzamide;

2-(6-aminopyridin-3-y 1)-4-(4-{[2 -(4-chlorophenyl)-4_J4-dimethyl cyclohex- 1-en-l5 y l]methyl) piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino] phenyl }sulfonyl)benzamide;

4-(4-{1 -[2 -(4-chloropheny 1)-4,4-di methylcyclohex-1 -en-1 -y l]ethy I} piperazin-1 -yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-2-[(6-fluorolH-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-lyl)propyl]amino} phenyl )sulfony I] benzamide;

4-(4-{[2-(4-chloropheny I )-4,4-d imethy Icyclohex-1-en-l-y I] methyl} pi perazin-l-y 1)-2-((6-fl uoro1 H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-315 ylmethyl]amino}phenyl)sulfonyl]benzamide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyc lohex-1 -en-! -yl] methy 1} pi perazin-1 -y 1)-2- [(6-fluoro1 H-i ndol-5-y l)oxy] -N-[(3 -n i tro-4- {[(3 R)-tetrahydro-2H-pyran-3 ylmethyl]amino}phenyl)sulfonyl]benzamide;

tert-butyl 5-(5-(4-{[2-(4-chlorophenyl)-4.4-dimethylcyclohex-l-en-1-yl]methyl}piperazin-1-yl)20 2-{ [({3 -nitro-4-[(tetrahydro-2 H-pyran-4y Imethy I)amino] phenyl} su lfonyl)am ino]carbonyl} phenoxy )-3,4-d ihydroisoqu inoline-2( 1H)carboxylate;

2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazm-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin~425 yl)amino]phenyl}sulfonyl)benzamide;

4-(4- {(2-(4-chloropheny 1)-5,5 -dimethy 1 eye lohex-1 -en-1 -y I] methyl} p iperazin-I -y l)-2-[(6-fluorol H- indo l-5-y l)oxy ]-N -({3 -n itro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl} sulfonyl )benzam ide;

4-(4- {[2-(4-ch 1 oropheny 1)-4,4-d i methy Icyclohex-1 -en-1 -yl] methy I} pi perazin-1 -y 1)-2- ((6-fluoro30 1 H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyI)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-ch!oroph eny I )-4,4-dimethylcyc lohex-l-en-l-yl]methyl} pi perazin-1-yl )-2-[(6-fluoro] H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4y I methoxy )pheny 1] su Ifony 1} benzam ide;

2-(( 3 -chloro-1 H-indol-5 -yl)oxy] -4-(4- {[2-(4-ch 1 oropheny 1)-4,4-dimethy Icyclohex-1 -en-1 35 yl]methyl} piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(3 -chloro-1 H-indoM-y l)oxy] -4-(4- {[2-(4-chloropheny 1 )-4,4 -dimethyl eye lohex-1 -en-1 y 1] methyl} piperazin-l-yl)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4.(4. {[2-(4-chIorophenyl)-4,4-dimethy Icy clohex- 1-en-l -yl] methyl} piperazin-1 -y l)-N-( {3 -nitro-45 [(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)-2-[(2-oxo-2,3-dihydro-1 H-indol-5yl)oxy]benzamide;

4-(4-{ [2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-y!]methyl} piperazin-1-yl)-N-({3-nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyI} sulfony l)-2-[(2-oxo-2,3-dihydro-lH-indol-4yl)oxy] benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-l-yl]methyl} piperazin-1-y l)-2-[(6-fluorolH-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;

tert-butyl 5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex- 1-en-l-yl]methy 1}piperazin- 1 -y I)2- {[({3 -nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]phenyl} sul fony l)amino] carbonyl} phenoxy )pyrid in-2-ylcarbamate;

tert-butyl 4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)2- {[({3 -n i tro-4 - [ (1 -tetrahydro-2 H-pyran -4 -yl piperi din-4y l)am ino] phenyl} sulfony l)am in o]carbonyl} phenoxy )py rid in-2-ylcarbamate;

2-[(6-aminopyridin-3-yI)oxy]-4-(4-·] [2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-ly 1 ]m ethy 1} piperazin-1 -yl)-N-({3 -nitro-4- [(tetrahydro-2H-py ran-4 20 y I methy I)am ino] phenyl }su Ifony l)benzam ide;

2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly I]methyl} piperazin-1-yl)-N-( {3-nitro-4-[(l-tetrahydro-2H-pyran-4-y Ip iperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-[(5-bromopyridin-3-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l25 y l]methy 1} pi perazin-1 -y l)-N-( {3 -n i tro-4-[(tetrahydro-2 H-py ran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-chloro-1 H-indol-5-y I)oxy ] -4-(4- {[ 4-( 4-ch lorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran3-yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y 1 methy 1 )am ino]pheny 1} su I fony 1 )benzamide;

2-[(6-chloro-1 H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-ly l]methy 1} p i perazin-1 -y I )-N-( {3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino] phenyl] sulfony I )benzam ide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-1-y 1)-2-((6fl uoro-1 H-indol-5 -y l)oxy ] -N-( {3 -n itro-4- [(tetrahydro-2 H-pyran-435 ylmethyl)amino]phenyl}sulfonyl)benzamide;

tert-butyl 5-(5-(4-{[2-(4-chloropheny 1)-4,4-dimethyIcyclohex-1-en-1-yl]methyI}piperazin-1-yΟΙ- {[({3-nitro-4-[(tetrahydro-2H-pyran-4y 1 methy l)amino] phenyl} su lfonyl)amino]carbonyl} phenoxy )pyridin-3-yl carbamate;

2-[(5-aminopyridin-3-yI)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-]5 yI]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

tert-buty I 4-(5-(4- {[2-(4-ch loropheny I )-4,4-dimethyl eye lohex-1 -en-1 -yl]methy 1} piperazin- 1 -y 1)2- {[({3 -nitro-4-[(tetrahy dro-2 H-pyran-4ylmethyl)ainino]phenyl}sulfonyl)amino]carbonyl} phenoxy )pyridin-2-yIcarbamate;

2- [(3 -ch loro-1 H-indol-5-y l)oxy]-4-(4- {[2-(4-chl oropheny 1 )-4,4-d imethy 1 eye lohex- 1-en-ly l]methy 1} piperazin-1 -yl)-N-({ 3-nitro-4-[( 1 -tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl)sulfonyl)benzamide;

2-[(2-atninopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4_!4-dimethylcyclohex-l-en-lyl]methyl) piperazin-i-yl)-N-( {3-nitro-4-[(tetrahydro-2H-pyran-415 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-( [2-( 4-chloropheny 1)-4,4-d imethy Icy clohex-1 -en-1 -yl]methyl} piperazin-l-yl)-2-[(6hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y 1 methy l)am ino] phenyl} su lfonyl)benzam ide;

2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l20 yl]methyl}piperazin-I-yl)-N-({3-n!tro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4- {[2 -(4-chloropheny I )-4,4-di methy Icy c lohex-1 -en-1 -yl] methy 1} piperazin-1 -yl)-N-{[4-(l,4dioxan-2-ylmethoxy)-3-nitrophenyl]sulfbnyl}-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide;

2-((3 -chloro-1 H-indo!-4-yl)oxy]-4-(4-{[2 -(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 25 yl]methyI}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {[2-(4-chIoropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -y 1] met hy 1} piperazin-1 -y I )-N-( {4-[(4methy lpiperazin-1-y l)amino]-3-nitrophenyl} sulfonyl )-2-[(2-oxo-2,3-dihydro-IH-indo 1-4yl)oxy]benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-di methy Icyc lohex-1 -en-1 -y I] methyl} pi perazin-1 -y l)-N-( {4-[( 1 methylpiperidin-4-yl)amino]-3-nitrophenyl }sulfonyl)-2-[(2-oxo-2,3-dihydro- lH-indol-4y l)oxy]benzam ide;

4-(4- {[2-(4 -ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -y 1] met hy I} piperazin-1 -y l)-N-( {3 -nitro-4[(l-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny I }sulfony l)-2-[(2-oxo-2,3-dihydro-1H35 indo 1-4-yl)oxy]benzam ide;

2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-lyl]methyl}piperazin-l-yl)-N-{[4-(l,4-dioxan-2-ylmethoxy)-3-nitrophenyl]suIfonyl}benzamide; 2-[(6-chIoro-lH-indol-5-yl)oxy]-4-(4-([2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-lyl]methyl}piperazin-l-yl)-N-( (4-(( l,4-dioxan-2-ylmethyl)amino]-35 nitrophenyl} su Ifony l)benzam ide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y I] methy 1} piperazin- l-yl)-N-({4-[(l,4dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-((6-fluoro-lH-indol-5-yl)oxv]benzamide;

Trans-2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-]yl]methyl}piperazin-I-yI)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-310 nitrophenyl} sul fony l)benzam ide;

Trans-2-((6-ch loro-lH-indol-5-yi)oxy]-4-(4-{[4-(4-ch loropheny 1)-6,6-d imethy 1-5,6-dihydro-2Hpyran-3-yI]methyl} piperazin-l-yI)-N-({4-[(4-morpholin-4-ylcycIohexyl)amino]-3nitrophenyl} su lfonyl)benzam ide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(615 fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{(2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-y I] methyl} piperazin-l-yl)-2-[(6-fluoro1H -indo 1-5 -yl)oxy]-N -({4- [(4-fl uorotetrahydro-2H-py ran-4-y 1 )methoxy]-3 nitrophenyl} sulfonyl)benzamide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-l-yl)-2-[(6f]uoro-lH-indol-5-yl)oxy]-N-({4-[(4-f]uorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl} sul fony l)benzam ide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-]-yl)-N{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyI}-2-[(6-fluoro-lH-indoI-525 yl)oxy] benzamide;

2-((3-(2 -am inoethyl)-1 H-indol-5 -y l]oxy} -4-(4 - {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -enl-yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-{[3-(2-ammoethyl)-lH-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyciohex-l-en30 l-yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yI)amino]-3nitrophenyl}su Ifony l)benzamide;

4-(4 - {[2-(4-ch lorophenyl)-4,4-dimethy Icyclohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1)-N- {(5 -cyano6-(tetrahydro-2 H-py ran-4-y lmethoxy)pyridin-3 -y l]su Ifony 1} -2- [(6-fl uoro-1 H-indol-5 yl)oxy] benzamide;

2-[(6-am ino-5-fl uoropyridin-3 -y l)oxy] -4-(4-{ [2-(4-ch 1 oropheny 1 )-4,4-dimethy Icy clohex- 1-en-lyl]methyl)piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl)su Ifony l)benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-1-yljmethy I) piperazin-l-yI)-N-{[5-chloro5 6-( tetrahydro-2 H-pyran-4-yl meth oxy )pyrid in-3-yl] sulfonyl) -2-[(6-fluoro-1 H-indo 1-5yl)oxy]benzamide;

Trans-4-(4-{[2-(4-chloropheny 1)-4,4-di methy Icyclohex-1 -en-l-y I] methyl) piperazin-l-yl)-N-({4[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl)sulfonyl)-2-[( 1-oxo-1,2,3,4tetrahydroisoquinoIin-5-yI)oxy]benzamide;

4-(4- {[2-(4 -ch loropheny 1)-4,4-d imethy Icycl ohex-1 -en- ] -yl] methyl} piperazin-1 -yI)-N- {[5-cy ano6-( 1,4-d ioxan-2-ylmethoxy )pyridin-3 -y IJsulfony 1} -2- [(6-fluoro-1 H-indo l-5-yl)oxy] benzam ide; N-{[5-bromo-6-( 1,4-d ioxan-2-y Imethoxy )py ridin-3 -y I ] sulfonyl} -4-(4- {[2-(4-chlorophenyl)-4,4dimethylcyclohex-1 -en-1 -yl]methyl)piperazin-1 -yl )-2-[(6-fluoro-1H-indo 1-5-yl)oxy] benzam ide; T rans-N-( {5-bromo-6- [(4-morphol in-4-y Icy c lohexy I )amino]pyridin-3-y I} sul fony 1 )-4-(4- {[2 -(415 chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yI]methy]}pipeFazin-l-yl)-2-[(6-fluoTO-lH-mdol-5yl)oxy]benzamide;

4-( 4- {[2-(4-chloropheny 1)-4,4-d i methylcyclohex-1 -en-1 -yl ] methy 1} piperazin-1 -y l)-N-( {5 -cyano6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl)sulfonyl)-2-[(6-fluoro-lH-indol-5yl)oxy] benzamide;

2-(3-amino-5-chlorophenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy ley clohex-1-en-1y!]methyl}piperazin-l-yI)-N-((3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl)sulfonyl)benzamide;

4-(4-{[2 -(4-chlorophenyl)-4,4-dimethyIcyclohex-l -en-1 -yl]methyl) piperazin-]-yl)-N-{ [5-cyano6-(2-morpho I in-4-y lethoxy)pyridin-3 -yl]su Ifony 1} -2-[(6-fluoro-1 H-i ndol-5-yl)oxy] benzam ide;

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl cyclohex-l-en-l~yl] methyl) piperazin-1-y 1)-2-((6fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3n itropheny 1} sulfony l)benzamide;

N -({5 - bromo-6-[( 1 -tetrahydro-2H-pyran-4-y lpiperidin-4-y 1 )amino] pyridin-3 -y 1} sul fony 1)-4-(4{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yl]methyl} piperazin-1 -yI)-2-[(6-fluoro-1H30 indol-5-yl)oxy] benzamide;

4-(4-{[2-(4-ch!oropheny 1)-4,4-dimethylcyclohex-l-en-l-ylJmethyl} piperazin-l-yl)-N-({4-[(4fluorotetr ahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl) su I fony l)-2-[(2-ox o-2,3-d ihydro-lHindol-4-yl)oxy] benzamide;

Trans-2-[(6-ch!oro-l H-mdol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-435 yljmethy I) piperazin- l-yl)-N-( {4-[(4-morpholin-4-y lcyclohexyl)amino]-3[(trifluoromethyl)sulfonyl]phenyl)sulfonyl)benzamide;

Trans-2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4yl]methyl} piperazin-l-yl)-N-({4-[(4-morpholin-4-ylcyclohexy!)amino]-3n itropheny 1} sul fony l)benzamide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yI]methyl} piperazin-1-y l)-2-[(6fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl} sulfony I )benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-! -yl] methyl} piperazin-1 -yl)-2-[(6-fIuorolH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide; 2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyljmethyl} piperazin-1 -yl)-N-( {3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-]-yl]methy I }piperazin-l-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-[(4-{[l-(methylsulfonyl)piperidin-4-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

T rans-4-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyc 1 ohex-1 -en-1 -y 1] methy 1} p i perazin-1 -y l)-N-( {4[(4-morpho I in-4-ylcyclohexyl)amino]-3-nitrophenyl} sulfonyI)-2-[(2-oxo-2,3-dihydro-lH-indol-4yi)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl) piperazin-1-yl)-N-({4-[(2methoxyethy I )am i no]-3 -n itropheny I} sulfony l)-2-[(2-oxo-2,3 -dihydro-1 H-indo 1-4yl)oxy] benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-d i methy Icyclohex-1 -en-1 -y 1] methy 1} piperazin-1 -y 1)-N- {[5ethyny l-6-(tetrahydro-2 H-pyran-4-y Imethoxy )pyrid in-3-y l]s u Ifony 1} -2-[(6-fluoro- lH-indol-5yl)oxy] benzamide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-l-yl)-N{[5-ethynyI-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-lH-indol-5yl)oxy]benzamide;

Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-I“ en-l-yl]methyl} piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3n itropheny!} sulfony IJbenzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-diinethylcycIohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({5-cyano6-[(l-tetrahydro-2H-pyran-4-y Ipiperid in-4-yl)oxy]pyrid in-3-y I} su I fony 1)-2-[(6-fluoro-lH-indol5-yl)oxy] benzamide;

N-( {5 -ch loro-6- [(4-fluorotetrahydro-2 H-pyran-4-y l)methoxy]pyridin-3 -yl} sulfony 1 )-4-(4- {[2-(4ch loropheny 1)-4,4-d imethy Icyclohex-1-en-1-yl] methy l}piperazin-!-y 1)-2-[(6-fluoro-l H-indo 1-5y 1 )oxy ]benzam ide;

4-(4- {[2 -(4-chloropheny I)-4,4-d imethy Icy clohex-1 -en-1 -yl] methy I} pi perazin-1 -y l)-N-( {4-((1cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-l H-indol-5yl)oxy]benzamide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyclohex-1 -en-1 -y l]methy 1} piperazin-1 -y 1 )-N-( {4- [(4 5 ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-l H-indol-5yl)oxy]benzamide;

4-(4-{[2-(4-ch loropheny l)-4,4-d imethy Icyc lohex-l-en-l-yl] methy 1} piperazin-1-y 1)-2-((6-fluorolH-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-l-tetrahydro-2H-pyran-4-ylpiperidin-3yl]amino}phenyl)sulfonyl]benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-lyijmethyl} piperazin-l-yl)-N-({4-[(4-fluorotetrahydro-2H-pyTan-4-yl)methoxy]-3nitrophenyl }su Ifony l)benzamide;

4-(4- {[2-(4-ch 1 orophenyl )-4,4-d imethy Icyclohex-1 -en-1 -y I] methy 1} piperazin-1 -y l)-N-( {4- [(1,1 d ioxidoth iomorpholin-4-yl)amino] -3 -nitropheny 1} sulfony l)-2-[(6-fl uoro-1 H-indo 1-5 15 y l)o xy] benzamide;

4-(4-{[2-(4-chIorophenyl)-4,4-dimethy Icyclohex-1-en-l-yijmethyl} piperazin-l-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3ylmethyl)amino]phenyl}sulfonyl)benzamide;

T rans-N-( {5 -bromo-6-[(4-morpho I in-4-y Icyclohexy 1 )oxy ] pyridin-3 -y 1} sulfony 1)-4-(4- {[2 -(420 ch lorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-2-[(6-fluoro-lH-indol-5y I )oxy] benzamide;

Trans-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icy clohex-1-en-1-yijmethyl} piperazin-l-yI)-N-[(4{[4-(dicyclopropylainino)cyclohexyl]amino}-3-nitrophenyl)sulfonylJ-2-[(6-fluoro-lH-indol-5y[)oxy]benzamide;

Trans-4-(4-{ [2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-l-en-1 -yl]methyl) piperazin- l-yl)-2-[(6fl uoro-1 H-indol-5 -yl)oxy] -N-[(3 -nitro-4- {[4-(tetrahy dro-2H-pyran-4ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;

Trans-4-(4- {[2-(4-chiorophenyl )-4,4-d imethylcyclohex-] -en-1 -yijmethyl} piperazin-1 -y 1)-2-((6fl uoro-1H- i ndo 1-5 -y l)oxy ]-N-[(3 -nitro-4- {[4-(4-tetrahydro-2H-pyran-4-y Ipiperazin-1 30 y 1 )cyclohexy l]ami no }phenyl)sulfony I] benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy Icyc I ohex-1 -en-1 -y l]methy 1} pi perazin-1 -y 1 )-2-(( 6-fluoro1 H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3n itropheny l)su Ifony l]benzam ide;

Trans-4-(4-{[2-( 4-chloropheny 1)-4,4-d imethy ley c lohex-l-en-1-y I] m ethy 1} piperazin-1-y 1)-2-[(635 fluoro-lH-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3nitrophenyl)su Ifony l]benzamide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-1-y 1)-2-({3-[3(d imethy lamino)propyl] -1 H-indo 1-4-yl} oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-({3-[35 (dimethylamino)propyl]-l H-indo l-4-yl} oxy )-N-( {4-[(4-methylpiperazin-1-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({4-[(lcy c 1 opropy 1-4-fluoropiperid in-4-y l)methoxy] -3-nitropheny 1} sulfonyl )-2-(( 6-fluoro-1 H-indo 1-5 yl)oxy]benzamide;

4-( 4. {[2-(4-chloropheny 1)-4,4-d imethy lcyclohex-1-en-1-y I] methyl} piperazin-1-y 1)-2-{[ 1-(4m ethoxy benzyl)-1H-1,2,3 -benzotriazol -4-y I]oxy} -N-( {3 -n itro-4-[(tetrahydro-2H-py ran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly I]methy 1} piperazin-1 -y l)-N-( {4- [(4-methy Ipi perazin-1 -y l)amino]-3 - nitrophenyl}sulfonyl)benzamide;

2-[(6-amino-5-chIoropyridin-3-yl)oxy]-4-(4-{[2-(4-chIorophenyl)-4₁4-dimethyicyclohex-l-en-lyl] methy 1} p iperazin-1 -y 1)-N- {(4-( 1,4-dioxan-2-y I methoxy)-3 -nitropheny l]su Ifony I} benzam ide;

Trans-2-[( 6-amino-5-chloropyrid in-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icycloh ex-1en-1 -yl]methyl} piperazin- l-yl)-N-((4-{ [(4-methoxycyclohexyl)methyl]amino}-3- nitrophenyl)sulfonyl] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{(2-(4-chloropheny 1)-4,4-dimethyIcyclohex-l-en-lyljmethy 1} piperazin-1 -y l)-N-( {4-((1,4-dioxan-2-y I methy l)amino] -3 n itro phenyl} sul fony l)ben zam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l25 yl]methyl}piperazin-l-yl)-N-({4-[(3-morphoIin-4-ylpropyl)amino]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzaniide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly I] methy 1} piperazin-1 -yl)-N-( {4-[(4-fluorotetrahydro-2H-pyran-4-y l)methoxy] -3 [(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridm-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclobex-l-en-lyl]methyl} piperazin-l-yl)benzamide;

2-[(6-amino-5-bromopyridm-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy lcyclohex-l-en-1y I] methy 1} piperazin-1 -y l)-N-( {3 -n itro-4- ((tetrahydro-2 H-pyran-4 - ylmethyl)amino]phenyl} sul fony l)benzam ide;

2-am ino-5-(5-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-l-y IJmethy I Ipiperazin-1-y 1)-2{[({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)animo]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide;

2-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethyIcyclohex- 1-en-1 5 yl]methyl} piperazin-1 -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino] phenyl} sulfony l)benzamide;

2-[(6-am ino- 5-chloropyridin-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icy c lohex- 1 -en-1 y I] methy I} piperazin-1 -y l)-N-[(4- {[(3 R)-1 -(2,2-d i fl uoroethy l)pyrrolidin-3 -y I Jamino} -3 nitrophenyl)sulfonyl]benzamide;

2-[(6-am ino-5 -ch 1 oropyridin-3 -y l)oxy ]-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-3[(trifluoromethyl)su!fonyl]phenyl)sulfonyl)benzamide;

2-{[6-(acetylamino)pyri din-3-y I ]oxy )-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-l-en-lyl]methyl) piperazin-1 -yl)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-415 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc!ohex-l-en-l-yl]methyl)piperazin-l-yl)-2-({6[(methy lsulfonyl)amino]pyridin-3-yl} oxy )-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)ammo]phenyl)5ulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 -en-1 -yl]methyl) piperazin- l-yl)-N-{ [4-( {(3R)20 ]-[2-f1uoro-l -(fluoromethyl)ethyl]pyrrol id in-3-yl) amino )-3-nitrophenyl]sul fonyl)-2-[(6-fl uorolH-indol-5-yI)oxy]benzamide;

2-[(6-amino-5-chloropyridin-3-y])oxy]-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en-lyl]methyl)piperazin-l-yl)-N-({4-[(l-cyclopropylpiperidin-4-yl)amino]-3nitrophenyl} sulfony l)benzam ide;

5 2-[(6-amino-5-bromopyridin-3 -yl)oxy] -4-(4- {[2-(4-chloropheny 1 )-4,4 -d imethy Icyc lohex-1 -en-1 yl] methyl) piperazin-l-yl)-N-({ 4-[(4-meth yip iperazin-l-y l)amino]-3nitropheny 1} su Ifony l)benzam ide;

2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-330 nitrophenyl} sulfony l)benzamide;

2-[(6-am ino-5 -bromopyrid in-3 -y l)oxy]-4-(4-{ [2-(4-chloropheny 1 )-4,4-d i methylcyclohex-1 -en-1 y I]methy]} piperazin-l-yI)-N-({4-[( l,4-dioxan-2-y Imethy l)am ino]-3nitrophenyl} sulfony l)benzamide:

2-[(6-amino-5-methy Ipyrid in-3 -yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-d imethy Icyc lohex- l-en-l 35 y l]methyl} piperazin-l-yl)-N-({ 3-n itro-4-[(tetrahydro-2H-py ran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridm-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-lyl]methyl} piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3nitrophenyl)sulfonyl] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l5 yl]methyl} piperazin-l-yl)-N-({3-nitro-4-[(l-oxetan-3-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en1-yljmethy I} piperazin-1-yl)-N-( {3-nitro-4-[(tetrahy dro-2H-pyran-4ylmethy l)amino] phenyl} sulfonyl )benzamide;

2-[(6-am ino-5 -eye 1 opropy Ipyrid in-3 -y 1 )oxy] -4 -(4- {[2-(4-ch loropheny 1)-4,4-di methy Icyclohex-1 en-l-yl]methyl] piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl )amino]phenyl} sulfonyl)benzamide;

Trans-2-[(6-amino-5-biOmopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-len-l-yl]methyl} piperazin-l-yl)-N-[(4-{[(4-methoxycyciohexyl)methyl]amino}-315 nitrophenyl)sulfonyl]benzamide;

4-( 4-{[2-(4-chloropheny l)-4,4-d imethy Icyclohex-1-en-l-yl] methyl} piperazin-1-y I )-2-[(3-methyl2-oxo-2,3-dihydro-1 H-benzimidazol-4-yl)oxy]-N-( {3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl} sulfonyl )benzam ide;

2-[(6-am ino-5 -ch loropyridin-3 -y l)oxy ]-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icy c lohex-1 -en-1 20 yl]methyl) piperazin-]-yl)-N-[(4-{[(4-cyclopropylmorpho!in-2-yl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex- 1-en-lyl] methyl} piperazin- 1-y I)-N-[(4-{ [(3 R)-l -cyclopropylpyrrol id in-3 -yl]amino} -3nitrophenyl)sulfonyl]benzamide;

2- [(6-amino-5 -ch 1 oropyridin-3 -y I)oxy]-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyc 1 ohex- 1-en-lyl]methy!}piperazin-l-yl)-N-{[4-({4-fluoro-l-[2-fluoro-l-(fluoromethyl)ethyl]piperidin-4yl}methoxy)-3-nitrophenyl]sulfonyl}benzamide;

tert-butyl 6-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-l-en-iyl]methyl} piperazin-1-y I)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-430 y[methyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridm-2-ylcarbamate;

tert-butyl 4-( 5-(4-((2-(4-chloropheny 1)-4,4-d imethyIcyclohex-l-enyl)methyl)piperazin-1-y I )-2-(3nitro-4-((tetrahydro-2H-pyran-4-yl)metbylarnino)phenylsulfonylcarbamoyl)phenoxy)pyridme2,6-diyldicarbamate;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-1-y I] methyl} piperazin-1-y 1)-2-{[63 5 (eye 1 opropylam ino)pyridin-3 -y l]oxy } -N-( {3 -nitro-4 -[(tetrahydro-2 H-pyran-4 y Imethy l)amino] phenyl} su lfonyl)benzam ide;

Trans-4-(4-{ [2-(4-chlorophenyl)-4.4-dimethy Icyclohex-1-en-l-yljmethyl} piperazin-l-y 1)-2-({6[(2,2-d ifluoroethy l)am ino]pyridin -3 -y 1} oxy )-N-[(4- {[(4-methoxy cyclohexy l)methy l]am ino} -3 nitrophenyl)sulfonyl]benzaniide;

4-(4- {[2-(4-ch loropheny I )-4,4-d imethy Icyclohex-1 -en-1 -yl] methy I} piperazin-1 -y 1 )-2-( {6-[(2,25 d ifluoroethy I )am ino]pyridin-3 -y 1} oxy)-N-( {3 -n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-([2-(4-chlorophenyl)-4₎4dimethylcyclohex-l-en-I -yljmethyl} piperazin-l -y!)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2- [(6-am ino-5-chloropyridin-3 -y l)oxy]-4-(4- {[2 -(4-chloropheny 1)-4,4 -d imethy 1 cyclohex-1 -en-1 yl}methyI}piperazin-l-yl)-N-({4-[({4-[2-fluoro-l-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-lyljmethyl} piperazin-l -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-415 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-i-yl]methyl }piperazin-1 -yl)-2-[(2,6diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)aTnino]phenyl}sulfonyl)benzamide;

2- [(6-am ino-5 -ch loropyridin-3 -y l)oxy] -4-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyclohex-I -en-1 20 yljmethyl }piperazin-1 -yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4yl meth oxy)phenyl] sulfonyl} benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1-en-lyl]methyl}piperazin-l-yl)-N-{[4-({(3R)-l-[2-f]uoiO-l-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyI]sulfbnyl}benzamide;

tert-butyl 5-bromo-4-(5-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-I-en-l yl ]methy 1} piperazin-1 -yl )-2- {[({3 -n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}suIfonyl)ammo]carbonyl}phenoxy)pyridm-2-ylcarbamate;

4-(4-{ [2-(4-chlorophenyl)-4_J4-dimethylcyclohex-1 -en-1 -yl]methy 1} piperazin-1 -yl)-2-[(4-chloro1 H-pyrrolo [2,3 -b]pyridin-5 -y l)oxy]-N-( {3 -nitro-4-[(tetrahydro-2 H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-[[2-(4-ch loropheny 1)-4,4-d imethy icyclohex-1-en-l-yl J methy 1} piperazin-l-y))-N-({ 3-nitro-4[ (tetrahydro-2H-pyran-4-y I methy l)am ino] pheny I} sulfony I )-2 -({6-[(2,2,2trif!uoroethyl)amino]pyridin-3-yl}oxy)benzamide;

2-[(6-am ino-5-chloropyridin-3-yl)oxy 1-4-(4-{[2-(4-chloropheny 1)-4,4 -dimethy Icyclohex- 1-en-l 3 5 yljmethyl} piperazin-1 -yl)-N-[(4- {[(4-hydroxycyclohexyl)methyI]ammo} -3nitrophenyl)sulfonyl]benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2Hpyran-3 -y I] methy I} p iperazin-1 -y l)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]phenyl}sulfonyl)benzam ide;

N-({5-ch loro-6-[(4-fl uorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl} sulfonyl )-4-(4-{[4-(45 chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyI}piperazin-l-yl)-2-[(6-fluoro-lHindol-5-yl)oxy]benzamide;

2-[(6-am ino-5-chloropyrid in-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en-1y 1 ] methy 1} piperazin-1 -y 1)-N -({3 -ni tro-4-[(tetrahydrofuran-3 y Imethy l)amino]phenyl) sulfony l)benzam ide;

2- [(6-am ίηο-5-ch I oropyridi n-3 -y 1 )oxy ] -N-( { 5 -ch loro-6- [(4-fluorotetrahydro-2H-pyran-4 yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6.6-dimethyl-5,6-dihydro-2Hpyran-3-yl]methyl} piperazin-l-yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-I(fluoromethy l)ethy 1 ] - 3 -azaspiro[5,5]undec-8-en-8-y 1} methy 1 )piperazin-1 -y I ]-N-( { 3 -nitro-415 [(tetrahydro-2H-pyran-4-y Imethy] )am ino]pheny 1} sulfony l)benzamide;

2-[( 6-am ino-5-chloropyrid in-3-yl)oxy]-4-(4-{ [9-(4-ch loropheny 1)-3-isopropy 1-3azaspiro[5.5] undec- 8 -en - 8-y l]methy 1} piperazin-1 -y I )-N-( {3 -nitro-4-[(tetrahy dro-2H-pyran-4 ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-am ino-5 -ch loropyridin-3 -y 1 )oxy]-N-[(5 -chloro-6- {[ 1 -(N,N-d imethy Iglycy 1)-420 fl uoropiperidin-4-yl]methoxy}pyrid in-3-yl)sulfony I]-4-(4-{[2-(4-ch loropheny 1)-4,4dimethy Icyc lohex-1 -en-1-yl] methyl} piperazin-1 -yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en-1 y l]methy)} piperazin-l-yl)-N-{ [4-( {(3 R)-l-[2-fluoro-1-( fluoromethy l)ethy l]pyrrolidin-3y]}amino)-3-nitrophenyl]sulfonyl} benzamide;

2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en-lyl]methy 1} piperazi π-1 -y l)-N-( {3 -n itro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly 1 ] methy 1} piperazi η-1 -y I)-N-[(4- {[(4,4-d i fluorocyc lohexy l)methy IJam too} -3 30 nitrophenyl )sulfonyl] benzamide;

- [(6-am ino-5 -ch loropyri din -3 -y I)oxy]-4-[4-( {4'-ch loro-3 - [2-(dimethy lamino)ethoxy] -1, Γb i pheny 1-2-y I} methy l)p iperazin-1 -y I]-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)ammo]phenyl} sulfony l)benzamide;

- [(6-amino-5 -ch 1 oropyrid in-3 -y l)oxy]-N- {[5 -ch loro-6-( {(3 R)-1 - [2-fluoro-1 35 (fluoromethy l)ethyl]pyrrolidi n-3-yl] methoxy )pyridin-3-yl]sulfony I)-4-(4-{[2-(4-chioropheny 1)4,4-dimethylcyclohex-1 -en-1 -yljmethyl }piperazin-1 -yl)benzamide;

2-[(6-am ino-5-chloropyridin-3 -yl)oxy]-N-[(5 -chi oro-6- {[(3 R)-1 -(2,2-di fluoroethy Qpyrrol id in-3 y I] methoxy }pyrid in-3-yl)su!fonyl]-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyc I ohex-l-en-1yl]methyl}piperazin-1 -yl)benzamide;

Trans-2- [(6-amino-5 -ch I oropyrid in-3 -yl)oxy]-4-(4- {[2 -(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 5 en-1 -yl] methyl} pi perazin-1 -yl )-N-[(4- {[(4-cyanocyclohexy l)methy l]am ino}-3nitrophenyl)sul fony 1] benzamide;

2-[(6-am ino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d imethy Icyclohex-1 -en-1 y I] methyl} piperazin-1 -y I )-N-( {5-fluoro-6-[(4-fl uorotetrahydro-2H-pyran-4-y l)methoxy]pyri din3-yl}sulfonyl)benzamide,

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[l-(2,2-difluoroethyl)-4-fluoropiperidir)4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc[ohex-l-en-lyl]methyl} piperazin-1 -yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-l15 yl]methyl}piperazin-l -yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-ch!orophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-1-y l)-N-{ [6-( {4-fluoro-l-[2-fluoro-l-(fluoromethyl)ethyl]piperidin-4y 1} methoxy )-5 -(trifl uoromethy I )py rid in-3 -y 1] su 1 fony 1} benzamide;

4-(4- {[2-(4-ch loropheny I )-4,4-di methy Icy c lohex-1 -en-1 -y l]methy 1} pi perazin-1 -y 1 )-N-( {3 -n itro-420 [(tetrahydro-2H-py ran-4-y Imethy l)amino] phenyl} sulfony 1) - 2 - [ 2 -(1 H-pyrazo 1-4yl)phenoxy]benzamide;

2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycIohex-l-en-lyl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y lmethyl)amino]pheny 1} sulfonyl )benzamide;

5 4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y 1] methyl} piperazin-1 -y 1 )-N-( {3 -nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(lH-pyrazol-5yl )phenoxy] benzamide;

2-[(6-amino-5-chloropyridm-3-yl)oxy]-N-((5-chloro-6-((4,4difluorocyclohexy 1 )methoxy]pyrid ΐη-3 -yl} su 1 fony 1)-4-(4- {[2-(4-chl oropheny 1)-4,430 dimethylcyclohex-1 -en-l-yl]methyl} piperazin-1 -yl)benzamide;

N-({5-chloro-6-[(4,4-difluorocyc I ohexyl)methoxy]pyrid in-3-yl}sul fony l)-4-(4-{ [4-(4chloropheny 1)-6,6-dimethy 1-5,6-dih ydro-2H-pyran-3 -yl ] methy I} pi perazin-1 -y 1)-2- [ (6-fluoro-1Hindol-5-y I )oxy] benzamide;

4-(4- {[2 -(4-ch loropheny I )-4,4-dimethy Icy clohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1 )-N- [(4- {[(4,435 d ifluorocyclohexyl)methy I] amino}-3-n itropheny l)su!fonyl]-2-[(6-fluoro-IH-indo I-5yl)oxy]benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

Still another embodiment pertains to 2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yIJmethyl} piperazin-l-yl)-N-({3-nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

Another embodiment pertains to a composition for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, 10 oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of the compound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, 15 esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of Formula (I).

Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, 25 prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (1) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.

It is meant to be understood that proper valences are maintained for all moieties and combinations thereof, that monovalent moieties having more than one atom are drawn from left to right and are attached through their left ends, and that divalent moieties are also drawn from left 35 to right.

It is also meant to be understood that a specific embodiment of a variable moiety herein may be the same or different as another specific embodiment having the same identifier.

The term alkenyl as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The 5 term “C_x-Cy alkyl” means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond containing x to y carbon atoms. The term “C₂-C4 alkenyl” means an alkenyl group containing 2-4 carbon atoms. Representative examples of alkenyl include, but are not limited to buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyI, 5-hexenyl, 2-heptenyl, 2-methy 1-1 -heptenyl, and 3-decenyl.

The term alkenylene means a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double bond. The term “Cx-Cy alkylene” means a a divalent group derived from a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and containing x to y carbon atoms. Representative examples of alkenylene include, but are not limited to, -CH=CH- and

-CH₂CH=CH-.

The term alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term “Cx-C_y alkyl” means a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms. For example “Cj-Cio alkyl” means a straight or branched chain, saturated hydrocarbon containing 2 to 10 carbon 20 atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, nbutyl, sec-butyl, iso-butyl, tert-butyl, π-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyi, 2,2dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, π-nonyl, and n-decyl.

The term alkylene means a divalent group derived from a straight or branched, saturated hydrocarbon chain of 1 to 10 carbon atoms, for example, of 1 to 4 carbon atoms. The 25 term “C_x-Cy alkylene” means a divalent group derived from a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms. For example “C₂-Ce alkylene means a straight or branched chain, saturated hydrocarbon containing 2 to 6 carbon atoms. Examples of alkylene include, but are not limited to, -CH₃-, -CH₃CH₃-, -CH₂CH₂CH₃-, -CH₃CH₃CH₃CH₂-, and -CH₂CH(CH₃)CH_r.

The term alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. The term “Cx-Cy alkynyl” means a straight or branched chain hydrocarbon group containing from x to y carbon atoms. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term alkynylene, as used herein, means a divalent radical derived from a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.

The term aryl as used herein, means phenyl.

The term cyclic moiety, as used herein, means benzene, phenyl, phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene, cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl, cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term cycloalkylene or cycloalkyl or “cycloalkane” as used herein, means a monocyclic or bridged hydrocarbon ring system. The monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds.

Examples of monocy'clic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two ηοπ-adjacent carbon atoms of the ring system. Non-limiting examples of such bridged cycloalkyl ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2,2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3J]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.0³’⁷]nonane (octahydro-2,5methanopentalene or noradamantane), and tricyclo[3.3.1.1^3,7 ] decane (adamantane). The monocyclic and bridged cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term cycloalkenylene, or cycloalkenyl or “cycloalkene” as used herein, means a monocyclic or a bridged hydrocarbon ring system. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The monocyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems.

The term cycloalkyne, or cycloalkynyl, or cycloalkynylene, as used herein, means a 35 monocyclic or a bridged hydrocarbon ring system, The monocyclic cycloalkynyl has eight or more carbon atoms, zero heteroatoms, and one or more triple bonds. The monocyclic cycloalkynyl ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. The monocyclic and bridged cycloalkynyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems.

The term heteroarene, or heteroaryl, or heteroarylene, as used herein, means a five- membered or six-membered aromatic ring having at least one carbon atom and one or more than one independently selected nitrogen, oxygen or sulfur atom. The heteroarenes of this invention are connected through any adjacent atoms in the ring, provided that proper valences are maintained. Representative examples of heteroaryl include, but are not limited to, furanyl (including, but not limited thereto, furan-2-yl), imidazolyl (including, but not limited thereto, 1Himidazol-l-yl), isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyI (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl (including, but not limited thereto, thien-2-yl, thien-3-yl), triazolyl, and triazinyl.

The term heterocycloalkane, or heterocycloalkyl, or heterocycloalkylene, as used herein, means monocyclic or bridged three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of Ο, N, and S and zero double bonds. The monocyclic and bridged heterocycloalkane are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom 20 contained within the rings. The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quartemized. Representative examples of heterocyc ioalkane groups include, but are not limited to, Representative examples of heterocycloalkane groups include, but are not limited to, morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl, diazepanyl, dithiolanyl, dithiany 1, isoxazolidinyl, isothiazolidinyl, oxadiazo lidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, and trithianyl,

The term heterocycloalkene, or heterocycloalkenyl, or heterocycloalkenylene, as 30 used herein, means monocyclic or bridged three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of Ο, N, and S and one or more double bonds. The monocyclic and bridged heterocycloalkene are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the rings. The nitrogen and sulfur heteroatoms in 35 the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quartemized. Representative examples of heterocycloalkene groups include, but are not limited to, tetrahydrooxociny!, 1,4,5,6-tetrahydropyridazinyl, 1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazo liny 1, isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl, thiadiazolinyI, thiazolinyl, and thiopyranyi.

The term phenylene, as used herein, means a divalent radical formed by removal of a 5 hydrogen atom from phenyl.

The term spiroalkyl, as used herein, means alkylene, both ends of which are attached to the same carbon atom and is exemplified by C₂-spiroalkyl, Cj-spiroalkyl, Ci-spiroalkyl, C₅-spiroalkyl, C₆-spiroalkyl, C₇-spiroalkyl, Cg-spiroalkyl, Cj-spiroalkyl and the like.

The term spiroheteroalkyl, as used herein, means spiroalkyl having one or two CIT 10 moieties replaced with independently selected 0, C(O), CNOH, CNOCHj, S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replaced with N.

The term spiroheteroalkenyl, as used herein, means spiroalkenyl having one or two CH₂moieties replaced with independently selected O, C(0), CNOH. CNOCH₃, S, S(0), S0₂ or NH and one or two CH moieties unreplaced or replaced with N and also means spiroalkenyl having 15 one or two CH₂ moieties unreplaced or replaced with independently selected O, C(0), CNOH, CNOCHj, S, S(0), SO; or NH and one or two CH moieties replaced with N.

The term, spirocyclo, as used herein, means two substituents on the same carbon atom, that, together with the carbon atom to which they are attached, form a cycloalkane, heterocycloalkane, cycloalkene, or heterocycloalkene ring.

The term C₂-C₅-spiroaIkyl, as used herein, means C₂-spiroalkyl, C₃-spiroalkyl,

C4-spiroalkyl, and Cj-spiroalkyl.

The term C₂-spiroalkyl,” as used herein, means eth-l,2-ylene, both ends of which replace hydrogen atoms of the same CH₂ moiety.

The term C₃-spiroalkyl,” as used herein, means prop-l,3-ylene, both ends of which 25 replace hydrogen atoms of the same CH₂ moiety.

The term C4-spiroalkyl,” as used herein, means but-l,4-ylene, both ends of which replace hydrogen atoms of the same CH₂ moiety.

The term Cj-spiroalkyl,” as used herein, means pent-1,5-ylene, both ends of which replace hydrogen atoms of the same CH₂ moiety.

The term Cs-spiroalkyl,” as used herein, means hex-l,6-ylene, both ends of which replace hydrogen atoms of the same CH₂ moiety.

The term NH protecting group, as used herein, means trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 35 phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,

4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl, 1,1dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N,N-dimethylaminomethylene, 5 benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene, diphenylphosphoryl, dibenzyl phosphoryl, 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl, trimethylsilyl, triethyl silyl, and triphenylsilyl.

The term C(O)OH protecting group, as used herein, means methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyi, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitro benzoylmethyl, para-bromobenzoylmethyl, paramethanesulfonylbenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 215 (trim ethyl silyl)ethyl, acetoxymethyl, propionyloxy methy I, pivaloyl oxymethyl, phthal imidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyI, 2-(trimethyIsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, l,l-dimethyl-2-propenyl, 3-methyl-3butenyl, allyl, trimethylsilyl, triethylsilyl, tri isopropyl silyl, diethyl isopropylsilyl, tert20 butyldimethylsilyl, tert-butyl diphenyl silyl, diphenylmethylsilyl, and tert-butylmeth oxy phenylsilyl.

The term OH or SH protecting group, as used herein, means benzyloxycarbonyl, 4nitrobenzyloxy carbonyl, 4-bromobenzyIoxycarbonyI, 4-meth oxy benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 25 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2(tri methylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxy carbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 830 quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, tri fluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsiIylethyl, l,l-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydro furyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 35 2-methoxyethoxymethyI, 2,2,2-trichIoro-ethoxymethyl, 2-(trimethylsilyl)ethoxyrnethyl, 1ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, tri ethylsilyl, triisopropyl silyl, diethyl isopropylsilyl, tert-buty Id imethy Isilyl, tert-buty Id iphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein 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 the carbon-carbon or carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may also exist as a mixture of “E” and “Z” isomers. Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being ofZ or E relative configuation. For examples, see C. D. Jones, M.

Kaselj, R.N. Salvatore, W, J. Ie Noble J. Org. Chem. 1998, 63. 2758-2760 and E. L. Eliel, and S.H. Wilen. (1994) Stereochemistry of Organic Compounds. New York, NY: John Wiley &amp; Sons, Inc.

Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms R and S are as defined by the IUPAC 1974

Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 1310. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%, Accordingly, this invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties may have attached thereto prodrug-forming moieties. The prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance. An example of a compound with a prodrug-forming moiety is [3-ch loro-5-(5-(4-{[2-(4-ch loropheny I )-4,4-dimethy Icy clohex-l-en-l-yl] methyl} piperazin-1-y I)2-{[({3 -n itro-4-[(tetrahydro-2 H-pyran-4- ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-!minopyridin-l(2H)-yl]methyI dihydrogen phosphate (EXAMPLE 397), which is a prodrug of 2-[(6-amino-5-chloropyridin-3 yl)oxy]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methylJ piperazin-1-yl)-N({3-nitro-4- [(tetrahydro-2 H-pyran-4-ylmethyl Jam ino]pheny 1} su Ifony I Jbenzamide (EXAMPLE 318).

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-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 abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H, ^,3C, ^l4C, ^,5N, ^l8O,⁵²P, ³⁵S, ¹⁸F, ³⁶CI, and ^,2S1. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. In another embodiment, the isotope-labeled compounds contain deuterium (²H), tritium (³H) or ^,4C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as DiSCMDjO. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);

Brickner, S J et al., J Med Chern, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, W01995007271, WO2006008754; US Patent Nos. 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416;and

20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may 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 investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non isotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove 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. Labelled Comp. Radiopharmaceut.,

36(10):927-932(1995): Kushner et al., Con. J. Physiol. Pharmacol,, 77, 79-88 (1999).

In addition, non-radio active isotope containing drugs, such as deuterated drugs called “heavy drugs,” can be used for the treatment of diseases and conditions related to Be 1-2 activity, Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of the amount of enrichment include from about 0,5, I, 2, 3, 4, 5, 6, 7, 8, 9, 5 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 %. Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann, N.Y, Acad, Set. 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). Acute replacement of as high as 15%-23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in Dosimetry &amp; 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)).

Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa 15 and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond 20 involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmcokinetic profile or efficacy relative to the non-istopic compound.

Amides, Esters and Prodrugs

Prodrugs are derivatives of an active drug designed to ameliorate some identified, undesirable physical or biological property. The physical properties are usually solubility (too much or not enough lipid or aqueous solubility) or stability related, while problematic biological properties include too rapid metabolism or poor bioavailability which itself may be related to a physicochemical property.

Prodrugs are usually prepared by: a) formation of ester, hemi esters, carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates, imines, Mannich bases, and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide, and ether functional groups, c) use of polymers, salts, complexes, phosphoramides, acetals, hemiacetals, and ketal forms of the drug. For example, see Andrejus Korolkovas's, Essentials of Medicinal Chemistry, John Wiley35 Jnterscience Publications, John Wiley and Sons, New York (1988), pp. 97-118, which is incorporated in its entirety by reference herein.

Esters can be prepared from substrates of formula (I) containing either a hydroxyl group or a carboxy group by general methods known to persons skilled in the art. The typical reactions of these compounds are substitutions replacing one of the heteroatoms by another atom, for example:

Scheme 1 ° S . Θ ⁺ °OCH₂CH₃ ---- h₃c och₂ch₃^C1

Acyl Chloride Alkoxide Ester

Amides can be prepared from substrates of formula (1) containing either an amino group or a carboxy group in similar fashion. Esters can also react with amines or ammonia to form amides.

Scheme 2

<img file="MY179077A_D0004.tif" />

R—O-R' ® nh₃

<img file="MY179077A_D0005.tif" />

<img file="MY179077A_D0006.tif" />

H-O-R'

Another way to make amides from compounds of formula (I) is to heat carboxylic acids and amines together.

Scheme 3

O heat 9

R^OH ⁺ ^^’&gt;2 ----* R^-N(R')₂

In Schemes 2 and 3 above, R and R' are independently substrates of formula (I), alkyl or hydrogen.

Suitable groups for for A', B¹, D¹, E¹, Y^l, L¹, Z^1a, Z^2A, Z¹, Z², and Z* in compounds of Formula (I) are independently selected. The described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention.

For example, it is contemplated that embodiments for any of A¹, B¹, D^l, E¹, Y^l, L¹, Z^,A, Z^2A, Z¹, Z², and Z³can be combined with embodiments defined for any other of A¹, B¹, D¹, E¹, Y¹, L¹, Z^1A, Z^2A, z', Z², and Z³.

One embodiment of this invention, therefore, pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (I)

<img file="MY179077A_D0007.tif" />

(IX wherein

A¹ is N or C(A²j;

A² is H, R¹, OR¹, SR¹, S(O)R^!, SO₂R^], C(O)R', C(O)OR^!, OC(O)R’, NHR^!,

C(O)NHR‘_} C(O)N(R')₂, NHC(O)R‘, NR'CtOJR¹, NHCtOjOR¹, NR'CtOjOR¹, NHC(O)NH2, NHC(O)NHR', NHC(0)N(R‘)2, NR'QOjNHR¹, NR'CfOJNiR’h, SO2NH₂, SO₂NHR^!, SO2N(R')2, NHSO2R^l, NR'SOjR¹, NHSO2NHR', NHSO₂N(R')_2! NR'SO₂NHR', NR'SOjNCR'X, C(O)NHNOH, C(O)NHNOR', C(O)NHSO₁R¹1 C(NH)NH2j C(NH)NHR^l, C(NH)N(R')2

NHSO₂NHR^l, NHSOiNCCHjJR¹, N(CH₃)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂, Nj, OH, C(O)H,

CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A;

B¹ is H, R¹, OR¹, SR¹, S(O)R', SO2R¹, CtOjR¹, C(O)OR', OC(O)R’, NHR¹, NtR’h, C(O)NHR^[, C(O)N(R^l)2, NHCtOjR¹, NR'CtOjR¹, NHC(O)OR’, NR'CtOjOR¹, NHC(O)NH2, NHC(O)NHR’, NHC(O)N(R')_2j NR'CtOjNHR¹, NR'CtOjNfR'),, so2nh2, so2nhr¹, 15 SO2N(R‘)₂, NHSOjR¹, NR’SOiR¹, NHSOiNHR¹, ΝΉ5Ο₂Ν(Κ*)₂, NR'SOiNHR¹, NR’SOjNtR’h,

C(O)NHNOH, C(O)NHNOR^l, C(O)NHSO2R^[, C(NH)NH2, C(NH)NHR^l, Ο(ΝΗ)Ν(Κ’j2 NHSOjNHR¹, NHSOiNtCHOR¹, NtCHjjSOiNtCHjjR¹, F, Cl, Br, I, CN, NO2. N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₂ or C(O)OR^1A;

D¹ is H, R¹, OR¹, SR¹, SfOjR¹, SOaR¹, CtOjR¹, C(O)OR’, OC(O)R^!, NHR¹, NiR¹):, 20 C(O)NHR’, C(O)N(R’)2, NHC(O)R^l, NR'CtOjR¹, NHC(O)OR', NR'CtOjOR¹, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R‘)₂, NR’C(O)NHR', NR'CfOjNtR¹):, SO2NH2, SO2NHR', SOjNtR’h, NHSOzR¹, NRⁱSO2R¹, NHSOjNHR¹, NHSOjNtR’h, NR’SOiNHR¹, NR’SOzNtR’h, C(O)NHNOH, CtOjNHNOR¹, C(O)NHSOY, CfNH)NH2, C(NH)NHR', C(NH)N(R')2 NHSO2NHR’, NHSO2N(CH3)R¹, N(CH3)SO₂N(CH₃)R^l, F, Cl, Br, 1, CN, NO₂,N₃, OH, C(O)H, 25 CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A;

E^l is H, R^l, OR¹, SR¹, S(O)R^l, SOiR¹, C(O)R’, CtOjOR¹, OC(O)R^l, NHR¹, N(R’)2, C(O)NHR’, C(O)N(R‘)2, NHCtOjR¹, NR'CtOjR¹, NHC(O)OR’, NR'C(O)OR^l, NHC(OjNH2, NHCtOjNHR¹, NHC(O)N(R')2, NR'CtOjNHR¹, ΝΚΥ(Ο}Ν(Κ')2, SO₂NH₂, SOjNHR¹, SOiNfR¹):, NHSOiR¹, NRⁱSO3R¹, NHSOjNHR¹, NHS02N(R')_2i NR^lSO2NHR', NR'SOjNtR'h, 30 C(O)NHNOH, CtOjNHNOR¹, CtOjNHSO^¹, C(NH)NH2, C(NHjNHR’, CfNHjNtR'ji NHSO₂NHR^l, NHSOrNtCH^R¹.. N(CH₃)SO₂N(CH₃)R', F, Cl, Br, 1, CN, NO₂ N₃, OH, C(OjH, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or CtOjOR^lA; and

Y¹ is H, CN, NO;, C(O)OH, F, Cl, Br, I. CF3, OCF3, CF2CF3, OCF2CF3, R¹⁷, OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR'⁷, SO2R¹⁷, NH2, NHR¹⁷. N(R^,7)2j NHC(O)R¹⁷, C(O)NH2, C(O)NHR¹⁷, C(O)N(R¹⁷)2, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, are benzene, naphthylene, 5 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A³, B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R^l, SO2R', C(O)R', C(O)OR', OC(O)R’, NHR', N(R')2, C(O)NHR’, C(O)N(R’)2, NHC(O)R', NR'CiOjR’, nhc(O)or', nr'c(O)or', nhc(O)nh2, nhc(O)nhr', nhc(O)N(r')2i nr'c(O)nhr', NR'C(O)N(R')2t SO2NH2, SOjNHR¹, SO2N(R')₂, NHSO₂R', NR’SOiR', NHSOjNHR¹, 10 NHS02N(R')2, NR'SOjNHR¹, NR'SOzNtR'K C(O)NHN0H, C(O)NHNOR', C(O)NHSO2R',

C(NH)NH₂, C(NH)NHR^l, C(NH)N(R')2 NHSO2NHR^!, NHSOzNiCHOR', N(CH3)SO₂N(CH₃)R', F, Cl, Br, I, CN, NOj Nj, OH, C(0)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(0)NH₂ or C(O)OR^1A; or

Y¹ and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 15 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

A³, D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SOjR¹, C(O)R’, C(O)OR^!, OC(O)R', NHR¹, N(R’)2, C(O)NHR’, C(O)N(R')2, NHC(O)R', NR'C(O)R^l, NHC(O)OR', NR'C(O)OR', NHC(O)NH2, NHC(O)NHR', NHC(O)N(R')₂, NR’CfOiNHR', NR'C(O)N(R')₂, SO₂NH₂, SO₂NHR', SO₂N(R')_2j NHSOjR¹, NR’SOjR¹, NHSO^NHR¹, 20 NHSO2N(R')2, NR'SOiNHR’, NR’SO2N(R')2, C(O)NHNOH, C(O)NHNOR', ΟίΟίΝΗβΟϊΚ¹, C(NH)NH2j C(NH)NHR', C(NH)N(R’)₂ NHS02NHR¹, NHSO2N(CH3)R', NiCH^SOjNiCHOR¹, F, Cl, Br, I, CN, NO2 N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^ia; or

A² and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 25 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SOiR¹, C(O)R', C(O)OR', OC(O)R‘, NHR¹, N(R')2, C(O)NHR', C(O)N(R^l)2, NHC(O)R’, NR'C(O)R‘, NHC(O)OR', NR'CiOJOR¹, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R')2, NR'CiOjNHR¹, NR'C(O)N(R')2, SO₂NH_3j SOjNHR¹, SO2N(R')2, NHSO.R¹, NR’SOiR’, nhso2nhr', 30 NHS0₂N(R')₂, NR'SOiNHR', NR'SOiNtR¹)!, C(0)NHN0H, C(O)NHNOR', C(O)NHSO₂R^!,

C(NH)NH_2i C(NH)NHR', C(NH)N(R‘)₂ NHSOsNHR', NHSO₂N(CH₃)R', N(CH₃)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO_2&gt; N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^1A; or

A³ and D¹, together with the atoms to which they are attached, are benzene, naphthalene, 35 heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

B', E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R', SO,R^l, C(O)R', C(O)OR', OC(O)R‘, NHR¹, N(R')31 CtOJNHR¹, CtOJNCR'jj, ΝΗ^Ο^¹, Ν^ϋίΟ)^, NHC(O)OR‘, NR'CtOJOR¹, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R’)j, NR'CiOJNHR¹, NR'C(O)N(R¹)2s SO2NH2, SOjNHR¹, SO2N(R')₂, NHSO3R’, NR’SChR¹, nhso2nhr', 5 NHSO2N(R')2, NR'SOzNHR¹, NR’SO^R¹):, C(O)NHNOH, C(O)NHNOR’, CCO)NHSO3R', C(NH)NH₂, C(NH)NHR‘, C(NH)N(R')₂ NHSO₂NHR^l, NHSO2N(CH3)R¹j N(CH₃)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂.N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^,a;

R^l is R², R³, R⁴ or R³;

R^IA is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene or R^2A; R^2A is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^3A; R^3A is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^4A; R^4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶, NC(R^6A)(R^6B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO2R⁷, NHR⁷, 20 N(R⁷)2, C(O)R⁷, C(O)NH2,C(O)NHR⁷, C(O)N(R⁷K NHC(O)R\ NR⁷C(O)R⁷, nhso2r⁷,

NHC(O)OR⁷, SO2NH2, SO2NHR⁷, SO2N(R⁷)2, NHC(O)NH2, NHC(O)NHR⁷, NHC(O)CH(CH3)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR', OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-Cr spiroalkyl, each of which is unsubstituted or substituted with OH, (0), N₃, 25 CN, CF_3j CF₂CF_3j F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;

R^6A and R^6S are independently selected alkyl or, together with the N to which they are attached, R^6C;

R^6C is aziridin-l-yl, azetidin-l-yl, pyrrolidin-1 -yI or piperidin-l-yl, each having one CH₂moiety unreplaced or replaced with O, C(0), CNOH, CNOCH₃, S, S(0), S0₂ orNH;

R⁷isR⁸, R⁹, R^orR¹';

R^s is phenyl, which is unfused or fused with benzene, heteroarene or R^8A; R^8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^9A; R^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycioalkenyl each of which is unfused or fused with benzene, heteroarene or R^lt)A; R^10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 5 two or three of independently selected R¹², OR¹², SR¹², S(O)R¹², SO2R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹², NH2, NHR¹², N(R¹²)2, NHC(O)R¹², NR^I2C(O)R¹², NHS(O)2R¹², NR^!2S(O)2R¹², NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH2j NHC(O)NHR¹², NHC(O)N(R^,2)2j NR^I2C(O)NHR¹², NR¹²C(O)N(R¹²)2, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)2, C(O)NHOH, C(O)NHOR¹², C(O)NHSO;R¹², C(O)NR¹²SO2R¹², SO2NH2, SO2NHR¹², SO2N(R¹²)2, C(O)H, 10 C(O)OH, C(N)NH2, C(N)NHR¹², C(N)N(R¹²)2, CNOH, CNOCH₃, OH, (O), CN, N₃, N0₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R¹² is R¹³, R¹⁴, R^1J or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene or R^13A; R^13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^14A; R^14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene, each of which is unfused or fused with benzene, heteroarene or R^I5A; R^l5A is cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷isR^ia, R¹⁹, R²⁰ orR²¹;

R^ls is phenyl, which is unfused or fused with benzene, heteroarene or R^1EA; R^IBA is cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^19A; R^19A is 25 cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycioalkenyl each of which is unfused or fused with benzene, heteroarene or R^20A; R^20A is cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 30 two or three of independently selected R²², OR²², SR²², S(O)R²², SOjR²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²², NH2, NHR²², N^h, NHC(O)R²², NR²²C(O)R²², NHS(O)2R²², NR²²S(O)2R²², NHC(O)OR-², NR²²C(O)OR²¹, NHC(0)NH2, NHC(O)NHR²², NHC(O)N(R²²)2, NR^CfOJNHR²², NR²²C(O)N(R²²)2, C(O)NH₂, C(O)NHR²², CtOjNfR²²)^ C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO2R²², SO2NH_2j SO₂NHR²², SOA'iR0₂, C(O)H, 35 C(O)OH, C(N)NH₂, C(N)NHR²², CfNJNfR²²^, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or 1:

R²² NGrTk R²ⁱ; ni rt rt A rt rt A

R is phenyl, which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroarene or R^24A; R^24A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloaikyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^25A; R^2iA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^,A and Z^2A are both absent or are taken together to form CH₂, CHiCHi or Z^12A;

Z^,2A is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH, N(CH₂), S, S(O) or SO₂;

L' is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO2R³⁷, C(O)R⁵⁷, CO(O)R³⁷, OC(O)R³⁷, OC(O)OR³⁷, 15 NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO:R³⁷, SO₂NH, SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with benzene or heteroarene or R^26A; R^26A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroarylene, which is unfused or fused with benzene or heteroarene or R ; R 20 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R^2S is phenylene, which is unfiised or fused with benzene, heteroarene or R^2SA; R^28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene or heteroarene or R^29A; R^29Ais cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene or heterocycloalkenylene, each of which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^37A;

R^37Ais alkylene, alkenylene, or alkynylene, each of which is unsubstituted or substituted 30 with one or two or three independently selected R^37B, OR³⁷⁸, SR^37B, S(O)R^37B, SO2R^37B, C(O)R^37B, CO(O)R³⁷⁸, OC(O)R^37B, OC(O)OR^3?b, NH2j NHR³⁷⁸, N(R^37B)2, NHC(O)R³⁷⁰, NR^37BC(O)R^37B, NHS(O)2R^37B, NR^37SS(O)2R^37B, NHC(O)OR^37B, NR^37BC(O)OR^37B, NHC(O)NH2, NHC(O)NHR^37B, NHC(O)N(R^37B)2j NR^37BC(O)NHR^37B, NR^37BC(O)N(R^37B)2, C(O)NH_2iC(O)NHR³⁷⁶, C(O)N(R^37B)2j C(O)NHOH, C(O)NHOR^37B, C(O)NHSO2R^37B, C(O)NR^37BSO2R^37B, 35 SO2NH₂, SO₂NHR^37B, SO2N(R^37B)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR^3TB, C(N)N(R³⁷⁸)₂,

CNOH, CNOCH₃, OH, (O), CN, Nj, N0₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and 1 substituents;

R^37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^38A; R^38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^39A; R^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is un fused or fused with benzene, heteroarene or R^40A; R^40A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R³⁶ and R²⁷ are substituted (i.e., if Z^,A and Z^2A are absent) or further substituted (i.e., if Z^IA and Z^ZA are present) with one or two or three or four of 15 independently selected R⁴¹, OR⁴¹, SR⁴', S(O)R⁴¹, SO2R⁴', C(O)R⁴¹, CO(O)R⁴’, OC(O)R⁴¹, OC(O)OR⁴¹, NH2, NHR⁴¹, N(R^4l)2, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹, NHS(O)2R⁴¹, NR^4IS(O)2R⁴¹, NHC(O)OR⁴¹, NR⁴'C(O)OR⁴', NHC(O)NH2, NHC(O)NHR^4!, NHC(O)N(R^4,)2: NR^4,C(O)NHR⁴¹, NR^4lC(O)N(R⁴¹)2, C(0)NH₂, C(0)NHR⁴¹, C(0)N(R^4l):, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO2R^4l: C(O)NR^4ISO2R^4!: SO2NH2, SO2NHR⁴¹, SO2N(R⁴¹)₂, C(O)H, C(0)0H,

C(N)NH₂, C(N)NHR⁴¹, C(N)N(R^4,)₂, CNOH, CNOCH₃, OH, (0), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF_3j F, Cl, Br or I;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴ⁱ;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene or R^42A; R^42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^43A; R^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^44A; R^44A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁴⁶, OR⁴⁶, SR⁴⁶, SfOfR⁴⁶, SO2R⁴⁶, C(O)R⁴⁶, COfOJR⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH2, NHR⁴⁶, N(R⁴⁶)2, NHC(0)R⁴\ NR⁴⁶C(O)R⁴⁶, NHS(O):R⁴⁶, NR⁴⁶S(O)2R⁴⁶, NHC(O)OR⁴⁶, NR⁴⁶C(O)OR⁴⁶, NHC(O)NH2, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)2, NR⁴⁰C(O)NHR^4c, NR⁴⁶C(O)N(R⁴⁶)2, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH,

C(O)NHOR⁴⁶, C(O)NHSO2R⁴⁶, C(O)NR⁴⁶SO2R⁴⁶, SO2NH2j SO2NHR⁴⁶, SO2N(R⁴⁶)₂, C(O)H,

C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)_2i CNOH, CNOCH₃,OH, (O), CN, N₃, N0₂₁ CF₃, CF₂CF₃, 0CF₃, OCF₂CF_3j F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R^47A; R^47A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl, which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^49A; R^49A is cycloalkane, cycloalkene, 10 heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R⁴², R^42A, R⁴³, R^43A, R⁴⁴, R^44A, R⁴⁷, R^47A, R⁴⁸, R^48A, R⁴⁹, and R^49A are independently substituted with one or two or three or four of independently selected R⁵“, OR⁵⁰, SR⁵⁰, S(O)Rⁱ⁰, SO2R⁵°, C(O)Rⁱ⁰, CO(O)Rⁱ⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH2, NHR^J0, N(R⁵⁰)2, NHC(O)R⁵⁰, NR^s0C(O)R⁵⁰, NHS(O)2Rⁱ⁰, NR^;0S(O)2R⁵⁰, NHC(O)OR⁵⁰, 15 NRⁱ⁰C(O)OR⁵⁰, NHC(0)NH2; NHC(O)NHRⁱ⁰, NHC(O)N(R^S0)2, NRⁱ⁰C(O)NHR⁵⁰, NRⁱ⁰C(O)N(Rⁱ⁰)2, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R^s0)2, C(0)NH0H, C(0)NH0R^s°, C(O)NHSO2R⁵⁰, C(O)NR⁵⁰SO2R^5il, SO2NH₂, SOjNHR⁵⁰, SO2N(Rⁱ⁰)2, C(O)H, C(0)0H, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(Rⁱ⁰)₂, CNOH, CN0CH₃, OH, (0), CN, N₃, N0₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R^iOisR⁵¹, R⁵², R⁵³orRⁱ⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene or R^S1A; R^5lA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroarene or R^52A; R^52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^i3A; R^53A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁵⁵, OR⁵³, SR⁵⁵, S(O)R⁵⁵, SO2R^ss, C(O)R^S5, CO(O)R⁵⁵, 30 OC(O)R^iS, OCiOJOR”, NH2, NHR⁵⁵, N(R⁵ⁱ)2, NHC(O)R⁵⁵, NRⁱ⁵C(O)R⁵⁵, NHS(O)2R^J5, NR⁵ⁱS(O)2R⁵⁵, NHC(O)OR⁵⁵, NR⁵ⁱC(O)OR⁵ⁱ, NHC(0)NH2, NHC(O)NHR⁵⁵, NHC(O)N(R^S5)2, NR^5!C(O)NHR⁵⁵, NR⁵ⁱC(O)N(R⁵⁵)2, C(0)NH₂, C(O)NHR^Si, C(O)N(R^iS)2, C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO2R⁵⁵, C(O)NR⁵⁵SO3R⁵⁵, SO2NH₂, SO₂NHR^5S, SO2N(R⁵⁵)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R^ss)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO_:, CF₃, 35 CF₂CF₃, OCF₃, OCF₂CF₃₁ F, CI, Br or I;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of 5 independently selected R^57A, R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO2R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)Rⁱ⁷, OC(O)OR⁵⁷, NH21 NHR⁵⁷, N(R⁵⁷)2, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵\ NHS(O)2R⁵⁷, NRⁱ⁷S(O)2R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH2, NHC(O)NHR⁵⁷, NHC(O)N(R^S7)2, NRⁱ⁷C(O)NHR^S7t NR⁵⁷C(O)N(R⁵⁷)2, C(O)NH2, C(O)NHR⁵⁷, C(O)N(R^S\ C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO2R⁵⁷, C(O)NR⁵⁷SO2R⁵⁷, SO2NH₂, SO₂NHR⁵⁷, SO2N(R^S7)2, C(O)H, C(O)OH, 10 C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R^S7)_2j CNOH, CNOCHs, OH, (O), CN, n₃, no₃, cf₃, cf₂cf₃,

OCF_3i OCF₂CF₃, F, Cl, Br or I;

A R^57A is spirocyclyl;

R⁵⁷ is R^iB, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^SSA; R’^8A is 15 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^i9A; R^59A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^60A; R⁶⁰* is cycloalkane, cycloalkene, 20 heterocycloalkane or heterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶/ OR⁶², SR⁶², S(O)R⁶², SO2R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶², NH2, NHR⁶², N(R⁶²)2, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)2R⁶², NR⁶²S(O)2R⁶², NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH;, NHC(O)NHR⁶², NHC(O)N(R⁶²)2, 25 NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶-)2, C(O)NH2, C(O)NHR⁶², C(O)N(R⁶²)2j C(O)NHOH, C(O)NHOR⁶², C(O)NHSO2R⁶², C(O)NR⁶²SO2R⁶², SO2NH2, SO2NHR⁶², SO2N(R⁶²)2i C(O)H, C(O)OH, C(N)NH2, C(N)NHR⁶², C(N)N(R⁶²)2i CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene or R^63A; R^63A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^64A; R^MA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is 35 unfused or fused with benzene, heteroarene or R^65A; R^65A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶⁷, OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO2R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶\ OC(O)OR⁶⁷, NH2, NHR⁶⁷, N(R⁶⁷)2, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)2R⁶⁷, NR^SfO^R⁶⁷, NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH2, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)2, 5 NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷K C(O)NH_2s C(O)NHR⁶⁷, C(O)N(R⁶⁷)2, C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO2R⁶⁷, C(0)NR⁶⁷SO₂R⁶⁷, SO2NH2, SO2NHR⁶⁷, SO2N(R⁶⁷)2, C(O)H, C(0)0H, C(N)NH2, C(N)NHR⁶⁷, C(\)N(R⁶Y CNOH, CN0CH310H, (0), CN, N₃, N0₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, 10 heterocycloalkyl or heterocycloalkenyl;

wherein the moteties represented by R^S7A, R^5S, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, and R⁶⁷are unsubstituted or substituted with one or two or three or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO2R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH2, NHR⁶⁸, N(R⁶⁸K NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)2R⁶⁸, NR^6SS(O)2R^6!, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,

NHC(0)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)2, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)2, C(0)NH₂, C(O)NHR⁶⁸, C(O)N(R^6S)2, C(0)NH0H, C(O)NHOR⁶⁸, C(O)NHSO2R⁶⁸, C(O)NR⁶⁸SO2R⁶⁸, SO2NH_:, SO₂NHR⁶⁸, SO2N(R^aY C(0)H, C(0)0H, C(N)NH2, C(N)NHR⁶⁸, C(N)N(R⁶⁸&gt;2, CNOH, CNOCHj, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or 1;

R⁶⁸ is R⁶⁹, R™, R^7[ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene or R^69A; R^69A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^70A; R^70a is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is 25 unfused or fused with benzene, heteroarene or R^7IA; R^7,A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁷³, OR⁷³, SR⁷³, S(O)R⁷³, SO;R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH2, NHR⁷³, N(R⁷³)2, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)2R⁷³, 30 NR^SfOJrR⁷³, NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH2, NHC(O)NHR⁷³, NHC(O)N(R⁷³)3, NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)2j C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)_2j C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO2R⁷³, C(O)NR⁷³SO2R⁷³, SO2NH2, SO2NHR⁷³, SO2N(R⁷³)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂₁ CNOH, CNOCHj, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃₁ OCFiCFj, F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and the moieties represented by R⁶⁹, R^7D, and R⁷¹ are unsubstituted or substituted with one or two or three or four of independently selected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, n₃, no₂, cf₃, cf₂cf₃, ocf₃, ocf₂cf₃, F, Cl, Br or I.

Another embodiment of this invention pertains to compounds of Formula (I), wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, SfOjR¹, SO^, C(O)R‘, C(O)OR‘, OC(O)R', NHR¹, N(R')2j CiOJNHR¹, C(O)N(R')2, NHC(O)R’s NR'qOJR¹, NHC(O)OR', NR'CiOjOR¹, NHC(O)NH2, NHC(O)NHR'S NHCtOjNCR'h, NR'CiOjNHR¹, NR'CCOjNCR¹^, SO2NH₂, SO₂NHR’, 10 SO2N(R^l)2, NHSO2R^l, NR'SOiR’, NHSOjNHR¹, NHSO2N(R')2, NR'SOjNHR¹, NR'SO2N(R')2, C(O)NHNOH, C(O)NHNOR’, 0(0)^50^, C(NH)NH2, C(NH)NHR', C(NH)N(R')2 NHSOzNHR¹, NHSO2N(CH₃)R^!, N(CH₃)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₂ or C(O)OR^IA;

B¹ is H, R¹, OR¹, SR¹, S(O)R', SOiR¹, C(O)R’, C(O)OR', OC(O)R^!, NHR¹, NCR'Jj, 15 C(O)NHR^J, C(O)N(R')2j NHC(O)R', NR’C(O)R', NHC(O)OR‘, NR^!C(O)OR', NHC(O)NH2, NHC(O)NHR', NHC(O)N(R')₂, NR’CtOjNHR’, NR¹C(O)N(R*)2, SO2NH2, SOjNHR¹, S02N(R')_2j NHSOjR¹, NR’SOjR¹, NHSO2NHR', NHSO2N(R')2, NR^,SO2NHRⁱs NR^lSO2N(R‘)₂, C(O)NHNOH, C(O)NHNOR', C(O)NHSO₂R‘, C(NH)NH_2j C(NH)NHR', CCNHJNiR¹^ NHSOjNHR¹, NHSO₂N(CH₃)R', N(CH₃)SO₂N(CH₃)R\ F, Cl, Br, I, CN, NO₂, Nj, OH, C(O)H, 20 CHNOH, CH(NOCH₃), CF_3j C(0)0H, C(0)NH₂ or C(O)OR^1A,

D' is H, R¹, OR¹, SR¹, S(O)R’, SO^¹, C(O)R^l, C(O)OR\ OC(O)R‘, NHR¹, NfR’h, C(O)NHR', C(O)N(R^l)2, NHC(O)R’, NR'C(O)R', NHC(O)OR', NR'CfOjOR¹, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R^l)2, NR'C(O)NHR^l, NR'C(O)N(R')2, so₂nh₂, so₂nhr‘, SO₂N(R‘)_2j NHSOjR¹, NR'SOiR¹, NHSO2NHR', NHSO-NfR¹);, NR^,S02NHR^,1 NR'SO2N(R')2, 25 C(0)NHN0H, C(O)NHNOR', C(O)NHSO2R‘, C(NH)NH2j C(NH)NHR', CCNHJNfR'h NHSO2NHR', NHSO2N(CH3)R’; NfCH^SOjNiCHOR¹, F, Cl, Br, I, CN, NO2.N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₂ or C(O)OR^1A;

E¹ is H, R¹, OR¹, SR¹, S(O)R', SO2R', C(O)R', C(O)OR^], OC(O)R', NHR¹, N(R')2, C(O)NHR', C(O)N(R')_2j NHC(O)R^l, NR'CtOJR¹, NHC(O)OR', NR'C(O)OR', NHC(O)NH2, 30 NHC(O)NHR', NHC(O)N(R')2, NR'QOJNHR¹, NR'C(O)N(R’)2, so₂nh₂, so₂nhr', SO₂N(R')₂, NHSO₂R', NR'SO.R¹, NHSOzNHR¹, NHS02N(R^l)2, NR'SOjNHR¹, NR'SO^CR'h, C(O)NHNOH, C(O)NHNOR‘, C(O)NHSO2R', C(NH)NH2, C(NH)NHR', C(NH)N(R')2 NHSO2NHR', NHSO2N(CH3)R¹, N(CH3)SO₂N(CH₃)R', F, Cl, Br, I, CN, NO₂ N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₂ of C(O)OR^ia; and

7]

Y¹ is H, CN, Ν02) C(O)OH, F, Cl, Br, I, CF3, OCF3, CF2CF3, OCF2CF3, R¹⁷, OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO2R¹⁷, NH21 NHR¹⁷, N(R^,7)21 NHC(O)R¹⁷, C(O)NH2, C(O)NHR¹⁷, CCOJNtR¹⁷^, NHS(O)R¹⁷ or NHSO2R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, are benzene, naphthylene, 5 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene; and

A\ B¹, and D¹ are independently selected H, R^l, OR¹, SR¹, S(O)R^!, SO:R', C(O)R\ C(O)OR’, OC(O)R', NHR¹, N(R');, C(O)NHR’, CiOjNiR¹^, NHC(O)R‘, NR¹C(O)R¹, NHCtOjOR¹, NR‘C(O)OR^l, NHC(O)NH2, NHC(O)NHR', NHC(O)N(R’)i, ΝΚ’^ΟίΝΗΚ¹, SO2NH₂, SO^HR¹, SO^R¹)^ NHSO2R', NR¹SO2R¹, NHSOjNHR¹, 10 NHSO2N(R‘)2, NR'SOAHK¹, NR¹ SO2N(R^l)₂, C(O)NHNOH, C(O)NHNOR\ 0(0)ΝΗ50₂Κ',

C(NH)NH₂, C(NH)NHR’, CCNHjNtR'jj NHSOzNHR¹, NHSO2N(CH3)R', N(CH3)SO2N(CH3)R¹, F, Cl, Br, I, CN, NO2.N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF_3i C(O)OH, C(O)NH₂ or C(O)OR^1A; or

Y¹ and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 15 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R', SO^, C(O)R^!, C(O)OR', OC(O)R‘, NHR¹, NfR¹^, C(O)NHR’, C(O)N(R¹)2j NHCCOjR¹, NR'CtOjR¹, NHC(O)OR‘, NR’CtOJOR¹, NHC(O)NH2, NHC(O)NHR', ΝΗΟίΟΪΝίΚ¹);, NR'C(O)NHR', NR'etOiNiR'E SO2NH2j SOjNHR¹, SO2N(R‘)₂, nhso₂r‘, nr’so.r¹, nhso.nhr¹, 20 NHSO2N(R¹)2, NR'SOiNHR¹, NR‘SO2N(R')2, C(O)NHNOH, CtOjNHNOR¹, CiOJNHSOzR¹, C(NH)NH2, CCNHjNHR¹, C(NH)N(R‘)2 NHSO2NHR^j, NHSOzNiCHjJR¹, N(CH3)SO₂N(CH₃)R', F, CI, Br, I, CN, N0₂,N_3i OH, C(O)H, CHNOH, CH(NOCH₃), CF_3j C(O)OH, C(O)NH₃ or C(O)OR^1A; or

A² and B¹, together with the atoms to which they are attached, are benzene, naphthylene, 25 heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R‘, SO2R^!, C(O)R', C(O)OR’, OC(O)R’, NHR¹, N(R')2, CfOjNHR¹, QOjNtR'h, NHC(O)R^!, NR'CiOJR’, NHC(O)OR‘, NR’CtOJOR¹, NHC(O)NH2, NHC(O)NHR^l, NHQOMR¹),, NR’QOJNHR¹, NR^lC(O)N(R^l)2, SO₂NH₂, SO.NHR¹, SO2N(R')2, NHSO^R¹, NR’SOjR¹, nhso2nhr', 30 NHSOjNCR’E NR’SOjNHR¹, NR'SOiNfR¹):, C(O)NHNOH, C(O)NHNOR^!, C(O)NHSO2R\ C(NH)NH:, C(NH)NHR', CiNHjNtR¹): NHSOzNHR¹, NHSO2N(CH₃)R¹, NiCHjlSOjNCCHaJR¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^iA; or

A² and D¹, together with the atoms to which they are attached, are benzene, naphthalene, 35 heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocydoalkene; and

B’.E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R’, SOiR', C(O)R^], C(O)OR', OC(O)R‘, NHR¹, N(R')2, C(O)NHR^l, C(O)N(R’)2, NHC(O)R', NR’CfOjR¹, NHC(O)OR', NR'CtOJOR¹, NHC(O)NH21 NHC(O)NHR', NHC(O)N(R')2, NR'CtOJNHR¹, NR'CtOjNtR^, SO2NH_2j SO₂NHR', SO₂N(R')₂, nhso₂r^!, nr'so2r¹, nhso2nhr', 5 NHSOiNiR’h, NR’SO₂NHR¹, NR’SOiNtR'h, C(O)NHNOH, C(O)NHNOR', CiOjNHSOjR¹, C(NH)NH:, C(NH)NHR’, C(NH)N(R')2 NHSOjNHR¹, NHSOiNfCHjJR¹, N(CH3)SO₂N(CH₃)R’, F, Cl, Br, I, CN, NO₂,N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^ia;

R^l is R², R\ R⁴ or R’:

R^|A is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene or R^2A; R^2A is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^3A; R^3A is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^4A; R^4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R^e, NC(R^6A)(R^6B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO2R⁷, NHR⁷, 20 N(R⁷)2, C(O)R⁷, C(O)NH2, C(O)NHR⁷, CfOjNfR⁷^, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO2R⁷,

NHC(O)OR⁷, SO2NH2, SO2NHR⁷, SO2N(R⁷)2, NHC(O)NH2, NHC(O)NHR⁷, NHC(O)CH(CH3)NHC(O)CH(CH₃)N^ NHQOJCHiCHjJNHCtOKHfCHaJNHR¹, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is CrCj-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N₃, 25 CN, CFj, CF₂CF₃, F, Cl, Br, I, NH₂. NH(CH₃) or N(CH₃)₂;

R^6a and R⁶⁰ are independently selected alkyl or, together with the N to which they are attached, R^f’^C;

R^6c is aziridin-l-yl, azetidin-l-yl, pyrrolidin-1 -yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹',

R^s is phenyl, which is unfused or fused with benzene, heteroarene or R^SA; R^iA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^9A; R^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^IOA; R^10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 5 two or three of independently selected R^ia, OR¹⁷, SR¹⁷, S(O)R¹², SO2R¹², C(O)R¹², CO(O)R¹⁷, OC(O)R¹⁷, OC(O)OR¹², NH2, NHR’², N(Rⁱ⁷)2, NHC(O)R¹², NR¹⁷C(O)R'², NHS(O)2R¹², NR¹⁷S(O)2R¹², NHC(O)OR¹², NR¹⁷C(O)OR¹², NHC(O)NH2, NHC(O)NHR¹², NHC(O)N(R^,2)2, NR^CiCflNHR¹², NR^I7C(O)N(R¹²)2, C(O)NH₂, C(O)NHR^!2, C(O)N(R'⁷)2, C(O)NHOH, C(O)NHOR^!7, C(O)NHSO2R¹², C(O)NR¹²SO2R¹², SO:NH₂, SO₂NHR¹⁷, SO2N(R^I7)2, C(O)H_s10 C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R^i:)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO_a, CF₃, CF₂CF₃, OCF_3j OCF₂CF₃, F, CI, Br or I;

R^[7 is R'\ R¹⁴, R^,3or R¹⁶;

R¹³ is phenyl, which is unfbsed or fused with benzene, heteroarene or R^i3A; R^I3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^,4A; R^,4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene:

R¹³ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R^13A; R^13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

Rⁿ is R¹⁸, R¹⁹, R²⁰ orR⁷';

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^ISA; R^I8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Rⁱ⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^,9A; R^I9A is 25 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁰ is cycloalky!, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfnsed or fused with benzene, heteroarene or R^20A; R^70A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or 30 two or three of independently selected R⁷⁷, OR²², SR²², S(O)R⁷², SO:R²², C(O)R²², CO(O)R²², OC(O)R⁷², OC(O)OR²², NH2, NHR⁷², N(R²⁷)2, NHC(O)R²⁷, NR⁷⁷C(O)R⁷⁷, NHS(O)2R⁷⁷, NR²²S(O)2R²², NHC(O)OR²², NR²⁷C(O)OR²², NHC(O)NH2, NHC(O)NHR²², NHC(O)N(R²0, NR⁷⁷C(O)NHR²², NR⁷²C(O)N(R²²)2, C(0)NH2j C(O)NHR⁷², C(O)N(R²⁷)2, C(O)NHOH, C(O)NHOR²², C(O)NHSO2R²², C(O)NR²⁷SO2R²⁷, SO2NH2, SO2NHR²², SO2N(R²²)2i C(O)H, 35 C(O)OH, C(N)NH2, CtNJNHR²², C(N)N(R⁷⁷)2, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃₁ OCF₃, OCF₂CF₃, F, CI, Br or I;

R²² is R²³, R²⁴ or R^:i;

R²³ is phenyl, which is unfused or fused with benzene, heteroarene or R^23A; R^23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroarene or R^24A; R^24A is 5 cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R^25A; R^25A is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^,A and Z^2A are both absent or are taken together to form CH₂, CH₂CH₂ or Z^I2A;

Z^12A is CrCi-alkylene having one or two CH₂ moieties replaced by NH, N(CH₃), S, S(O) or SO₂;

L' is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO:R⁵⁷, C(O)Rⁿ, CO(O)R³⁷, OC(O)R³⁷, OC(O)OR³⁷, 15 NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO:R³⁷, SO₂NH, SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with benzene or heteroarene or R^26A; R^26A is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R is heteroarylene, which is unfused or fused with benzene or heteroarene or R ; R 20 is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene or R^28A; R^28A is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene or heteroarene or R^29A; R^29Ais cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene ;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene or heterocycloaikenylene, each of which is unfused or fused with benzene, heteroarene or R^30A; R^30A is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R³⁷ is a bond or R^37A:

R^J7A is alkylene, alkenylene, or alkynylene, each of which is unsubstituted or substituted 30 with one or two or three independently selected R³⁷⁰, OR³⁷⁰, SR^37B, S(O)R^37B, SO2R^37B, C(O)R^37B, CO(O)R^37B, OC(O)R^37B, OC(O)OR³⁷⁰, NH2, NHR³⁷⁰, N(R^37B)2, NHC(O)R^37B, NR^37BC(O)R^37B, NHS(O)2R^37B, NR³⁷⁰S(O)2R^37S, NHC(O)OR^37B, NR^37BC(O)OR^37B, NHC(O)NH2, NHC(O)NHR³⁷⁰, NHC(O)N(R³⁷⁰)2, NR^37BC(O)NHR^37B, NR^37BC(O)N(R^37B)2j C(O)NH_2jC(O)NHR^37B, C(O)N(R^3?b)2, C(O)NHOHS C(O)NHOR³⁷⁰, C(O)NHSO2R^37B, C(O)NR^37BSO2R³⁷⁸, 35 SO2NH_2; SO₂NHR^37B, SO2N(R^37b)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR^37B, C(N)N(R^37B)₂,

CNOH, CNOCH₃,OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and 1 substituents;

R^37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^38A; R^3SA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^39A; R^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfiised or fused with benzene, heteroarene or R^40A; R^40A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted with OR⁴¹;

R⁴' is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene or R^42A; R^42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^43A; R^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is 20 unfused or fused with benzene, heteroarene or R^44A; R^44A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl. each of which is unsubstituted or substituted with one or two or three of independently selected R⁴⁶, OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, SO:R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH2, NHR⁴⁶, N(R⁴⁶)2t NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)2R⁴⁶,

NR⁴⁶S(O)2R⁴⁶, NHC(O)OR⁴⁶, NR⁴⁶C(O)OR⁴⁶} NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂,

NR⁴⁶C(O)NHR⁴⁶, NR⁴⁶C(O)N(R⁴⁶)2, C(O)NH2, C(O)NHR⁴⁶, C(O)N(R⁴⁶)2i C(O)NHOH, C(O)NHOR⁴⁶, C(O)NHSO2R⁴⁶, C(O)NR⁴⁶SO2R⁴⁶, SO2NH2j SO2NHR⁴⁶, SO2N(R⁴⁶)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR⁴⁶, C(N)N(R⁴⁶)2, CNOH, CNOCHj,OH, (O), CN, Nj, NO₂, CF₃, CF_:CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R^47A; R^47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^48A; R^48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene orR^49A; R^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R⁴², R^42A, R⁴³, R^43A, R⁴⁴, R^44A, R⁴⁷, R^47A, R⁴⁸, R^48A, 5 R⁴⁹, and R^49A independently substituted with one or two or three or four of independently selected

R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO2R³⁰, C(O)R⁵⁰, CO(O)Rⁱ⁰, OC(O)R³⁰, OC(O)OR⁵⁰, NH2, NHR³⁰, N(Rⁱ⁰)2, NHC(O)R^3D, NR^5DC(O)R⁵⁰, NHS(O)2Rⁱ⁰, NR⁵⁰S(O)2R³⁰, NHC(O)OR³⁰, NR⁵⁰C(O)ORⁱ⁰, NHC(O)NH2, NHC(O)NHR³⁰, NHC(O)N(R³⁰)2, NR^S0C(O)NHR⁵⁰, NR^S0C(O)N(R⁵⁰)2S C(O)NH₂, C(O)NHR³⁰, C(O)N(R^S0):, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO2R⁵⁰, C(O)NR^S0SO₂R³⁰,

SO₂NH₂, SO_:NHR³⁰, S02N(R^s°)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR^S0, C(N)N(R³⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N* NO₂, CF_3f CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R³⁰ is R⁵¹, R³², R⁵³ orR⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene or R^ilA; R^5lA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroarene or R^52A; R^32A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R³³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^53A; R^53A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

Rⁱ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁵⁵, OR³³, SR³³, S(O)R⁵⁵, SO2R⁵ⁱ, C(O)Rⁱ⁵, CO(O)R⁵³, OC(O)R³³, OC(O)OR³³, NH2, NHR⁵³, NCR⁵⁵):, NHC(O)R⁵⁵, NR⁵ⁱC(O)R^ss, NHS(O)2R^iS, NRⁱ⁵S(O)2R^5J, NHC(O)OR^SS, NIV⁵C(O)OR⁵\ NHC(O)NH2, NHC(O)NHR⁵³, NHC(O)N(R^ss)2, NRⁱ⁵C(O)NHR^Si, NR⁵ⁱC(O)N(R⁵⁵):, C(O)NH2, C(O)NHR⁵⁵, C(O)N(R⁵⁵)2, C(O)NHOH,

C(O)NHOR³⁵, C(O)NHSO;R⁵/ C(O)NR⁵⁵SO2R^iS, SO2NH2, SO2NHR⁵ⁱ, SO2N(R³³)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR^S5, C(N)N(R⁵³)2, CNOH, CNOCH_3j OH, (O), CN, N₃₁NO₂, CF₃₁CF₂CF₃, OCF₃₎ OCF₂CF₃, F, Ci, Br or I;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and wherein each foregoing cyclic moiety is independently unsubstituted, further un substituted, substituted or further substituted with one or two or three or four or five of independently selected R^57A, Rⁱ⁷, OR⁵⁷, SR³⁷, S(O)R³⁷, SO2R³⁷, CiOJR³⁷, CO(O)R³⁷, OC(O)Rⁱ⁷, OC(O)OR⁵⁷, NH2, NHR³⁷, N(Rⁱ⁷)2, NHC(O)R³⁷, NR⁵⁷C(O)R³⁷, NHS(O)2R³⁷, NR‘+(O).;R”, NHC(O)OR³⁷, NR⁵⁷C(O)OR³⁷, NHC(O)NH2, NHC(O)NHR³⁷, NHC(O)N(R⁵⁷)₂, NR³⁷C(O)NHR³⁷,

NR³⁷C(O)N(R^S7)₂, C(O)NH₂, C(O)NHR³⁷, C(O)N(R³⁷)3, C(O)NHOH, C(O)NHOR³⁷,

C(O)NHSO₂R³⁷, C(O)NR³⁷SO2R³⁷, SO2NH₂, SO₂NHR³⁷, SO2N(R³⁷)2, C(O)H, C(O)OH,

C(N)NH₂, C(N)NHR⁵⁷, C(N)N(Rⁱ⁷)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, N0₃, CF₃, CF₃CF₃, OCF₃, OCF₃CF₃, F, Cl, Br or I;

Rⁱ⁷ is R^R⁵⁹, R⁴⁰ or R⁴¹;

R is spirocyclyl;

Rⁱ⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R^i8A, R^i8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^59A; R^i9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is 10 unfiised or fused with benzene, heteroarene or R^40A; R^60A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁴², OR⁶², SR⁴², S(O)R⁴², SO2R⁴², C(O)R⁴², CO(O)R⁴², OC(O)R⁶², OC(O)OR⁴², NH2, NHR⁴², N(R⁴²)2, NHC(O)R⁴², NR⁴²C(O)R⁴², NHS(O)3R⁴², 15 NR⁴²S(O)3R⁴², NHC(0)0R⁴², NR⁴²C(O)OR⁴², NHC(0)NH2, NHC(O)NHR⁴², NHC(O)N(R⁶²k

NR⁴²C(O)NHR⁴², NR⁴²C(O)N(R⁴²)3, C(0)NH2j C(O)NHR⁴², C(O)N(R⁴²)2, C(0)NH0H. C(O)NHOR⁴², C(O)NHSO2R⁴², C(O)NR⁴²SO2R⁶³, SO3NH3, SO.NHR⁴², SO2N(R⁴²)2, C(0)H, C(O)OH, C(N)NH2, C(N)NHR⁴², C(N)N(R⁴²)2, CNOH, CNOCH₃, OH, (0), CN, N_3l NO₂, CF₃₁CF₂CF₃, OCF₃, OCF₃CF₃, F, Cl, Br or I;

R⁴² is R⁴³, R⁴⁴, R⁶⁵ or R⁴⁴;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene or R^43A; R^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^44A; R^44A is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R⁴⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^45A; R^4iA is cycloalkane, cycloalkene, heterocycioalkane or heterocycloalkene;

R⁴⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶⁷, OR⁴⁷, SR⁴⁷, S(O)R⁴⁷, SO2R⁴⁷, C(O)R⁶⁷, CO(O)R⁶⁷, 30 OC(O)R⁴⁷, OC(O)OR⁶⁷, NH2, NHR⁴⁷, N(R⁴⁷)2, NHC(O)R⁴⁷, NR⁴⁷C(O)R⁴⁷, NHS(O)2R⁴⁷,

NR⁴⁷S(O)3R⁴⁷, NHC(0)0R⁴⁷, NR⁴⁷C(O)OR⁴⁷, NHC(O)NH2, NHC(O)NHR⁴⁷, NHC(O)N(R⁴⁷)2, NR⁶⁷C(O)NHR⁴⁷, NR⁴⁷C(O)N(R⁴⁷)2, C(0)NH₂, C(O)NHR⁴⁷, C(O)N(R⁴⁷)2, C(O)NHOH, C(O)NHOR⁴⁷, C(O)NHSOZR⁴⁷, C(O)NR⁴⁷SO2R⁴⁷, SO2NH₂, SO₃NHR⁴⁷, SO2N(R⁴⁷)2, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁴⁷, C(N)N(R⁴⁷)₂, CNOH, CNOCH₃,OH, (O), CN, N₃, NO_:, CF₃, 35 CF₂CF₃, OCF_3j OCF₃CFj, F, Cl, Br or I substituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^i7A, R⁵⁸, Rⁱ⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or three or four of independently selected R^6S, OR⁶⁸, 5 SR⁶⁸, S(O)R⁶⁸, SO2R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH2j NHR⁶⁸, N(R⁶⁸)₃,

NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)2R^6B, NR⁶⁸S(O)2R⁶⁸, NHC(O)OR⁶⁸, NR^6SC(O)OR⁶⁸, NHC(O)NH2, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)2, NR^6SC(O)NHR^6S, NR^6GC(O)N(R^6S)_2j C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)2, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO2R⁶⁸, C(O)NR⁶⁸SO2R⁶⁸, SO2NH_2j SO.NHR⁶³, SO₂N(R⁶⁸)2j C(O)H, C(O)OH, C(N)NH2j C(N)NHR^6S, C(N)N(R⁶⁸)2j

CNOH, CNOCH₃, OH, (O), CN, Nj, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷' or R⁷²;

/ R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene or R^69A; R^69A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroarene or R^70A; R^T0A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R^7IA; R^71A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or 20 two or three of independently selected R⁷³, OR⁷³, SR⁷³, S(O)R⁷³, SO2R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH:, NHR⁷³, N(R⁷³)2, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)2R⁷³, NR⁷³S(O)2R⁷³, NHCtOjOR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH2, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂, NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)2, C(O)NH2, C(O)NHR⁷³, C(O)N(R⁷³)2, C(O)NHOH, / C(O)NHOR⁷³, C(O)NHSO_;R⁷³, C(O)NR⁷³SO₂R⁷³, SO2NH2, SO2NHR⁷³, SO2N(R⁷³)₂, C(O)H,

C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH, CNOCH₃, OH, (O), CN, Nj, NO_:, CF₃, CF₂CF₃, OCF₃, OCF₂CF_3j F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl; and the moieties represented by R⁶⁹, R⁷⁰, and R^7! are unsubstituted or substituted with one or 30 two or three or four of independently selected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or 1.

In one embodiment of Formula (I), A¹ is N. In another embodiment of Formula (I), A¹ is C(A²). In another embodiment of Formula (I), A¹ is C(A²); and A² is H.

In one embodiment of Formula (I)_: B¹ is OR¹, or NHR¹. In another embodiment of Formula (I), A¹ is C(A²); A² is H; and B¹ is NHR¹. In another embodiment of Formula (I), A¹ is C(A²); A² isH;andB^lis OR¹.

In one embodiment of Formula (I), D¹ is H. In another embodiment of Formula (I), A¹ is 5 C(A²); A² is Η; B¹ is NHR¹; and D¹ is H. In another embodiment of Formula (I), A¹ is C(A³); A² is H;B' is OR¹; and D¹ is H.

In one embodiment of Formula (I). E¹ is H, In another embodiment of Formula (I), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (I), Y¹ is H, CN, NO2, F, Cl, Br, CF3, R¹⁷, or SO2R^1T. In another embodiment of Formula (I), Y¹ is NO2. In another embodiment of Formula (I), Y¹ is Cl. In another embodiment of Formula (I), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (I), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. In another embodiment of Formula (I), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. In another embodiment of Formula (I), A¹ is C(A²);

A² is H; B^l is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 or SO2R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In another embodiment of Formula (I), A¹ is C(A³); A² is H; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹isNO2 In another embodiment of Formula (I), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is SO?R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In another embodiment of Formula (I), A¹ is C(A²); A² is H; B^[ is OR¹; D¹ is Η; E¹ is H; and Y¹ is Cl.

In one embodiment of Formula (I), R¹ is R⁴ or R³. In one embodiment of Formula (I), R¹ is R⁴. In one embodiment of Formula (I), R¹ is R⁵. In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl. In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is 25 unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with R³⁷, NHR³⁷, or N(R³⁷)₂. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R³⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (I), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R³⁷; R³⁷ is R⁶⁰; and R⁶⁰ is heterocycloalkyl. In another embodiment of Formula (J), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R³⁷; R³⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In another embodiment of Formula (1), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(R³⁷)₂. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2 In another embodiment of Formula (I), R^l is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R^S7)2, R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted.

In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R^S7)₂, R⁵⁷ is R^so, and R⁶⁰ is cycloalkyl which is unsubstituted. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. In another embodiment of Formula (I), R’ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein 10 the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of Formula (I), R¹ is R⁴;

and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹ is R⁴;

and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted as defined herein, In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted with R⁵⁷. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the heterocycloalkyl ring is substituted with one or two or three or four or five more R⁵⁷; SO2R^S7,or OH, and R⁵⁷ is R⁶⁰ or R⁶¹, In another embodiment of Formula (I), R^l is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl. pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl or oxetanyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R^S7 is R⁶⁰, R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R^S7; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is Ci-alkyl, C₂- alkyl, or C₃-alkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five Rⁱ⁷; Rⁱ⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C|-alkyl, C₂-alkyl, or C₃-alkyI; wherein the C_t-alkyl, C₂-alkyl, or C₃-alkyl are unsubstituted or substituted.

In one embodiment of Formula (I), R¹ is R^s; and R⁵ is alkyl which is unsubstituted or 5 substituted. In one embodiment of Formula (I), R^l is R⁵; and R^s is alkyl which is unsubstituted or substituted with R⁷, OR⁷, N(R% or OH.

In one embodiment of Formula (I), R⁷ is R¹⁰ or R¹¹ which are unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R⁷ is R¹⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R⁷ is Rⁿ which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (I), R¹⁰ is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl, 15 piperizinyl, or pyrrolidinyl, which are unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is tetrahydropyranyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is morpholinyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is cycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (I), R¹⁰ is 20 cyclohexyl which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (I), R¹¹ is alkyl which is unsubstituted. In another embodiment of Formula (Γ), R¹' is methyl, which is unsubstituted or substituted as defined herein, In another embodiment of Formula (I), R¹¹ is alkyl, which is substituted as defined herein. In another embodiment of Formula (1), R¹¹ is alkyl, which is substituted with OR¹², R¹² is R^lfi, and 25 R¹⁶ is alkyl.

Another embodiment of this invention pertains to compounds of Formula (Γ), wherein

A¹ isNorC(A²);

A² is H;

B^l is OR¹, NHR¹;

D^l is H;

E¹ is H; and

Y¹ is H, CN, NO2, F, Cl, Br, Cl\ R¹⁷, or SO2R¹⁷;

R¹ is R⁴ or R',

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁷, OR⁷, N(R⁷)₂, OH, F, Cl, Br or I;

R⁷ is R¹⁰ orR;

Rⁱ⁰ is cycloalkyl or heterocycloalkyl;

R¹¹ is alkyl, each of which is unsubstituted or substituted with one or two or three of independently selected F, Cl, Br or 1;

R'⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected F, Cl, Br or I;

Z' is R²⁶;

Z² is R³⁰;

Z^{1 A} and Z^2A are both absent:

L¹ is a R³⁷;

R²⁶ is phenylene;

R³⁰ is heterocycloalkylene:

R³⁷ isR³⁷^

R^3TA is alkylene, alkenylene, or alkynylene, each of which is unsubstituted or substituted with one or two or three independently selected F, Cl, Br and 1 substituents;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^38A; R^38A is heterocycloalkane;

R⁴⁰ is cycloalkenyl, or heterocycloalkenyl;

wherein the moieties represented by R²⁶ and R²⁷are substituted (i.e., if Z^IA and Z^2A are absent) or further substituted (i.e., tfZ^,A and Z^2A are present) with one or two or three or four of independently selected R⁴¹, OR⁴¹, or NHR⁴¹;

R⁴' is R⁴², R⁴³, or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with heteroarene or R^42A; R^42A is heterocycloalkane;

R⁴³ is heteroaryl, which is unfused or fused with heteroarene;

R⁴⁵ is alkyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁴⁶, F, Cl, Br or I;

R⁴⁶ is R⁴⁷, or R⁴⁸;

R⁴⁷ is phenyl;

R⁴⁸ is heteroaryl;

wherein the moieties represented by R⁴², R^42A, R⁴³, R^43A, R⁴⁴, R^44A, R⁴⁷, R^47A, R⁴⁸, R^48A, R⁴⁹, and R^49A are independently substituted with one or two or three or four of independently selected R⁵⁰, OR⁵⁰, CO(O)R⁵⁰, NH:, NHR^S“, N(R⁵⁰)2, NHC(O)R^S0, NHS(O)2R⁵⁰, NHC(O)ORⁱ⁰,, 35 C(O)NH2, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, OH, (O), CN, NO₂, CF_3i F, Cl, Br or I;

R⁵⁰ is R^5l_tR⁵², R⁵³ or R⁵⁴;

R⁸¹ is phenyl;

Rⁱ² is heteroaryl;

R⁵³ is cycloalkyl or heterocycloalkyl;

R⁵⁴ is alkyl, each of which is unsubstituteci or substituted with one or two or three of independently selected R^iS, OR⁵³, C(O)Rⁱ⁵, NH,. NHR^5S, N(R^SS)2, NR^CtOJOR⁵⁵, C(O)N(R⁵ⁱ)2, OH, F, CI, Bror I;

R⁵ⁱ is alkyl, phenyl, or heterocycloalkyl; and wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R^i7A, Rⁱ⁷, ORⁱ⁷, SO2Rⁱ⁷, C(O)R⁵\ CO(O)Rⁱ⁷, NH2, NHR^S7, N(Rⁱ⁷)₂, OH, (O), CN, F, Cl, Br or 1;

R^S7A is spirocyclyl;

R^S7 is R^5!, R⁶⁰ or R⁶¹;

R^SK is phenyl;

R^so is cycloalkyl, or heterocycloalkyl;

R⁶· is alkyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R⁶², OR⁶², N(R⁶²)2, C(O)N(R⁶²)2, OH, F, Cl, Br or 1;

R⁶² is R⁶³, R⁶⁴, R⁵⁵ or R⁶⁶;

R⁶³ is phenyl;

R⁶⁴ is heteroaryl;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl, each of which is unsubstituted or substituted with one or two or three of independently selected OR⁶⁷, F, Cl, Br or 1 substituents;

R⁶⁷ is alkyl;

wherein the moieties represented by R^S7A, R⁵⁸, R^s’, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, and Rⁱ⁷are unsubstituted or substituted with one or two or three or four of independently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R^7lorR⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl which is is unsubstituted or substituted with one or two or three of independently selected F, Cl, Br or I.

Still another embodiment pertains to compounds having Formula (I), which are 4-(4-((4 '-ch loro-1,1 ’-bipheny 1-2-y I )methy l)p iperazin-1 -y I )-2 -(3((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyTan-435 ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4'-chloro-1,1 '-bipheny 1-2-y l)methy] )p i perazin-1 -y 1)-2-(3 -(methy lam ino)phenoxy )-N -((3 nitro-4-((tetrahy dro-2 H-pyran-4-y Imethy l)amino)phenyl )su Ifony l)benzam ide;

4-( 4-((2-( 4-chloropheny 1)-4,4-dimethylcyciohex-l-en-1-yl)methyl)piperazin-l-yl )-2-((2-methyllH-indol-5-yl)oxy)-N-((4-((l-methylpiperidin-4-y])amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -y l)methy Qpiperazin-1 -yl)-2-((2-methyllH-mdol-5-yl)oxy)-N-((4-((3-morpholin-4-y]propyl)amino)-3-nitrophenyl)suifonyl)benzamide; 4-(4-((4'-chloro-l,r-biphenyl-2-y])methyl)piperazin-l-yl)-2-(2-chlorophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-y Imethy 1 )am ino )pheny l)su Ifony I )benzam ide;

4-(4-((4'-chloro-1, Γ-biph eny 1 -2-y 1 )methy 1 )piperazin-1 -y 1)-2-(3 -ch 1 orophenoxy )-N-((3 -n itro-410 ((tetrahydro-2H-pyran-4-ylmethyI)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-bipheny 1-2-yl)methyl)piperazin-1 -yl)-2-(4-ch!orophenoxy)-N-((3 -nitro-4((tetrahydro-2H-pyran-4-yl methy l)amino)ph eny l)sulfonyl)benzami de;

4-(4-((4'-c h loro-1, Γ-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(3-nitrophenoxy )-N-((3-nitro-4((tetrahydro-2 H-pyran-4-y I methy l)amino)pheny I)su 1 fony I )benzam ide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l -yl)-2-(3-(hydroxymethyl)phenoxy)-N-((4((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)suIfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-bipheny 1-2-yljmethy 1 )piperazin-1 -yl)-2-(2-ch lorophenoxy )-N-((4-((3 morpholin-4-ylpropyl)amino)-3-n itropheny l)sulfonyl)benzamide;

4-(4-((4'-ch)oro-1,1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-chlorophenoxy)-N-(( 4-((320 (dimethylamino)propyI)amino)-3-nitrophenyl)suIfonyl)benzamide;

4-(4-((4'-chloro-l,l’-bipheny1-2-yI)methyl)piperazin-l-yl)-2-(3-chlorophenoxy)-N-((4-((3morpholin-4-ylpropyl)amino)-3 -nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,r-bipheny!-2-yl)methyl)piperazin-l-yl)-2-(4-ch!orophenoxy)-N-((4-((3morpholm-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1,1 '-bipheny 1 -2-y l)methyl)p i perazin-1 -y J )-2-(3 -chlorophenoxy )-N-( (4-((3 (dimethy 1 amino)propy l)amino)-3 -n itropheny l)su Ifony l)benzam ide;

4-(4-( (4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-chlorophenoxy)-N-((4-( (3(d imethy lamino)propyl)amino)-3-nitrophenyl)suIfonyl)benzamide;

4-(4-((4’-ch loro-1,1 ¹-bipheny 1-2-yl)methyl)pi perazin-1 -yl)-N-((4-((33 0 (dimethylam i no)propy l)am ino)-3 -n itropheny l)sul fony 1)-2-(( 1 -methy I-1H - indol -4yl)oxy)benzamide;

2-(3-(acetylamino}phenoxy)-4-(4-((4'-chloro-1, Γ-bipheny 1-2-yl)methyl)piperazin-1-y 1)-14-((3nitro-4-((tetrahydro-2H-pyran-4-y Imethy l)am ino)ph eny 1 )sulfony l)benzamide;

2-(4-aminophenoxy )-4-(4-((4 '-chloro- l,l’-bipheny 1-2-yl)methyl)piperazin-l-yl)-N-((3-nitro-435 ((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

2-(3-aminophenoxy)-4-(4-((4'-chloro-1,1 '-biphenyl-2 -y l)methyl )pi perazin-1 -yl)-N-((3-nitro-4((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzam ide:

4-(4-((4'-chloro-l, 1 '-bipheny 1-2-yl)methyl)piperazin-l -y 1)-2 -(3-methoxyphenoxy )-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-1,1 '-bipheny 1-2-y l)methy l)p iperazin-1 -y 1)-2-(3 -(d imethy lamino)phenoxy)-N -((3nitro-4-((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,]'-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4’-chloro-1,1 '-bipheny 1-2-y l)methy 1 )piperazi n-1 -y 1 )-2 -((2-methy 1-1,3 -benzothiazo 1-610 yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-1, Γ-bipheny 1-2-y l)methyl)piperazin-l-y 1)-2-((2-methy 1-1,3-benzothiazol-5y l)oxy)-N-((4-((3 -morphol in-4-y Ipropy I)am ino)-3 -n itropheny l)su Ifony l)benzam ide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazm-I-yl)-N-((4-((3(d imethy lamino)propyl)amino)-3-nitrophenyl )sulfony 1)-2-((2-methy 1-1,3-benzothiazol-515 yl)oxy)benzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-(3-(dimethylamino)-3oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y 1 methy l)amino)phenyl)su Ifony I )benzam ide;

4-(4-((4'-chloro-l,l '-bipheny 1-2-y I )methyl)piperazin-1 -y 1)-2-(2-(2-(d imethy lamino)-220 oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-1 ,Γ-bipheny 1-2-y l)methy I )piperazin-1 -yl)-2-(2-(3(dimethylamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethy l)amino)phenyl)sulfonyl)benzam ide;

4-(4-((4'-chloro-1,1 '-biphenyl-2-y!)methyl)p iperazin-1 -y 1)-2-(2-(2(d imethy lamino)ethy l)phenoxy)-N -((3 -nitro-4 -((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)stilfonyl)benzamide;

2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yI)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)pheny I sulfonylcarbamoyl)phenoxy)-N,N-d imethy Ibenzam ide;

0 4-(4-((4 '-chloro-1,1 '-b ipheny 1-2-y 1 )m ethyl)piperazin-1 -y 1)-2-(2 ((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4^,-chloro-l,Γ-bipheπyl·2-y])methyl)pipeΓazin-l-y])-N-((4-((3(dimethy 1 am ino)propy I )ami no )-3-n itropheny l)sulfony 1)-2-(3-morpho I in-4-ylphenoxy)benzam ide;

4-(4-((4'-chloro-l,r-biphenyl-2-yI)methyl)piperazin-l-yI)-2-(3-(2,4-dimethyl-I,3-thiazol-5y l)phenoxy)-N-((4 -((3 -morpholin-4-y 1 propy l)ami no)~3 -nitropheny l)su Ifonyl )benzam ide;

2-(2-chlorophenoxy )-4-(4-((2-( 4-c h loropheny 1)-4,4-d imethy Icyclohex- 1-en-lyl)methyl)piperazin- l-yl)-N-( (4-(( 1 -methyIpiperidin-4-yl)amino)-3n itropheny l)sulfonyl)benzam ide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-2-(3,55 dichlorophenoxy )-N-((4-((l-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4-((2-(4-chloropheny 1)-4,4-d imethylcyclohex- 1-en-l yl)methyl)piperazin-1 -yl)-N-((4-(( 1 -methylpiperidin-4-yl)amino)-3n itropheny l)sul fony] )benzamide;

4-(4-((4'-chloro-4-(2-(dimethy lam ino)ethoxy )-1, Γ-bi phenyl-2-yl )methyl)p iperazin-1-y 1)-2-(310 chlorophenoxy)-N-((4-((l-methylpiperidin-4-yl)amino)-3-n itropheny l)sulfonyl)benzamide:

2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3y])methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-l,r-biphenyl-2-yl)methyl)piperazin-l-y 1)-2-(3-(215 (dimethy lamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)pheny!)sulfonyl)benzamide;

2-(4-amino-3-chlorophen oxy )-4-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-lyl)methyI)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3n itropheny l)sulfony l)benzam ide;

0 2-(2-ch lorophenoxy )-4-(4-((2-(4-ch loropheny l)-4,4-dimethy Icyc lohex-1 -e n -1 yl)methyl)piperazin-l-yl)-N-((4-((l-isopropylpiperidin-4-yi)amino)-3n itropheny l)sulfonyl)benzamide;

2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl)methyl)piperazin-1 -yl)-N-((4-(( 1 -methy lpiperidin-4-yl)amino)-325 nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohex-]-en-l-yl)methyl)piperazin-l-yl)-N-((4((l-methylpiperidin-4-y!)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl)niethyl)piperazm-l-yl)-2-((3-methyllH-indazol-4-y])oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-n itropheny I )sulfonyl)benzam ide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcydohex- 1-en-l -yl)methyl)piperazin-l-yl)-2-(2,3di fluorophenoxy )-N-((4-(( 1 -methy lpiperidm-4 -y l)amino)-3 -n itrophenyl)sul fony l)benzam ide; 2-(3 -bromophenoxy )-4-(4-( (2-(4-c h lorophenyl )-4,4-dimethy Icyclohex- 1-en-lyl)methyl)piperazin-l-yl)-N-((4-((I-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-ch loropheny 1)-4,4-dimethyIcyclohex-1 -en-1 y l)methyl)pi perazin-1 -y 1 )-N-((4-(( 1 -ethy lpiperidin-4-y l)am ino)-3nitrophenyl)sulfonyl)benzamide;

2-(2 -ch lorophenoxy )-4-( 4-((2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-15 yl)methyl)piperazin-l-yl)-N-((3-nitro-4-((l,2,2,6,6-pentamethylpiperidin-4yl)amino)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyclohex- 1-en-l -y l)methy l)piperazin-1 -y 1)-2-(2,3 difluorophenoxy )-N-((3-nitro-4-((l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino)phenyl)sulfonyl)benzamide;

4-( 4-((2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -y l)methy l)piperazin-1 -yl)-2-((7-fl uoroIH- i ndol-5 -y 1 )oxy )-N-((4-(( 1 -methy lpiperidin-4-y l)am ino )-3 -nitropheny l)su Ifony l)benzam ide; 4-(4-((2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -y l)methy 1 )piperazin-1 -y 1)-2 -(2,3difluorophenoxy )-N-( (4-((3-morphol in-4-ylpropyl)amino)-3-nitropheny l)sul fony l)benzamide; 2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l15 y))methyl)piperazin-I-yl)-N-((4-((3-morpholin-4-ylpropyl)ammo)-3“ n itropheny! )sulfonyl)benzam ide;

2-(3 -ch lorophenoxy )-4-(4-((4'-chloro-4-(2-pyrTolidin-1 -y lethy 1)-1,1 '-bipheny 1-2yl)methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-]-yl)methyl)piperazin-1-y 1)-2-(2,3dichlorophenoxy)-N-((4-((!-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-(4-((2-(4-chlorophenyl)-4₁4-dimethylcyclohex-]-en-l-yl)methyl)piperazin-l-yl)-2-((3-methyl1 H-indazol-4-y l)oxy)-N-((4-(( I -methy lpiperidin-4-yl )am ino)-3 -n itropheny l)su Ifony l)benzamide;

2-(2-ch lorophenoxy )-4-(4-((2-( 4-chlorophenyl)cyclohept- 1-en-l -yl)methyI)piperazin-l-yl)-N-((425 ((]-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-diniethylcyclohex-l-en-l-yl)methyl)piperazm-l-yl)-N-((4-((lmethy lpiperidin-4-yl)amino)-3 -nitropheny l)su Ifony 1)-2-(3 -(tri fluoromethyl)phenoxy)benzam ide; 4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3(d imethy lamino)propyl)amino)-3-n itropheny l)sulfony 1)-2-((2-0 xo-1,2,3,4-tetrahydroquinol in-5 30 yl)oxy)benzamide;

2-(2-chlorophenoxy )-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-l yl)methyl)piperazin-1 -yl)-N-( (4-(( 1 -methylpiperidin-4-yl)amino)-3((tri fl iioromethyl)su!fonyl)phenyl)su Ifony l)benzamide;

4-(4-((2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-)-en-1-y l)methy])piperazin-1-y 1)-2-(2,535 d ichlorophenoxy)-N-((4-(( 1 -m ethy Ip iperidin-4-y l)amino)-3 -nitropheny l)sul fony l)benzam ide;

2-(2-chloro-4-fluoraphenoxy )-4-( 4-((2-(4-chlorophenyl)-4,4-d imethy ley clohex-l-en-1yl)methyl)piperazin-1-yl)-N-((4-(( 1-methy lpiperidin-4-yl)amino)-3n itropheny l)sul fony l)benzam ide;

2-(2-chlorophenoxy)-4-(4-((2-(4-c h loropheny 1)-4,4-d imethy Icyc lopent-1 -en-1 5 yl)methyl)piperazin-1 -y l)-N-((4-(( 1 -methylpiperidin-4-yI)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-ch loropheny I )-4,4 -dimethy Icyc lohex-1 -en-1 -y l)methy l)piperazi η-1 -y 1)-2-(( 3 -methy I !H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-n itropheny l)su I fony l)benzam ide;

4-(4-( (2-(4-ch loropheny I )-4,4-d imethy Icyc lohex-1 -en-1 -yl)m ethyl)p iperazin-1 -yl)-2-(2-chl oro-3 10 (trifluoromethyl)phenoxy)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-(4-((2-(4-chl oropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yl)metbyl)piperazin-1-yl)-N-( (4-(( l-cyclopropylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl)methyI)piperazin-l-yl)-2-((3-methyl1 H-indol-4-y I)oxy)-N-( (4-((1 -methy Ip iperi d in-4-y 1 )am ino)-3 -n itropheny I )su 1 fony 1 )benzam ide; 4-(4-( (2-(4-ch loropheny 1)-4,4-dimethy Icy clohex-l-en-l-yl)methyl)piperazin-l-y 1)-2-(2,5dich!orophenoxy)-N-((4-((3-morphol in-4-ylpropy!)amino)-3-nitropheny l)sul fony I)benzam ide; 4-(4-((4'-ch loro-1 ,Γ-bipheny 1-2-y I )methyl)piperazin- 1-y 1)-2-((1 -methyl-1 H-indol-4-yl)oxy)-N20 ((4-((3-morpholin-4-ylpropy])amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-( (4'-chloro-1,1 '-biphenyl-2-yI)methyl)piperazin-l-yl)-2-(3-morpholin-4-ylphenoxy)-N-((4((3-morphol ίη-4-y Ipropy l)amino)-3-n itropheny l)sul fony l)benzam ide;

4-(4-((4'-ch loro-1 ,Γ-bipheny 1-2-yl)methyl)p iperazin-1 -yl)-N-((4-((3(dimethylamino)propy l)amino)-3 -n itropheny l)su Ifony 1)-2-((3 -(3 -morphol in-4-y 1-3 -oxopropyl)25 1 H-indol-5-yl)oxy)benzamide;

2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3-nitro4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4’-chloro-l ,Γ-bipheny 1-2-yl)methyl)p iperazin-l-yl)-2-(4-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4'-chloro-l,l'-bipheny 1-2-yl)methyl)piperazin-1-y 1)-2-((3-(3-morpho I in-4-y 1-3-oxopropyl)1H- indol-5 -y 1 )oxy )-N-((3 -n itro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l ,Γ-bipheny 1-2-yl)methyl)piperazin-l-yl)-2-((3-(3-morpholin-4-ylpropyl)-lHindol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-435 ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-1,1biphenyl -2 -y Ijmethy IJpiperazin-1 -y 1)-2-(4((dimethy 1 am i no)methy 1 Jphenoxy J-N-((3 -n itro-4-((tetrahydro-2H-pyran-4ylmethyljaminojphenyljsulfonyljbenzamide;

4-(4-((4'-chloro-l, l'-bipheny 1-2-y Ijmethy IJpiperazin-1 -ylJ-2-(4-(lH-imidazol-l -yl)phenoxy)-N5 ((3-nitro~4-((tetrahydro-2H-pyran-4-yImethylJaminoJphenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l,l'-biphenyl-2-yljmethyljpiperazin-l-ylj-2-(3 -nitrophenoxy)-N-((4-((tetrahydro2H-pyran-4-ylmethyI)amino)phenyl Jsulfony IJbenzamide;

tert-buty] 4-(5-(4-((4'-chloro-l,l'-biphenyl-2-ylJmethylJpiperazin-l-ylJ-2-((((3-nitro-4((tetrahydro-2 H-pyran-410 y Im ethyl )amino)phenyl)su Ifony l)amino)carbonyljphenoxyjbenzyl(ethyl)carbamate;

tert-butyl 3-(5-(4-((4'-chloro-1,l'-bipheny 1-2-y Ijmethy IJpiperazin-1-y 1)-2-((((3-nitro-4((tetrahydro-2H-pyran-4y Imethy l)amino)pheny] Jsulfony l)aminojcarbonyl)phenoxy)benzyl( ethylcarbamate;

4-(4-((4'-ch loro-1,1 '-bipheny 1 -2 -y I Jmethy I Jpiperazi η-1 -y lJ-2-(4-((ethy lami η o Jmethy I)phenoxy)-N15 ((3 -n itro-4-((tetrahy dro-2 H -py ran-4-y Imethy IJamino Jpheny 1 Jsu 1 fony 1 Jbenzamide;

4-(4-((4'-ch loro-1, l'-bipheny 1-2-y Ijmethy IJpiperazin-1-y I )-2-(3-((ethyl amino Jmethy] Jphenoxy J-N((3-nitro-4-((tetrahydro-2H-pyran-4-y Imethy IJaminoJpheny I Jsu Ifony IJbenzam ide;

2-(4-(acetylaminoJphenoxyJ-4-(4-((4'-chloro-l ₃l'-biphenyl-2-ylJmethy I Jpi perazin-1-yl)-N-((3nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)aminoJphenylJsulfonylJbenzamide;

tert-butyl 4-(5-(4-((4'-chIoro-l_Il '-biphenyl-2-ylJmethyIJpiperazin-] -ylJ-2-((((3-nitro-4((tetrahydro-2H-pyran-4ylmethyljaminojphenyl Jsu Ifony I Jamino JcarbonylJphenoxy Jpheny Icarbamate;

2-( l,r-biphenyl-2-yloxyJ-4-(4-((4'-chloro-l₁l'-biphenyl-2-ylJmethylJpiperazin-l-y!J-N-((3-nitro4-( (tetrahydro-2 H-pyran-4 -y Imethy 1 Jam ino Jpheny I Jsulfony 1 Jbenzam ide;

tert-butyl 3-(5-(4-((4'-chloro-1,1 '-biphenyl-2-yIJmethy 1 )piperazin-1 -yl J-2-((((3 -n itro-4((tetrahydro-2H-pyran-4y Imethyl Jamino Jpheny 1 Jsulfonyl Jam inojcarbony I JphenoxyJpheny Icarbamate;

2-(1,1 -bipheny 1-3 -y loxyJ-4-(4-((4'-ch loro-1,1 '-bipheny 1-2-y 1 Jmethyl Jpiperazin-1 -y 1J-N -((3 -n itro4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenylJsu Ifony IJbenzam ide;

4-(4-((4’-chloro-],l'-biphenyl-2-yljmethy IJpiperazin-1-y 1)-2-(4-(2(dimethylamino)ethylJphenoxyJ-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl Jsulfony IJbenzam ide;

2-(4-(benzyloxy)phenoxyJ-4-(4-((4^l-ch!oro-l,r-biphenyI-2-yJJmethyl)piperazin-]-yI)-N-((3-nitro4-((tetrahydro-2H-pyran-4-yImethylJamino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l₃ l’-bipheny 1-2-yl)methyl Jpiperazin-l-ylJ-2-(3-morpho]in-4-ylphenoxy J-N-((3nitro-4-((tetrahydro-2H-pyran-4-yl methy IJamino Jpheny l)su Ifony IJbenzam ide;

4-(4-((4'-chloro-l, 1 '-biphenyl-2 -yl)methyl)piperazin-1-y 1)-2-((2-methy 1-1,3-benzothiazol-5y I)oxy)-N-((3 -n itro-4-((tetrahy dro-2H-pyran-4-y lmethyl)am ino)pheny l)su Ifonyl jbenzamide; tert-butyl 4-(3-(5-(4-( (4'-chloro-l, r-biphenyl-2-yl)methyl)piperazin- 1-y 1)-2-((((3-nitro-4((tetrahydro-2H-pyran-45 ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyi)piperazine-l -carboxylate; 2-(3-(benzyloxy)phenoxy)-4-(4-((4’-chloro-l,r-biphenyl-2-y[)methyl)piperazin-l-yl)-N-((4-((3(dimethy lam ino)propyl)aimno)-3-nitrophenyl)sulfonyl)benzaniide;

2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloTO-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-( (4-((3morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-l₎r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-(2-morpholin-4ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4yl methyl )amino)pheny I )sulfonyl)benzamide;

4-(4-( (4'-ch loro-1J '-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfdnyl)-2-((2-oxo-l,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide;

2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-l,r-biphenyl-2-yI)methyl)piperazin-l-yl)-N-((4-((3morpholin-4-y Ipropy l)amino)-3-nitrophenyl)sulfonyl)benzamide;

tert-butyl 4-(4-(5-(4-( (4'-ch loro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-((((4-((3-morphol in4-ylpropyl)amino)-3-mtrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-lcarboxylate;

4-(4-((4'-ch loro-1,1 '-biphenyl-2-y l)methy 1 )pi perazi n-1 -yl)-N-((4-((3-morpholin-4ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamide;

4-(4-((4'-chloro-1,1 '-biphenyl -2-y l)methy 1 )piperazin-1 -yl)-N-(( 4-((3 -morpholin-4y Ipropy l)amino)-3 -n itropheny l)sul fony L)-2-(4-pyri di π-4-y Iphenoxy )benzam ide;

4-(4-((4'-chloro-l,Γ-biphenyl·2-yl)methyl)piperaziπ-l-yl)-N-((4-((3-morpholin-425 y Ipropy l)amino)-3-nitrophenyl )sulfony 1)-2 -(4-pyrid in-3 -ylphenoxy)benzam ide;

4-(4-((4'-chloro-l,r-biphenyI-2-yl)methyl)piperazin-l-yl)-2-(4-(2-(dimethylamino)-2oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4yl methyl )amino)phenyl)sulfonyl)benzamide;

4-(4-( (4’-chIoro-l ,1 '-biphenyl-2-yl)methyl)piperazin-l-yI)-2-((l-methyl-1 H-benzimidazol-53 0 y l)oxy)-N-((4-((3 -morphol in-4-y Ipropy l)amino)-3 -n itrophenyl)su Ifony l)benzamide;

4-(4-((4'-chlorobi phenyl-2-yl)methyl)piperazin- 1-y 1)-2-(3 -(methy Icarbamoy l)phenoxy )-N-(4-(3morphol inopropy lam ino)-3 -n itropheny Isul fony l)benzam ide;

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl)-N-(4-(3 -(dimethy lam inojpropy lam ino)-3nitrophenyIsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benzamide;

4-(4-((4'-chloro-l,l*-biphenyl-2-yl)methy I )piperazin-1-y I )-2-(3-(2-(dimethyJamino)-2oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-ch loro-l,r-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-((3-(3-(d imethy lam ino)propy I)-1H5 indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4 '-chloro-1,1 '-bipheny 1-2-y I )methy l)piperazin-1 -y l)-N-((4-( (3 (dimethy lamino)propy l)am ino)-3 -nitropheny l)sul fony 1)-2 -(3(hydroxymethyl)phenoxy)benzamide;

4-(4-((4'-c h loro-1,1 '-b ipheny 1-2-y I)methy I )piperazi η-1 -y 1)-2-((4-methoxy benzy l)oxy )-N-((3 -n itro4-((tetrahydro-2H -pyran -4-y I methy I jam ino)pheny l)sul fony l)benzam ide;

N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methy lam ino)-3-nitrophenylsulfony I )-2-(3chlorophenoxy )-4-(4-((2-(4-chloropheny 1)-4,4-di methylcyclohex-1 -enyl)methyl)piperazin-1yl)benzamide;

4-(4-( I-(4'-chlorobipheny 1-2-yl)ethyl)piperazin-1-y l)-2-(2-ch!orophenoxy)-N-(3-nitro-4((tetrahydro-2 H-py ran-4-y 1 )methy lamino)pheny Isu Ifonyl )benzamide;

N-{[4-{4-[(4'-chloro-l,r-biphenyl-2-yl)methyl]piperazin-l-yl}-2-(3,5dichlorophenoxy)phenyl]sulfonyl}-4-[(l-methylpiperidin-4-yl)amino]-3-nitrobenzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-(320 fluorophenoxy)-N-({4-[(l-methyIpiperidm-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4- {[2-(4-ch 1 oropheny 1)-4,4-di methy Icyclohex-1 -en-1 -y I ] methyl}p iperazin-1 -y 1)-2-(3 fluorophenoxy)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amtno]phenyl)sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl] piperazin-l-yI)-2-(325 fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-ly 1 ]methy 1} piperazin-1 -y l)-N-( {3 -nitro-4- [(1 -tetrahydro-2H-pyran-4-y Ip iperi din -4yl)amino]phenyl}sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-( 4- {[2-(4-chl oropheny 1)-4,4-dimethy Icyclohex- 1-en-l3 0 y 1] methy I} piperazin-1 -y 1)-N -({4-[(3-morpho 1 in-4-y Ipropy 1 )amino] -3 nitrophenyl}sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4- {[2-(4-chl oropheny 1)-4,4-dimethy Icyclohex-1 -en -1 yl]methyl}piperazin-l-yl)-N-({4-[(l-cyclopentylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 en-]-yHmethyl}piperazin-l-y 1)-2-(4fluorophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4-{[2-(4-chIorophenyl)-4,4-d imethylcyclohex-1 -en- ] yijmethyl} piperazin-l-yl)-N-({4-[( I-cycIopropylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(2 -ch loro-4-fluorophenoxy)-4-(4- {[2-(4-ch loropheny l)-4,4-dime thy Icyclohex-I-en-15 yijmethyl [piperazin-l-yl)-N-({4-[(3-morpholin-4-ylpropyl)am ino]-3nitrophenyl} sulfony l)benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 -y I] methy I} p i perazin -1 -y !)-N-( {4- [(I cy c lopropylpiperidin-4-y I )amino J-3 -n itropheny 1} sulfony 1)-2 -(2,3 -d ifluorophenoxy)benzam ide;

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -yijmethyl} piperazin-1 -y 1)-2 -(210 f!uorophenoxy)-N-({4-[(l-methy lpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4- {[2 -(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y I] methy 1} piperazin-1 -y I)-N-( {4-[( 1 cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;

4-( 4- {[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-l-en-l -yijmethyl }piperazin-l-y 1)-2-(2fl uorophenoxy )-N-( {3 -n itro-4-[( 1 -tetrahy dro-2H-pyran-4-y Ipiperid in-4 15 yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-l-yijmethyl} piperazin-1-y 1)-2-(2fluorophenoxy)-N-({4-[(3-morphoIin-4-ylpropyl)amino]-3-nitrophenyl[suIfonyI)benzamide: 4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l -yijmethyl} piperazin-l-y!)-2-(2fluorophenoxy)-N-( {4 - [(2 -morpho I in-4-y lethy l)am i no]-3 -nitropheny 1} su I fony l)benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-(3 -chlorophenoxy)-4-(4-{ [2-(4-ch loropheny 1)-4,4-dimethylcyclohex-1 -en-1 yijmethyl [piperazin-1-yl)-N-({4-[(3-morpholin-4-y Ipropy l)amino]-325 nitrophenyl} sulfonyl )benzam ide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1)-2-(3 fl uorophenoxy )-N-({4-[(2-morpho li n-4-y lethy 1 )am ino]-3 -n itropheny!} sul fony 1 )benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-I-en-lyl]methyl [piperazin-1-yl)-N-({4-[(l-cyclopentylpiperidin-4-y l)amino]-330 nitrophenyl} sulfony l)benzamide;

2-(3-chlorophenoxy)-4~(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-y])-N-({4-[(l-methylpiperidin-4-yl)amino]-3[ (trifl uoromethyl)sulfonyl]pheny I} sulfony l)benzam ide;

4-(4- {[2-(4-ch loropheny! )-4,4-dimethy Icyclohex-1 -en-1 -yijmethyl} piperazin-1 -yl)-N-( {4-[( 1 35 cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl[sulfonyl)-2-(3-fluorophenoxy)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-]-yl] methyl} piperazin-l-yl)-N-({4-[(lcyclopentylpiperidin-4-yI)amino]-3-nitropheny]}sulfonyl)-2-(2,3-difluoroplienoxy)benzamide; 4-(4-{[2-(4-chloropheny 1)-4,4-d imethylcyclohex-l-en-l-yl] methyl) piperazin-l-yl)-N-({4-[(leye lopentylpiperidin-4-yl)amino]-3-nitropheny I} sulfonyl )-2-(2-fluorophenoxy)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-]-yl]methyl) piperazin-l-yl)-2-(2,3difluorophenoxy )-N-({ 4-[(2-morpho I in-4-ylethyl)amino]-3-nitropheny I }sul fony l)benzam ide; 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-I-yI]methyl}piperazm-l-yl)-2-(2,3di fluorophenoxy )-N- [(3-n itro-4 - {[ 1 -(th ien-3 -y Imethy l)piperidi n-4yl]amino}phenyl)sulfonyl]benzamide;

4-(4- {[2-(4 -chlorophenyl )-4,4-d imethy Icyclohex-1 -en-1 -y l]methy 1} piperazin-1 -y 1)-N- [(4 - {[3 (d imethy lam ino)propyl] amino} -3 -n itropheny 1 )su Ifony 1 ]-2-(2-fluorophenoxy)benzam ide;

4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -yl] methyl} pi perazin-1 -y I )-N-[(4- {[3 (dimethy lamino)propy I ]am ino} -3 -n itropheny l)su Ifony l]-2-(3 -fluorophenoxy )benzam ide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 -en-l-yl]methy I) piperazin-l-yl)-N-[(4-{ [315 (dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4-fluorophenoxy)benzamide;

4-(4-{[2-(4-ch I oropheny 1 )-4,4-d imethy Icyclohex-1-en-l-y I] methyl} pi perazin-1-y 1)-2-(2,3difluorophenoxy)-N-[(4-([!-(2-fluoroethyl)piperidin-4-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3-chIorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l20 y l]methyl} piperazin-1-y l)-N-( {4-[(2-morpholin-4-y lethyl)amino]-3nitrophenyl} sul fony l)benzam ide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly I] methyl} pi perazi π-1 -y I )-N-[ (4- {[3 -(d imethyl am ino)propy l]am ino}-3n itropheny l)su Ifony I] benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyI)piperazin-l-yl)-N-[(4-{[3-(4-methylpiperazin-l-yl)propyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3 -chi orophenoxy )-4 -(4- {[4-(4-ch loropheny l)-6,6-dimethy 1-5,6-d ihy dro-2H-pyran-3 yl]methyl} piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-330 nitrophenyl }sulfonyl)benzamide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-l-yl)-2(2,3 -difl uorophenoxy)-N-( {4- [(1 -methy I p iperid in-4-y l)amino]-3 nitrophenyl }sulfonyl)benzamide;

N -({4- [(1 -al lylpi peridin-4-y l)am ino]-3 -nitropheny I} su I fony 1)-4-(4- {[2-(4-ch I oropheny 1)-4,4 35 dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-(2,3-djfluorophenoxy)benzamide;

2-(3 -chloro-2-fluoroph enoxy)-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 yl]methyl} piperazin- l-yl)-N-({4-[( l-methylpiperidin-4-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

2-(3-chloro-2-fluorophenoxy)-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-l-en-15 yl]methyl} piperazin-l-yl)-N-( {4-[(3-morpholin-4-ylpropyl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3 -ch loro-2-fluoroph enoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethyIcyc lohex-1 -en-1 yl]methyl} piperazin-1-yl)-N-({3-nitro-4-((3-pyrrolidin-ly I propyl )am ino]pheny 1} su Ifony I)benzam ide;

2-(3-ch loro-2-fl uorophenoxy )-4-(4- {[2 -(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1-en-Iyl] methy I} piperazin-1 -y I )-N-( {4- [(2-morpho I in-4-y lethy I )am ino] -3 nitrophenyl }su Ifony l)benzamide;

2-(2-chloro-6-fl uorophenoxy )-4-(4-{[2-(4-chIoropheny 1)-4,4-dimethy Icyclohex-1-en-lyl]methyl} piperazin-l-yl)-N-( {4-((1 -methy lpiperidin-4-yl)amino]-315 nitrophenyl} sulfonyl )benzam ide;

2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-yipiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-( 4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1-en-1-y I] methy I) piperazin-1-y 1)-2-[(6-fluoro20 lH-indol-5-yl)oxy]-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

-(3 -chlorophenoxy )-4-(4- {(2-(4-chloropheny 1 )-4,4-dimethy Icyc lohex- 1-en-lyljmethyl} piperazin-l-yl)-N-((4-{[(l-methylpiperidin-4-yl)methyI]amino}-3nitrophenyl )sul fony l]benzam ide;

4-(4- {[2-(4-chloropheny l)-4,4-d i methy Icyclohex-1 -en-1 -y I] methy I} piperazin-1 -y 1)-2 -(2,3 25 difluorophenoxy)-N-[(4-{[(I-methylpiperidin-4-yl)methyl]amino}-3n itropheny l)su I fony I] benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en- 1-y l]methyl} piperazin- 1-y l)-2-[(4-fluorol H- indol-5 -y l)oxy]-N-( (4-(( 1 -methy I piperidin-4-y I )am i no]-3 -n itropheny 1} su lfonyl)benzamide; 4-(4- {[2-(4-chloropheny 1)-4,4-d imethylcyclohex-l-en-l-yl]methyl} piperazin-1 -y 1)-2-(330 (methoxymethoxy)-2-methylphenoxy]-N-({4-[(l-methylpiperidin-4-yl)ammo]-3nitrophenyl} sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazm-l-yl)-2-(3-hydroxy2-methylphenoxy)-N-( {4-((1 -methy lpiperidin-4-yl)ammo]-3-nitropheny I }sulfonyl)benzamide;

2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-335 yl]methyl}piperazm-l-yl)-N-({4-[(l-methylpiperidm-4-yl)amino]-3nitropheny 1} su I fony l)benzam ide;

4-(4- {[4-( 4-chloropheny I )-6,6-d imethy 1-5,6-d ihydro-2 H-pyran-3-y l]methyl} piperazin-1 -y 1)-2-(3 iodophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(3-chlorophenoxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 yl]methyl}piperazin-l-yl)-N-[(4-{[I-(2-hydroxyethyl)piperidin-4-yl]amino}-35 nitrophenyl)sulfonyl] benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly l]methy 1} piperazin-1 -y 1)-N-[(3 -nitro-4- {[ 1 -(2-phenylethyl)piperidin-4yl] amino} phenyl)sulfonyl]benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icy c lohex-1 -en-1 -yl]methy 1} piperazin-1 -y 1)-2-(3,4 10 dichlorophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(2 -chloro-3,5-d i fl uorophenoxy )-4-(4- {[2-(4-ch loropheny 1 )-4,4-d i methy Icyc lohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(l-methy lpiperidin-4-yi)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {[2-(4-ch 1 oropheny 1)-4,4-di methy Icy c lohex-1 -en-1 -yl] methy 1} piperazi π-1 -y 1 )-2-(3 15 methoxyphenoxy)-N-({4-[(l-methyIpiperidin-4-yl)ammo]-3-nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethylcycIohex-1 -en-1 -yl]methyl} piperazin- 1-y l)-2-[3(hydroxymethy 1 )phenoxy] -N-( {4-[( 1 -methy 1 p i peridin-4-y I)amino] -3 nitrophenyl} sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-(4- {[2-(4-chIoropheny 1 )-4,4 -dimethy Icyc lohex-1 -en-1 20 y)]methyl}piperazin-l-yl)-N-( {4-((1,4-dimethylpiperidin-4-yl)amino]-3n itrophenyl} sulfony l)benzam ide;

2-(3 -chiorophenoxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 y 1] methyl} piperazin-1-y l)-N-( {4-[(1,4-dimethy lpiperidin-4-y] )amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-{[4-({l-[2-(2-methoxyethoxy)ethyl]piperidin-4-y I} amino )-3nitrophenyl]sulfonyl} benzamide;

2-(2-ch loro-3 -hydroxyphenoxy )-4 -(4- {[2-(4-chloropheny 1)-4,4-di methy Icyc lohex-1 -en-1 y l]methy 1} piperazin-1 -y l)-N-( {4-[( 1 -methyIpiperidin-4-yl Jam ino]-3 30 nitrophenyl} su Ifonyljbenzamide;

2-(3-chlorophenoxy)-4-(4-([2-(4-chlorophenyl )-4,4-dimethy Icyc lohex-1-en-lyl] methy I } piperazin-1 -yl)-N-[(3-nitro-4- {[1 -(3-phenylpropyl)piperidin-4yl]amino}phenyl)sulfonyl]benzamide;

2-(3-ch lorophenoxy)-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethylcyc lohex-1 -en-1 35 yl]methyl}piperazin-l-yl)-N-[(4-{[]-(2-methoxyethyl)piperidin-4-yl]amino}-3nitrophenyljsu I fonyl] benzamide;

2-(3-chlorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy leyclohex- 1-en-1 yl]methyl}piperazin-l-yI)-N-({4-((l-ethylpiperidin-4-yl)amino]-3n itropheny 1} su Ifony I )benzam ide;

2-(3 -ch lorophenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-d i methy Icyc lohex-1 -en-1 5 yl]methyl}piperazin-I-yl)-N-({4-[(l-isopropylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-y])-2-(3hydroxyphenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(2-chIoro-3 -fluorophenoxy )-4-(4- {[2-(4-ch loropheny] )-4,4-d imethy leyclohex-1-en-110 yl] methy 1} piperazin-1 -y ])-N-( {4-[( 1 -methy 1 piperid i n-4-y l)am ino]-3n itropheny! }sulfonyl)benzam ide;

-(2 -ch loro-3 -fl uorophenoxy)-4-(4- {[2 -(4-ch loropheny 1)-4,4 -d imethy Icy c lohex- i-en-1yljmethyl} piperazin-l-yI)-N-({3-nrtro-4-[(l-tetrahydro-2H-pyran-4-y!piperidin-4y I )amino] phenyl }sulfbnyl)benzam ide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyI)-4,4-dimethyIcyclohex- 1-en-1 yl]methyl} piperazin-]-yl)-N-[(4-{(3-(dimethylamino)propyl]amino}-3n i tropheny 1 )sul fony I] benzamide;

4-(4-{ [2-(4-ch loropheny 1)-4,4-dimethylcyc iohex- 1-en-1 -yl]methyl} piperazin- 1-y 1)-2-(2methoxyphenoxy)-N-( {4-(( 1 -methyip iperid i n-4 -yl)am ino] -3 -nitrophenyl} sulfony l)benzamide;

4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-1 -en-1 -yl]methyl} piperazin-1 -yl)-2-(2methylphenoxy)-N-( {4-((1-methy lpiperidin-4-yl)amino]-3-nitrophenyI}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-)-en-l-yl] methyl} pi perazin-1-y 1)-2-(3methy lphenoxy)-N -({4-((1 -methy lpiperidin-4-y l)am ino]-3 -n itropheny I} su I fony 1 )benzam ide;

2-(2-chlorophenoxy)-4-(4- {[6-(4-ch loropheny 1)-1,3 -benzodioxol-5 -y I] methy 1} piperazin-1 -y 1)-N25 ({4-[(l-methyIpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(2-ch lorophenoxy )-4-(4- {[2-(4 -ch loropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-((4-methylpiperazin-I-yl)amino]-3nitrophenyl} sulfony l)benzamide;

2-(3-chlorophenoxy )-4-(4- {[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-33 0 y l]methy 1} piperazin-1 -y 1 )-N-( {4-[(4-methy 1 piperazin-1 -y 1 )am ino]-3 nitrophenyl} su Ifony l)benzamide;

4-(4-{[4-(4-ch loropheny l)-6,6-di methy 1-5,6-dihydro-2H-pyran-3-yl]m ethyl} piperazin-i-y 1)-2(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3-chlorophenoxy )-4-(4-{[2-(4-chloropheny !)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-[(4-{[l-(cyclopropylmethyl)piperidin-4-yl]amino}-3n itropheny 1 )sulfonyl]benzamide;

2-(2-ch lorophenoxy)-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 5 yl]methyl} piperazin-l-yl)-N-[(4-{[l-(cyclopropy Imethy l)piperidin-4-yl]amino}-3nitrophenyl)sul fony I] benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-chloropheny I )-4,4-dimethy Icy c loh ex- 1-en-iyl]methyl} piperazin-l-yl)-N-{ [4-( {l-[2-(dimethylamino)-2-oxoethyi]piperidin-4-yl}amino)-3nitrophenyl]sulfonyl} benzamide;

2-(3 -ch lorophenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1yl]methyl}piperazin-l-yl)-N-[(4-{[]-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3n itropheny l)su I fony I]benzam ide;

N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfony]]-2-(2chlorophenoxy )-4-(4- {[2-(4-ch 1 oropheny 1)-4,4-d i m ethy 1 cycl ohex-1 -en-1 -y I] methy I} pi perazi n-1 15 yl)benzamide;

2-(2-chlorophenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-[(4-{ [(4-hydroxy-l-methylpiperidin-4-yl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1-en-1-y I] methyl} piperazin-1-yl)-2-[(6-fluoro20 lH-indol-5-yl)oxy]-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl} sulfony IJbenzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-lyl]methy!}piperazm-l-yl)-N-[(4-{[(3S)-l-methylpynOlidin-3-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3 -chlorophenoxy )-4-(4- {[ 2-(4-ch lorophenyl)-4,4-dimethy Icyclohex- 1-en-ly 1] methy 1} piperazin-l-yl)-N-[(4-{ [(3 R)-l-methy lpyrrolidin-3-yl] amino}-3nitropheny l)sulfonyl] benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1-en-i-y I] methy l}piperazi π-l-yl)-N-( {4-[(lmetbylpiperidin-4-yl)amino]-3-nitrophenyl}sulfbnyl)-2-[3-(lH-pyrrol-2-yl)phenoxy]benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-d i methylcyclohex-1 -en-1 -y I] methy 1} pi perazin-1 -y 1)-2-(3 fluorophenoxy)-N-[(4-{ [(4-hydroxy-l-methy lpiperidin-4-yl)methyl]amino}-3nitrophenyl)sul fony! ] benzamide;

2-(3-chlorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icycl ohex-1 -en-1 yflmethyl} piperazin-1-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-335 n itrophenyl }sul fony l)benzami de;

4-(4-{[2-(4-chlorop heny 1)-4,4-d imethy lcyclohex-l-en-l-yl]methyl} piperazin-1-y 1)-2-[(6,7difluoro-lH-indol-5-yl)oxy]-N-({4-[(]-methylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-( 4-ch loropheny 1)-4,4-d imethy Icyc lohex-l-en-l-yl]methyl} piperazin-l-yl)-2-[(6,75 difluoro-1 H-indol-5-yl)oxy]-N-({3-nitro-4-[(l-tetrahydro-2 H-pyran-4-y lpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

tert-butyl 4-(5-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)2-{[({4-[(I-methyl piperidin-4-yl)amino]-3-nitrophenyl }sulfonyl)am ino]carbonyl} phenoxy)-] Hindole-1 -carboxylate;

2-(3 -ch lorophenoxy)-4-(4- {[2-(4-ch loropheny 1 )-4,4-d i methy Icyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 y I] met hyl} p iperazin-1 -y I )-N- [(4- {[4-(d iethy lam ino)cyc lohexy l]am i no} -3 15 nitrophenyl)sulfony I] benzamide;

Trans-2-(3-chlorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy lcyclohex-l-en-1y I]methyl) piperazin-1-y I)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl) sulfonyl)benzamide;

4- {4-[l-(4'-ch loro- Ι,Γ-bipheny l-2-yI)ethyl] piperazin-1 -yl}-2-(2-ch lorophenoxy)-N-({4-[(l20 methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(2-chloro-4-hydroxyphenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy lcyclohex-l-en-1y l]methy I} pi perazin-1 -y I)-N-( {4 -[(1 -methy Ipiperid in-4-y 1 )amino] -3 n i tropheny I} s u I fony l)benzam ide;

2-(2-chloro-4-hydroxyphen oxy )-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 25 yl] methy 1} piperazin-1 -y l)-N-( {4- [(4-methy 1 piperazin-1 -y 1 )amino]-3 nitrophenyl} sulfonyl )benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycIohex-l-en-1-y l]methyl} piperazin-1-yl)-2-[(6-fiuoro1 H-indol-4-yl)oxy]-N-({4-[(]-methy lpiperidin-4-yl)aminoj-3-nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-l-en-l-yljmethyl} piperazin-l-yl)-2-[(6-fluoro3 0 1 H-indo l-4-y 1 )oxy]-N-({3 -n itro-4- [(1 -tetrahydro-2H-py ran-4-y Ipiperid in-4yl)amino]phenyl}sulfonyl)benzamide;

2-(2-ch loro-4-hydroxyphenoxy)-4-(4-{ [2-(4-ch loropheny 1)-4,4-d imethy lcyclohex-l-en-1yl]methyl}piperazin-I-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-( {1,3-bis[(4-methy Ipiperazin-1 -yl)methylj-1 H-indol-4-yl }oxy )-4-(4- {[2-(4-chlorophenyl)-4,4d imethy Icyc lohex- l-en-l -yl]methy 1} piperazin-1 -y 1)-N- [(4- {[3 -(dimethy lamino)propy l]am ino} -3 n itropheny l)sul fony 1 ]benzamide;

4-(4- {[2-(4-ch 1 oropheny l)-4,4-d i methy Icyc lohex- l-en-l -y 1 ]methy 1} piperazin-1 -y l)-N-[(4-{ [3 5 (dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-l-yI)methyl]1 H-indol-4-yl} oxy)benzam ide;

2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methyl)piperazm-l-yl)-2-(4-(lmethy Ipiperid in-4-y lamino)-3 -n itrophenylsulfony Icarbamoy l)phenoxy )-N,N-dimethy Ibenzam ide; 4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyclohex- l-en-l -y I] methy 1} piperazin-1 -y l)-N-( {3 -n itro-410 [(1-tetrahy dro-2H-pyran-4-y Ipiperid in-4-yi)amino] phenyl} sulfony 1)-2-{[2-( tri fluoromethyl)-1HindoI-4-yl]oxy}benzamide;

2-(2-chloro-4-hydroxyphenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydrD-2H-pyran-4-ylpiperidin-4yl)amino]pheny I} sulfony l)benzamide;

4-(4-{[2-(4-chlorophenyI)-4,4-dimethy Icyclohex-l-en-]-yl]methyl} piperazin-l-yl)-N-({4-[(lmethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-lH-indol-5yl]oxy} benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex- l-en-l -y l]methy I }piperazin-l-yl)-N-({3-nitro-4[(1 -tetrahy dro-2 H-pyran-4-y !piperidin-4-y 1 )am ino] phenyl} su 1 fony 1)-2- {[6-(trifluoromethy I)-1H20 indol-5-yl]oxy} benzamide;

2-[(2-am ino-1,3-th iazol-4-yl)methoxy]-4-(4-{[2-(4-ch I oropheny 1)-4,4-d imethy Icyclohex-l-en-lyljmethyl} piperazin-1-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino] phenyl} sulfony l)benzam ide;

4-(4-{[2-( 4-chloropheny 1)-4,4-d imethy Icyclohex- l-en-l -y IJmethy I }piperazin-l -yI)-2-[(6,725 d ifluoro-lH-i ndol-5-yl)oxy ]-N-({4-[(4-methy Ipiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1 )-4,4-dimethy Icyc lohex-l-en-l-yl]methyl} pi perazin-1-y 1)-2-[(6-fluoro1 H-indol-5-yl)oxy]-N-({ 4-[(4-methy 1 piperazin-l-yI)amino]-3-nitrophenyl} su lfonyl)benzam ide;

tert-butyl 4-[(5-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-1 -yl)30 2-{[({4-((1-methy Ipiperid in-4-y I )amino]-3n itropheny 1} sulfonyl )amino]carbony I} phenoxy )methy I] -1,3 -thiazo l-2-ylcarbamate;

2-[(2-am ino-1.3-th iazol-4-yl)methoxy]-4-(4-{[2-(4-chloropheny))-4,4-d imethy Icyclohex-l-en-lyl]methyl) piperazin-1-y 1)-bI-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

100

2-[ 3 -(ac ety lamino)phenoxy]-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 yljmethyl} piperazin-l-yl)-N-( {4-(( l-methylpiperidin-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3-( acetylamino )phenoxy]-4-(4- {[2-(4-ch loropheny 1)-4,4 -dimethylcyclohex-1 -en-1 5 y 1] methyl} piperazin-l-yl)-N-( {3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4yl)ami no] phenyl }sulfonyl)benzamide;

2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-!-en-lyljmethy I} piperazin-l-yl)-N-({3-nitro-4-[( I-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1-yljmethy I} piperazin-1-y 1)-2-(( 6methoxy-lH-indol-5-yI)oxy]-N-({3-nitro-4-[(l-tetTahydro-2H-pyran-4-yIpiperidin-4y I )amino)pheny I} su 1 fony I )benzam ide;

2-[(2-amino-1,3 -benzothiazo 1-6-y l)oxy] -4-(4- {[2-(4-chlorophenyl )-4,4-d imethy Icy c I ohex-1 -en-1 yl]methyI}piperazin-l-yl)-N-({4-[(l-methy lpiperidin-4-yI)amino]-315 nitrophenyl} sulfonyl)benzamide;

2-[(2-chlorophenyl)aminoJ-4-(4-{[2-(4-chlorophenyl)-4₎4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-[(]-methy lpiperidin-4-yl)amino]-3nitropheny 1} su 1 fony l)benzamide;

tert-butyl 5 - [ 5-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyc lohex-1 -en-1 -yljmethyl} p iperazin-1 -y 1)20 2-( {[(4-{ [3 -(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino} carbonyl )phenoxy J IH-indole-l-carboxylate;

2- [(2-amino-1,3 -ben zoth iazo 1-6-y l)oxy] -4-(4- {[2-(4 -ch loropheny 1)-4,4-dimethy Icy clohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{(2-(4-chloropheny l)-4,4-di methy Icyc lohex-1-en-1-yljmethy I} piperazin-1-y 1)-2-[(6-fluoroIH-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-lyl)propyl]amino}phenyl)sulfonyl]benzamide;

Trans-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-l-yl Jmethyl} pi perazin-1-y 1)-2-((6fluoro-lH-indoI-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)aminoJ-330 nitrophenyl} sulfonyl)benzam ide;

Trans-4-(4-{ [2-( 4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-1-yljmethy l}piperazin-l-yl)-2-[(6,7difIuoro-lH-indoI-5-yl)oxy]-N-({4-[(4-morpholm-4-ylcyclohexyI)ammo]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-[(4-{[l35 (cyclopropy Imethy l)piperidin-4-yl] amino}-3-nitrophenyl)su Ifony I ]-2-[(6-fl uoro-lH-indol-5yl)oxy]benzamide;

101

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-[(4-{[](cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6,7-dinuoro-lH-indol-5yl)oxy]benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y l]methyl} piperazin-1 -y 1)-2-(( 6-fluoro5 lH-indo!-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino] phenyl} sulfonyl)benzam ide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-l-en-l-yl]methyl} pi perazin-1-y I )-2-[(6,7difluoro-lH-indoI-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-lyl)propyl]amino}phenyl)sul fony I] benzamide;

4-(4- {[2 -(4-chloropheny 1)-4,4-d imethy Icycl ohex-1 -en-1 -y 1] methy I} p iperazin-1 -y 1)-2- [(6-fl uoro1H- indo 1-5-yl )oxy ]-N-( {4- [(2-hydroxy-1 -tetrahydro-2H-pyran-4-y 1 ethy l)am ino]-3 nitrophenyl} sul fony l)benzam ide;

4-(4 -{[2-(4-chloropheny 1)-4,4-di methy Icyclohex-l-en-l-yl]methyl} piperazin- l-yl)-2-((6-fluorolH-indol-5-yI)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3- nitrophenyl] sulfonyl} benzamide;

2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyciohex-l-en-lyl]methyl}piperazm-Lyi)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny l)-4,4-dimethy Icyclohex-1 -en- 1-y IJmethyl} pi perazin- 1-y 1)-2-((6,720 difluoro-1 H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

- [(6-chloro-1 H-indoI-5-y l)oxy]-4-(4- {[2-(4-ch 1 oropheny 1)-4,4-dimethylcyc lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-({4-[(4-methylpiperazin-I-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-ch loropheny 1 )-4,4-dimethylcyc lohex- l-en-l-yl]methyl} piperazin- l-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-[(3-nitro-4-{ (1-(1,3-th i azo 1-4-ylmethy l)piperidin-4yi]amino}phenyl)sulfonyl]benzamide;

2-(3-chIorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-I-en-lyl] methy 1} piperazin-1 -y l)-N-( {3 -n i tro-4-[(tetrahydro-2H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-( 4-am ino-3 -ch lorophenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex- 1-en-ly 1 ]methy 1} piperazin-1 -y I)-N-( {3-n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino] phenyl }su Ifony I )benzam ide;

N-[(4- {[(4-aminotetrahydro-2H-pyran-4-y I )methy I] amino} -3-nitrophenyl )sulfonyI]-4-(4-{ [2-(435 ch lorophenyl)-4,4-dimethy Icyclohex- 1-en- 1-y IJmethyl} pi perazin- 1-y l)-2-[(6-fluoro-lH-indo 1-5y l)oxy] benzam i de;

102

4-(4- {[2 -(4-chloropheny 1 )-4,4-di methy Icyc lohex- 1-en-l -y I Jmethy 1} piperazin-1 -y 1)-2- [(6-fluorolH-indol-5-yl)oxy]-N-[(4-{[(3S_J4R)-3-hydroxy-l-(l₁3-thiazol-4-ylmethyl)piperidin-4-yl]amino}3-nitrophenyl)sulfonyl]benzamide;

2-(2-chlorophenoxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethy Icyclohex- 1-en-l 5 yljmethyl} piperazin-1 -yl)-N-{ [4-( {[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl] methyl} am ino)-

-nitrophenyl] su Ifony 1} benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-di methy Icyc lohex-1 -en-1 -yljmethyl} piperazin-l -yl)-2-[(6-fluoro~ lH-indol-5-yl)oxy]-N-{ [3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl} benzamide;

4-(4-{[2-(4-chloropheny I )-4,4-d imethy Icyc lohex-1-en-l-yl]methyl} piperazin-l-yl)-2-[(6-fluoro10 lH-mdol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl} benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chIorophenyl)~4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl} benzamide; 2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4_!4-dimethylcyclohex-l-en-ly l]methy 1} piperazin-1 -y l)-N-[(3 -n itro-4- {[3 -(3 -oxop iperazin-1 15 yl)propyl]amino] phenyl)sulfonyl]benzamide;

2-(6-aminopyrid in-3-y 1)-4-(4-( [2-(4-ch lorophenyl)-4,4-d imethy Icyclohex- 1-en-l y I Jmethy]} p iperazin-I -y !)-N-({3 -nitro-4-[(1 -tetrahydro-2 H-pyran-4-y Ipiperid in-4yl)amino]phenyl}sulfonyl)benzamide;

4-(4-( 1-[2-(4-chloropheny 1)-4,4-di methy Icyclohex- 1-en-l -yl]ethyl} piperazin-l -yl)-2-[(6-fluoro20 I H-indol-5-y l)oxy]-N-( {3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-l -yljmethyl} piperazin-1 -yl)-2-[(6-fl uoro1 H-indoI-4-y l)oxy]-N-[(3 -n itro-4- {[3 -(3-oxopiperazin-1 yl)propyl]amino}phenyl)sulfonyl]benzamide;

4-(4-([2-(4-chlorophenyl)-4,4-dimethy Icyclohex- 1-en-l -yljmethyl} piperazin- 1-y l)-2-[(6-fluoro1 H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3y Imethy l]am ino }phenyl)su Ifony 1] benzamide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-d i methy Icyclohex-1 -en-1 -y 1] methy I} p iperazi η-1 -y I )-2-[(6-fl uoroI H-indol-5-y l)oxy]-N-[(3-n itro-4-{[(3 R)-tetrahydro-2H-pyran-330 ylniethyl]amino}phenyl)sulfonyl]benzamide;

tert-butyl 5 -(5 -(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y 1 ] methyl} pi perazin-1 -y 1)2- {[({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino] phenyl} sulfonyl )amino]carbony I} phen oxy )-3,4-dihydro isoquinol ine-2(lH)carboxylate;

103

2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly IJmethyl} p iperazin-1 -yl )-N-( {3 -nitro-4-[( 1 -tetrahydro-2H-pyran-4 -ylpiperidin-4yl)am ino] phenyl} sulfony l)benzamide;

4-(4-{ [2-(4-chloropheny 1)-5,5-dimethylcyclohex-l-en-1-yijmethyl} piperazin-l-yl)-2-[(6-fluoro5 1 H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)aminojphenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chIorophenyl)-4,4-dimethyicyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-[(6-fluoroiH-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-1 -en-1 -yijmethyl} piperazi η-1 -y 1)-2- [(6-fluoro10 1 H-indol-5-yl)oxy]-N- {[3-nitro-4-(tetrahydro-2H-pyran-4ylmethoxy)phenyl]su I fonyl) benzamide;

2-[(3-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyijmethyl) piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(3-chloro-lH-indol-4-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-lyijmethyl} piperazin-l-yl)-N-( {3-nitro-4-[( tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4- {[2-(4-ch loropheny l)-4.4-dimethy Icyc lohex-1 -en-1 -yl] methy I} piperazin-1 -y l)-N-( {3-nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl }sulfonyl)-2-[(2-oxo-2,3-dihydro-lH-indol-520 yl)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4.4-dimethylcyclohex-l-en-l-yijmethyl} piperazin-l-yl)-N-({3-nitro-4[(tetrahydro-2 H-pyran-4-yl methy l)amino] pheny I} su I fony l)-2-[(2 -oxo-2,3 -dihydro-1 H-indol-4yl)oxy]benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-d imethy Icy clohex-1 -en-1 -yijmethyl} piperazin-1 -y l)-2-[( 6-fluoro25 lH-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;

tert-butyl 5-(5 -(4- {[2-(4-ch loropheny 1)-4,4-di methy Icyc lohex-1 -en-1 -yI] methy 1} piperazin-1 -y 1)2-{ [({3-nitro-4-[(tetrahydro-2H-pyran-4yImethyl)ammo]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;

tert-butyl 4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yijmethyl}piperazin-1-yl)30 2-{[({3-nitro-4-[( 1 -tetrahydro-2 H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyI)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;

2-[(6-aminopyridin-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icy c lohex- 1-en-ly 1] methy I} piperazin-1 -y l)-N-( {3 -n i tro-4- [(tetrahy dro-2H-pyran-4y 1 methy l)am ino] pheny 1} su Ifony l)benzam ide;

104

2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yljmethyl} piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4y 1 JaminoJpheny I} sulfony I )benzam ide;

2- [(5 -bromopy ridin-3 -yl Joxy ] -4-(4- {[2-(4-chloropheny 1)-4 _f4-dimethy Icyc lohex-1 -e n-1 5 yl]methyl} piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino] phenyl} sulfonyl )benzamide;

2-[(6-ch loro-lH-indol-5-yl)oxy]-4-(4-{[4-(4-chl oropheny l)-6,6-d imethy I-5,6-dihydro-2H-pyran3-yl] methy I} piperazin-1 -y l)-N-( {3 -n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-ch!orophenyl)-4,4-dimethylcyclohex-l-en-ly!] methy 1} p iperazin-1 -y l)-N-( {3 -n i tro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]pheny I} sulfony l)benzamide;

4-(4- {[4-(4-chloropheny 1)-6,6-d imethy 1-5,6-d ihydro-2 H-pyran-3 -y l]methy I} piperazin-1 -y l)-2-[(6fl uoro-1 H-indo l-5-y I) oxy ] -N-( {3 -nitro-4- [(tetrahydro-2H-py ran-415 ylmethyl)amino]phenyl}sulfonyl)benzamide;

tert-butyi 5-(5-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-1-yI)2- {[({3 -nitro-4-[(tetrahydro-2H-pyran-4ylmethyljamino]phenyl}su!fonyljamino]carbonyl} phenoxy Jpyridin-3-ylcarbamate;

2-[(5-am inopyrid in-3 -yI)oxy]-4-(4- {[2-(4-ch 1 oropheny I )-4,4-d imethy Icyclohex-1-en-120 y I] methyl} piperazin-1-y l)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

tert-butyl 4-(5-(4-{[2-(4-chlorophenylJ-4,4-dimethylcyclohex-1-en-1-yljmethyl} piperazin-1-yl)2 - {[ ({3-n itro-4- [(tetrahy dro-2H-pyran-4 ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;

2-[(3-chloro-lH-indoi-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly l]methyl} pi perazin-1-y l)-N-({ 3-n itro-4-[(l-tetrahy dro-2 H-pyran-4-y lpiperidin-4y I Jam ino]pheny 1} sulfony 1 Jbenzam ide;

2-[(2-am inopyrid in-4-ylJoxy] -4-(4-{[2-(4-chloropheny 1)-4,4-d imethyIcyc lohex-1 -en-1 y 1 ] methyl} piperazin-1 -y l)-N-( {3 -n itro-4-[(tetrahydro-2 H-pyran-430 ylmethyl)amino]phenyl} sulfony IJbenzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-[(6hydroxypyrid i n-3 -y IJoxyJ-N -({ 3 -nitro-4-[(tetrahydro-2H-pyran-4y Imethyl Jamino]phenyl}suifonyl)benzamide;

2-{[6-(benzyloxy)pyridin-3-y]]oxy )-4-(4-{[2-(4-ch!orophenylJ-4,4-dimethylcyclohex-l -en-1 3 5 y 1 ]methy I} piperazin-1 -y 1)-N-( {3 -nitro-4- [(tetrahydro-2 H-pyran-4ylmethy l)amino] phenyl) sul fonyl Jbenzamide;

105

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [4-( 1,4dioxan-2-ylmethoxy )-3-nitrophenyl]su Ifony l}-2-[(6-fluoro-lH-indol-5-yl)oxy] benzamide;

2-[(3-chloro-lH-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-iy I] methy 1} piperazin-1 -y 1 )-N-({4- [(4-methy Ipi perazi η-1 -y l)am ino] -3 5 nitrophenyl} su Ifony l)benzam ide:

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1-y I] methyl} piperazin-1-yl)-N-({ 4-[(4methy Ipiperazin-1-y l)amino]-3-nitrophenyl }su Ifony l)-2-[(2-oxo-2,3-dihydro-1 H-indo 1-4yl)oxy] benzamide;

4-(4-{ [2-(4-chIorophenyI)-4,4-dimethy lcyclohex-l-en-l-yl]meihyl} piperazin-l-yl)-N-({4-[(l10 methy lpiperidin-4-yI)amino]-3-nitrophenyl} sulfonyl )-2-[(2-oxo-2,3 -dihydro- lH-indol-4yl)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({3-nitro-4[(l-tetrahydro-2H-pyran-4-y Ip iperidin-4-yl)ammo] phenyl} sulfonyl)-2-[(2-oxo-2,3-dihydro-1HindoI-4-yI)oxy]benzamide;

2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-!-en-ly I] methyl} piperazin- l-yl)-N-{ [4-( 1,4-dioxan-2-ylmethoxy )-3 -nitrophenyl] sulfonyl} benzamide; 2-[(6-chloro-l H’indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-1yl]methyl} piperazin-l-yI)-N-({4-[(l ,4-dioxan-2-y !methyl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy Icycl ohex-1 -en-1 -y 1 ] methyl} piperazin- 1 -y l)-N-( {4-[( 1,4dioxan-2-ylmethyI)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide; Trans-2-[(6-chloro-1 H-indol-5-yl)oxy]-4-(4- {[2-(4-ch loropheny! )-4,4-dimethy Icyclohex-1-en-1 y I] methy 1} piperazin-1 -y l)-N-( {4- [(4-morphol in-4-y Icy clohexy l)amino] -3 n itropheny I} sulfony l)benzam ide;

Trans-2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[4-(4-chloropheny!)-6,6-dimethyl-5,6-dihydro-2Hpyran-3-yl]methyl}piperazin-l-y!)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitropheny I} su Ifony l)benzam ide;

4-(4-{[4-(4-ch loropheny 1 )-6,6-d imethy 1-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-1-y 1)-2-[(6fluoro-IH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-330 nitrophenyl)sulfonyl)benzamide;

4-( 4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-]-en-l-yl]methyl} piperazin-l-yl)-2-[(6-fluoro!H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[4-(4-chlorophenyi)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-l-yl)-2-[(635 fluoro-1 H-indol-5-yl)oxy]-N-({4-[(4-f]uorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl}sulfonyl)benzamide;

106

4-(4- {[4-(4-ch loropheny I )-6,6-di methyl-5, 6-dihy dro-2 H-pyran -3 -y l]methy 1) piperazin-1 -y I)-N{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl)-2-[(6-fluoro-lH-indol-5y l)oxy]benzam i de;

2-{[3-(2-aminoethyl)-lH-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en5 1 -yl]methy 1} piperazin-1 -yl )-N-( {3 -nitro-4-[(tetrahy dro-2 H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-{[3-(2-aminoethy 1)-1 H-ίη do 1-5-y l]oxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1-en1 -y I] methy 1} piperazin-1 -y l)-N-( {4- [(4-methy 1 piperazin- i -y l)amino]-3 n itropheny I} sulfony l)benzam ide;

4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-1-en-1-yl]methy I) piperazin-l-yl)-N-{[5-cyano6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl)-2-[(6-fluoro-lH-indol-5y l)oxy]benzam i de;

2-[(6-amino-5-fl uoropyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny1 )-4,4-dimethy Icyclohex-1-en-lyljmethyl) piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran -415 ylmethyl)amino] phenyl) sulfonyl)benzamide;

4-(4- {[2-(4-ch loropheny! )-4,4-dimethyl eye lohex- 1-en-l -y l]methy I} piperazin-1 -yl)-N- {[5 -ch loro6-(tetrahydro-2H-pyran-4 -ylmethoxy)pyrid in-3-yl] sulfony 1} -2- [(6-fluoro-1H- indol-5yl)oxy] benzamide;

Trans-4-(4- {[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 -yl]methyl} piperazin-1 -yl)-N-( {420 [(4-morpho!in-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfbnyl)-2-[(l-oxo-1,2,3,4tetrahydroisoquino 1 in-5 -y l)oxy] benzam ide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1)-N- {[5-cyano6-( l,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl)-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide;

N-{[5-bromo-6-(l,4-dioxan-2-ylmethoxy)pyridin-3-yI]sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,425 dimethy Icyclohex-1-en-l-yljmethyl) piperazin-1-y 1)-2-[(6-fluoro-IH-indo 1-5-yl)oxy]benzamide;

Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl) sulfony l)-4-(4-{[2-(4chlorophenyl)-4,4-dimethylcyclohex- 1-en-l -yl]methyl) piperazin-1 -yl)-2-[(6-fluoro- lH-indol-5yl)oxy] benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl] methy I} piperazin-1-y 1)-N-( {5-cyano30 6-[(4-fluorotetrahydro-2H-pyran-4-yI)methoxy]pyridm-3-yl} sulfony l)-2-[(6-fl uoro-lH-indol-5y l)oxy]benzami de;

2-(3 -am ino-5 -ch lorophenoxy)-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en-1y l]methy 1) piperazin-1 -y l)-N-( {3 -n itro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyciohex-l-en-1-yl]methy I) piperazin-l-yl)-N-{[5-cyano6-(2-morpholin-4-ylethoxy)pyridin-3-yl]suIfonyl)-2-[(6-fluoro-l H-indol-5-yl)oxy]benzamide;

107

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc lohex-1-en-l-yl]methyl}piperazin-l-yl)-2-[(6fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3nitrophenyl}sulfonyl)benzamide;

N-( {5-bromo-6- [(1 -tetrahy dro-2H-pyran-4-y Ip iperidin-4-y I )am ino] pyridin-3 -y 1} sulfonyl)-4-(4{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-1-y I] methyl} piperazin-1-y 1)-2-[(6-fluoro-1Hindol-5-yl)oxy]benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1-y l]methyl} piperazin-1-y 1)-N-({4-[(4fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-lHindol-4-yl)oxy]benzamide;

Trans-2-[(6-chloro-1 H-indo l-5-yl)oxy]-4-(4- {[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4yl]methyl}piperazin-l-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3[(trifluoromethyl)sulfonyl]phenyl}sulfdnyl)benzamide;

Trans-2- [(6-chloro-1 H-indo 1-5 -y l)oxy] -4-(4- {[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4yl]methyl} piperazin-1-y l)-N-({4-[( 4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4- {[4-(4-ch loropheny I )-6,6-d i methy 1-5,6-dihydro-2 H-py ran-3 -y l]methy 1} piperazin-1 -y 1)-2 -[(6fluoro-1 H-indol-5-yl )oxy] -N-( {4-[(4-methy Ipiperazin-1 -y I )amino] -3 nitrophenyl }sulfonyl)benzamide;

4-(4- {[2 -(4-ch loropheny 1)-4,4-dimethylcy c lohex-1 -en-1 -y I ] methy 1} piperazin-1 -y I )-2-[(6-fl uorolH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxyl-3-nitrophenyl}sulfonyl)benzamide; 2-[(6-am i no-5-ch loropyridin-3 -y I )oxy ]-4-(4- {[2 -(4-ch lorophenyl)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)ammo]phenyl}sulfonyl)benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy leyc lohex-1 -en-1 -y I] methy I} p iperazin-1 -y 1)-2 -[(6-fluorolH-indol-5-yl)oxy]-N-[(4-{[l-(methylsulfonyl)piperidin-4-yl]amino}-3nitrophenyl)sul fony l]benzam ide;

Trans-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl] methy I} piperazin-l-yl)-N-({4[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-lH-indol-4yl)oxy] benzamide;

4.(4-( [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-l-yl]methyl} piperazin- l-yl)-N-({4-[(2methoxyethy l)amino]-3 -n itropheny 1} sul fony l)-2-[(2-oxo-2,3 -dihydro-1 H-indol-4yl)oxy] benzamide;

4.(4. {[2-(4-ch loropheny l)-4,4-dimethylcyc lohex-1 -en-1 -y l]methy 1} piperazin- l-yl)-N-{[5ethyny I -6-(tetrahydro-2H-pyran-4-y lmethoxy)pyridin-3-y 1] su I fony 1} -2-[(6-fluoro-1 H-indo 1-5 yl)oxy]benzamide;

108

4-(4- {[4-(4 - ch loropheny 1)-6,6-dimethy 1-5,6-dihydro-2 H-pyran-3 -yl] methyl} piperazin-1 -y l)-N {[5-ethynyI-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl)-2-[(6-fluoro-lH-indol-5yl)oxy] benzamide;

Trans-2-[(6-amino-5 -ch loropyridin-3-yl)oxy] -4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-15 en-l-yl] methyl} piperazin- 1-y l)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl) sulfony l)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-l-en-l-yl]methyl[ piperazin-l-yl)-N-({5-cyano6-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyI)-2-[(6-fluoro-lH-indol5-yl)oxy] benzamide;

N-({ 5 -ch loro-6-[(4-fl uorotetrahydro-2H-pyran-4-y 1 )methoxy ] pyri din-3 -y I} su Ifony 1)-4-(4- {[2-(4chloropheny 1 )-4,4-d imethy I cyclohex-1-en-l-yl] methyl [piperazin-1-yl)-2-[(6-fluoro-lH-indol-5yl)oxy] benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-l-yl] methyl} pi perazin-l-yl)-N-({4-[(leye lopropylpi peridi n-4-yl)amino]-3-nitropheny I [sulfony 1)-2-[(6-fluoro- lH-indol-5 15 y|)oxy]benzamide;

4-(4-{[2-(4-chloropheny])-4,4-dimethylcyclohex-l-en-l-yl]methyl[ piperazin-]-yI)-N-({4-[(4ethylmorpholin-3-yI)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-lH-indol-5yl)oxy] benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-d i methy Icyc lohex-1 -en-1 -y 1] methy 1} piperazin-1 -y l)-2-[(6-fl uoro20 1 H-indol-5-y l)oxy] -N-[(3-nitro-4-{ [(3 S)-1 -tetrahydro-2H-pyran-4-ylpiperidin-3yl]amino[phenyl)sulfonyl] benzamide;

2-[(6-amino-5-chloropy ridin-3-yl)oxy]-4-(4-{[2-(4-chl oropheny 1)-4,4-dimethy Icyc lohex-1-en-1yl] methy 1} p i p e raz in -1 - y! )-N-({4- [(4-fluorotetrahy dro-2H-pyran-4-y l)methoxy ]-3 nitrophenyl} su Ifony 1 )benzam ide;

4-(4- {[2 -(4-chloropheny I )-4,4-dimethy Icy c lohex-1 -en-1 -y l]methy I} pi perazin-1 -y l)-N-( {4-[( 1 * 1 dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl[sulfonyl)-2-[(6-fluoro-) H-indoI-5yl)oxy] benzamide;

4-(4- {[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -en-1 -yl]methyl[ piperazin-1-y l)-2-[(6-fluoro1 H-indol-5-y l)oxy] -N -({3 -n itro-4-[(tetrahy drofuran-330 ylmethyl)amino]phenyl}sulfonyl)benzamide;

Trans-N-( { 5-bromo-6-[(4-morphol in-4-y Icyclohexy I )oxy] pyridin-3 -y 1} su 1 fony 1 )-4-(4 -{[2-(4chlorophenyl)-4,4-dimethylcyclohex-I -en-l-yl]methyl)piperazin- l-yl)-2-[(6-fluoro-l H-indol-5yl)oxy]benzamide;

Trans-4-(4- {[2-(4-ch loropheny I )-4,4-dimethy Icyc lohex-1 -en-1 -yl] methy I} piperazin-1 -y 1 )-N-[(435 {[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-lH-indol-5yl)oxy] benzamide;

109

Trans-4-( 4-{[2-(4-ch!oropheny 1)-4,4-dimethy Icyclohex-1-en-1-y I ]metliy I} piperazin-1-y I )-2-[(6fluoro-lH-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4ylamino)cyc!ohexyl]amino}phenyl)sulfonyl]benzamide;

Trans-4-(4- ([2-(4-chloropheny I )-4,4-di methy Icy c lohex-1 -en-1 -y l]methy 1} piperazin-1 -y l)-2-[( 65 fluoro-1 H-indoI-5-y l)oxy]-N-[(3-nitro-4- {[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1 yl)cyclohexyl]amino)phenyl)sulfonyl]benzamide;

4-(4-( [2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -yl] methyl} p iperazin-1 -y 1)-2- [(6-fluoro1 H-indo l-5-yl )oxy]-N-[(4- {[(4-fl uorotetrahydro-2 H-py ran-4-y I )methy 1] amino} -3 nitrophenyl)su Ifony 1] benzamide;

Trans-4-(4- {[2-(4-chloropheny 1)-4,4-di methy Icyc lohex-1 -en-1 -y l]methy I} p iperazin- l-yI)-2-[(6fluoro-lH-indol-5-yl)oxy)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

4-(4- {[2-(4-ch loropheny l)-4,4-d imethy Icyclohex-1 -en-1 -yl] methyl} piperazin-1 -y 1)-2-( {3 -[3 (d imethy lam ino)propyl]-1 H-indol-4 -y I} oxy)-N-( { 3 -nitro-4-[(tetrahy dro-2H-pyran-415 ylmethyl)amino]phenyl)sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycIohex-l-en-l-yl]methyl}piperazin-l-yI)-2-({3-[3(dimethylamino)propyl]-lH-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

4.(4.( [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yl] methyl} piperazin-1 -yl)-N-( (4-[( 1 20 cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-lH-indo]-5yl)oxy] benzamide;

4-(4. {[2-(4-chloropheny 1)-4,4-d imethylcyclohex-1 -en-1 -y l]methy I} piperazin-1 -y 1 )-2- ([ 1 -(4methoxybenzyl)-lH-l,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4- {[2-(4-chlorophenyl)-4,4-d imethylcyclohex-! -en-1yl] methyl} piperazin-1 -y 1)-N-{[4-( 1,4-dioxan-2-y Imethoxy )-3 -n itropheny 1] su Ifony 1} benzam ide;

0 Trans-2 -[(6-amino-5-ch loropyridin-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 en-1 -yl] methy I} piperazin-1 -y l)-N-[(4- {[(4-methoxycyclohexy l)methy l]amino} -3 nitrophenyl)sulfonyl]benzamide;

2-[(6-amino-5-ch loropyridin-3-yl)oxy]-4-(4-{ [2-(4-ch I oropheny 1)-4,4-dimethy Icyc lohex-1-en-1yl]methyl} piperazin-1-yl)-N-((4-[( 1,4-dioxan-2-ylmethyl)amino]-335 nitrophenyl} su Ifony l)benzamide;

110

2- [(6-amin 0-5 -chIoropyridin-3 -y l)oxy]-4-(4- {[2-(4-ch 1 oropheny 1)-4,4-d imethy Icyc 1 ohex-1 -en-1 yl]methy I Ipiperazin-l-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3[(trifluoromethyl)sulfonyl]phenyl|sulfonyl)benzamide;

2-[(6-am ino-5-ch loropyridin-3-y I)oxy]-4-(4-{[2-(4-chl oropheny 1)-4,4-dimethy Icyc lohex- l-en-l 5 y|]methyl}piperazin-l-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3[(trifluoromethyl)sulfonyl]phenyl|sulfonyl)benzamide;

2-[(6-am ino-5 -chloropyridin-3 -yl)oxy] -N-( {5 -chloro-6-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy ]pyrid in-3 -y 1} sulfony 1)-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yljmethyl } piperazin-1 -yl)benzam&gt;de;

2-[(6-ammo-5-bromopyrid in-3 -y l)oxy] -4-(4- {[2-(4-ch loropheny 1)-4,4 -d imethy Icyclohex- 1 -en-1 y IJmethy 1} piperazin-1 -y l)-N-( {3 -n itro-4 -[(tetrahydro-2H-pyran-4y Imethy l)am ino] phenyl} sulfony IJbenzam ide;

2-am ino-5 -(5 -(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icy c 1 ohex-1 -en-1 -y I] methy 1} p iperazin-1 -y 1)-2{[({3-nitro-4-[(tetrahydro-2H-pyran-415 ylmethyl)amino]phenyl)suifonyl)amino]carbonyl| phenoxy )nicotinamide;

2-[(6-amino-5-cy anopyridin-3 -yl)oxy] -4-(4- {[2 -(4-ch loropheny 1)-4,4-d imethy Icycl ohex-1 -en-1 y IJmethy I} piperazin-1 -y I )-N -({3 -nitro-4- [(tetrahy dro-2H -pyran-4ylmethyl)amino]phenyl} sulfonyl )benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l20 yljmethyl} piperazin-1 -yl)-N-[(4-{ [(3 R)-1-(2,2-difIuoroethyl)pyrrolidin-3-yl]amino}-3n itropheny 1 )sulfony I Jbenzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4_i4-dimethylcyclohex-l-en-lyl]methyl}piperazm-l-yl)-N-({4-[(l-methylpiperidin-4-yl)ammo]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-diniethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy] )amino]pheny I }sulfonyl)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-di methylcyclohex- l-en-l-yljmethyl }piperazin- 1-y 1)-2-( {6[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4- {[2 -(4-chloropheny 1)-4,4-dimethylcyclohex-1 -en-1 -yl J methy 1} piperazi n-1 -yi )-N- {[4- ({(3 R)l-[2-fluoro-l-(fl uoromethyl)ethylJpyrrolidin-3-yl}amino)-3-nitrophenyl] sulfony I }-2-[(6-fluoro1 H-indol-5-yl)oxy]benzamide;

2-[(6-amin o-5-chloropyri din-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 35 yl]methyl}piperazin-l-yl)-N-({4-[(l-cyclopropylpiperidin-4-yl)amino]-3nitrophenyl}suifonyl)benzamide;

Ill

2-[(6-am ino-5 -bromopyrid in-3 -y 1 )oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-dimethyl eye lohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzaniide;

2- [(6-am i no-5-bromopyrid in-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icy c lohex-1 -en-1 5 yl]methyl} piperazin-l-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yI)methoxy]-3n itropheny 1} sulfony I )benzam ide;

2-[(6-amino-5 -bromopyridin-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyclohex- i -en-1 yl]metbyl} piperazin-l-yl)-N-({4-[(l,4-dioxan-2-y Imethy l)amino]-3nitropheny 1} sulfony l)benzam ide;

2-[(6-amino-5-methylpy ridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-ly|]methyI}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-1-en-lyl]methyl} piperazin-l-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-315 nitrophenyl)sulfonyl]benzamide;

2-[(6-am ino-5-chloropyridin-3-y I )oxy ]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy ley clohex-1-en-lyl]methyl} piperazin-l-yl)-N-( {3-nitro-4-[(l-oxetan-3-ylpiperidin-4y l)amino] phenyl} sulfony l)benzamide;

2-[(6-amino- 5-i sopropyl pyrid in-3 -yl)oxy] -4-(4- {[2-(4-ch 1 oropheny 1)-4,4-d imethy Icyclohex-1 -en2 0 1 -y l]methyl} piperazin-1 -y 1 )-N-( {3 -n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]pheny])sulfonyl)benzamide;

2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-( 4-chloropheny 1)-4,4-dimethylcyclohex-1en-1 -y fl methy I} piperazin- ] -y 1 )-N-( {3 -n itro-4-[(tetrahy dro-2 H-pyran-4ylmethyl)amino]phenyl}suifonyl)benzamide;

Trans-2-[(6-am i no-5-bromopy ridin-3 -y 1 )oxy]-4-(4- {[2-(4-chloropheny 1)-4,4-d imethy ley c lohex-1 en-1 -y l]methy 1} piperazin-1 -y l)-N-[(4- {[(4-methoxy cyclohexy l)methy I] amino} -3 n itropheny l)sulfonyl]benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy I eye lohex-1-en-1-yl] methyl} piperazin-1-y l)-2-[(3-methyl2-oxo-2,3 -d i hydro-1 H-benzim idazo l-4-yl )oxy]-N-( {3-n itro-4- [(tetrahydro-2 H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-ch loropyri din-3 -yI)oxy]-4-(4-{ [2-(4-ch loropheny 1)-4,4 -dimethylcyclohex- 1-en-l y I] methy I} piperazin-1 -y))-N-[(4- {[(4-cyc lopropy lmorpholin-2-y l)methy 1] am ino } -3 nitrophenyl)su 1 fony l]benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyi)-4,4-dimethylcyclohex-l-en-I3 5 yl] methy 1} piperazin-1 -y l)-N-[(4- {[(3 R)-1 -cy clopropy lpynolidin-3 -yl]amino}-3n itropheny l)sulfony!]benzam ide;

112

2-[(6-amino-5 -chloropyridin-3 -y l)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex- 1-en-lyl]methy]}piperazin-l-yl)-N-{[4-({4-fluoro-l-[2-fluoro-l-(fluoromethyl)ethyl]piperidin-4yl} meth oxy )-3-nitrophenyl] sulfonyl} benzamide;

tert-butyl 6-bromo-4-(5-(4- {[2-(4-ch I oropheny 1)-4,4-dimethy Icyclohex-1 -en-1 5 y l]methyl} piperazin- 1-y 1)-2-{[({3 -nitro-4-[(tetrahydro-2 H-pyran-4y Imethy 1 )amino]phenyl} su Ifony 1 )amino]carbony I} phenoxy )pyrid i n-2 -y Icarbamate;

tert-butyl 4-(5-(4-((2-(4-ch!orophenyl)-4,4-dimethyIcyclohex-l-enyl)methyIJpiperazin-1-y 1)-2-(3nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfbnylcarbamoyl)phenoxy)pyridine2,6-diyldicarbamate;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-l-en-]-yl]methy I} pi perazin-1-y 1)-2-{[6(cyclopropy lam ino)pyridin-3 -y l]oxy} -N -({3 -nitro-4-[(tetrahydro-2H -pyran-4 ylmethyl)amino]phenyl}sulfonyl)benzamide;

Trans-4-( 4-{[2-(4-chlorophenyl)-4,4-dimethy lcyclohex-1-en-1-yl]methyl} piperazin-l-yl)-2-({6[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-315 n itropheny I )su Ifony Ijbenzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-({6-[(2,2difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy I )amino]phenyl} sulfonyl )benzamide;

2-{[5-chloro-6-( methy lamino)pyri din-3-yl]oxy}-4-(4-{[2-(4-chloropheny 1)-4,420 dimethylcyclohex-1 -en-1 -yl]methyl}piperazin-l -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethy Icyclohex- 1-en-ly l]methyl} piperazin-1 -yl)-N-({4-[({4-[2-fluoro-1 -(fluoromethyl)ethyl]morpholin-2y 1} met hy l)am ino]-3 -nitrophenyl} su Ifony l)benzam i de;

2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly|]methyl} piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yljmethyl} piperazin-1 -yI)-2-[(2,6diaminopyridin-4-yl)oxy]-N“({3-nitro-4-[(tetrahydro-2H-pyran-430 ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4_&gt;4-dimethy Icyclohex-1-en-1y I ] methyl} piperazin-1 -y I )-N-{[3 -n itro-4-(tetrahydro-2H-py ran-4ylmethoxy)phenyl]sulfonyl}benzamide;

2-[(6-ammo-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-]-en-l35 y l]methyl} piperazin- 1-y l)-N-{ [4-( {(3 R)-l-[2-fluoro- l-(fluoromethy l)ethyl]piperid in-3 yl}amino)-3-nitrophenyl]sulfonyl}benzamide;

113 tert-butyl 5-bromo-4-(5-(4-{[2-(4-chloropheny 1)-4,4-dimethyleyclohex- 1-en-1 y]]methy 1) piperazin-1 -y 1)-2- {[({3 -n itro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl) sulfony l)amino]carbony I) phenoxy )pyridin-2-ylcarbamate;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en-l-yl] methyl) piperazin-1-y 1)-2-[(4-chloro5 lH-pynolo[2,3-b]pyridin-5-yl)oxy]-'N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy 1 )amino] pheny I} sulfony I )benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-diniethyIcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-N-({3-nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl)sulfonyl)-2-({6-[(2,2,2trifluoroethyl)amino]pyridin-3-yl}oxy)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl)piperazin-l-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2Hpyran-3-yl] methy 1} piperazin-1 -yl)-N-( {3 -n itro-4-[(tetrahydro-2H-pyran-415 y Imethy l)am ino] pheny I) sulfony l)benzam ide;

N-({5-chlorO“6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl)sulfonyl)-4-(4-{[4-(4chloropheny 1)-6,6-d imethy 1-5,6-dihydro-2H-pyran-3 -yl] methy 1} piperazin-1 -yl)-2-[(6-fluoro-lHindol-5-yl)oxy] benzamide;

2-[(6-amino-5-chloropyridin-3-y I )oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethy Icyc I ohex-l-en-120 yl]methyl} piperazin-1 -yl)-N-( (3-nitro-4-[(tetrahydrofuran-3y Imethy 1 )am ino] phenyl} sulfony l)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2Hpyran-3-yl]methyl}piperazin-]-yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-l(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-l-yl]-N-({3-nitro-4[(tetrahy dro-2H-pyran-4-y Imethy l)am ino] phenyl} sulfony l)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3azasp iro [ 5,5 ]undec-8-en- 8-y l]methy 1} piperazin-1 -y 1)-N-({3-nitro-4- [(tetrahydro-2H-py ran-430 ylmethyl)am ino] phenyl) sulfony I)benzamide;

-[(6-amino-5-chloropyrid in-3 -y I)oxy] -N-[(5-chIoro-6-{[ 1 -(N ,N-d imethy I glycy I )-4fluoropiperidin-4-yl]methoxy)pyridin-3-yl)suIfonyl]-4-(4-{[2-(4-chlorDphenyl)-4,4dimethylcyc!ohex-l-en-l-yl]methyl)piperazm-l-yl)benzamide;

2-[(6-amino-5-ch loropyridin-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy leyclohex-1-en-13 5 yl] methy 1} pi perazin-1 -y 1)-N- {[4-( {(3 R)-1 -[2-fluoro-1 -(f1uoromethyl)ethyl]pyrrolidin-3yl)amino)-3-nitrophenyl]sulfonyl) benzamide;

114

2-[(2-ammo-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-l-en-Iyl] methy 1} piperazin-1 -yl)-N-( {3 -n itro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyrid in-3-yl)oxy]-4-(4-{ [2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-l5 yl]methyl}piperazin-l-yl)-N-[(4-{[(4,4-difluorocyclohexyl)metbyl]amino}-3n itropheny l)sul fony 1] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-( {4'-chloro-3-[2-(d imethy lamino)ethoxy]-1,1*biphenyl-2-yl}methyl)piperazin-l-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl]sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-l-[2-fluoro-l(fluoromethy l)ethyl]pyrrolidin-3-y I] methoxy )pyrid in-3-y I] sulfonyl]-4-(4-{[2-( 4-chloropheny 1)4,4-dimethylcyclohex-l-en-l-yl]inethyl)piperazin-l-yl)benzamide;

2- [(6-am ino-5 -ch loropyridin-3 -yl )oxy] -N- [(5-ch 1 oro-6- {[(3 R)-l -(2,2-d ifl uoroethy I )pyrrol idin-3 yl]methoxy]pyridm-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4₍4-dimethylcyclohex-l-en-i15 yl]methyl}piperazin-l-yl)benzamide;

Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyi)-4,4-dimethylcyclohex-len-l-yl]methyl}piperazin-l-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

- [(6-am ino-5-ch I oropyridin-3-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l20 y I] methy I} p iperazin-1 -y I )-N-( { 5 -fluoro-6-[(4-fluorotetrahydro-2H-pyran -4-y i)methoxy] pyr id in3-yl]sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[ 1-(2,2-difluoroethyl)-4-fluoropiperidin4-yl]methoxy}pyridin-3-yl)su)fonyl]-4-(4-{[2-(4-chiorophenyl)-4_I4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)benzamide;

2- [(6-amino-5 -chloropyrid in-3 -yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]phenyl] sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex- 1-en-lyl]methyl} piperazin-1 -yl)benzamide;

2-[(6-amino- 5 -ch loropyridin-3 -yl)oxy] -4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl] piperazin-1 -yl)-N-{ [6-( {4-fluoro-l - [2-fluoro-1-(fluoromethyl )ethyl]piperi din-430 yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl )-4,4-dimethy Icyc lohex-1-en-l-yl] methyl] piperazin-l-yl)-N-( {3-n itro-4 [(tetrahydro-2H-pyran-4-y I methy I )amino]pheny 1} su I fony 1)-2- [2-( 1 H-pyrazol-4y 1 )phenoxy] benzamide;

2- [2-(2-aminopyridin-3 -y 1 )phenoxy ]-4-(4- {[2-(4-c h loropheny 1 )-4,4-d imethy Icyc lohex-1 -en-1 35 yl]methyl} piperazin-1 -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl]su Ifony l)benzam ide;

115

4-(4-( [2-(4-ch loropheny 1)-4,4-d i methylcyclohex-1 -en-1 -y 1 ] methy 1} piperazin-1 -y l)-N-( {3-nitro-4[(tetrahydro-2H-pyran-4-y Imethy I)amino] phenyl) sulfonyl)-2-[2-( 1 H-pyrazol-5yl)phenoxy] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,45 difluorocyclohexy l)methoxy]pyrid in -3 -y 1} sul fony 1)-4-(4- {[2-(4-chloropheny 1)-4,4dimethylcyclohex-1 -en-1 -yljmethy I }piperazin-l -yl)benzamide;

N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl)sulfonyl)-4-(4-{[4-(4chloropheny 1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methy I) piperazin-l-yl)-2-[(6-fluoro-lHindol-5-yl)oxy]benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icy clohex-l-en-l-yl]methy I) piperazin-l-yl)-N-[(4-{ [(4,4difl uorocyclohexy l)methyl]aminoj-3-nitrophenyl )sul fony l]-2-[(6-fluoro-lH-indol-5yl)oxy]benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

Still another embodiment pertains to 2-[(6-amino-5-c hl oropy rid in-3-yl)oxy]-4-(4-{ [2-(415 chlorophenyl)-4,4-dimethyIcyclohex-l -en-1 -yl]methyl) piperazin- l-yl)-N-({3-nitro-4[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

Still another embodiment pertains to [3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4d imethy Icy c loh ex-1 -en-1 -y 1 (methyl} piperazin-1 -y 1)-2 - {[({3 -n itro-4-[(tetrahydro-2H-py ran-420 ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-l(2H)-yl]methyl dihydrogen phosphate; and therapeutically acceptable salts, and metabolites thereof.

In another aspect, the present invention provides compounds of Formula (II)

<img file="MY179077A_D0008.tif" />

(Π) and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof,

116 wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are as described herein for Formula (1), n is 0, 1, 2, or 3; describing the number of additional substituents on R²⁶, and R¹⁰⁰ is as described for substituents on R²⁶, m is 1,2, 3, 4, or 5; describing the number of substituents on R⁴³, and R¹⁰¹ is as described for substituents on R⁴².

In one embodiment of Formula (II), A¹ is N. In another embodiment of Formula (Π), A¹is C(A²). In another embodiment of Formula (II), A¹ is C(A²); and A³ is H,

In one embodiment of Formula (II), B¹ is OR¹, or NHR¹. In another embodiment of Formula (II), A¹ is C(A²); A² is H; and B' is NHR¹. In another embodiment of Formula (II), A¹ is C(A³); A³ is H; and B^l is OR¹.

In one embodiment of Formula (Π), D¹ is H. In another embodiment of Formula (Π), A¹is C(A²); A³ is Η; B¹ is NHR¹; and D¹ is H, In another embodiment of Formula (II), A¹ is C(A²); A³ isH;B' is OR¹; and D¹ is H.

In one embodiment of Formula (II), E¹ is H. In another embodiment of Formula (Π), A¹is C(A³); A³ is Η; B¹ is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹ is C(A²); A³ is Η; B¹ is OR¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (II), Y¹ is H. CN, NO2, F, Cl, Br, CF3, R¹⁷, or SO2R¹⁷. In another embodiment of Formula (II), Y¹ is NO:. In another embodiment of Formula (II), Y¹ is Cl. In another embodiment of Formula (II), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (Π), Y¹ is SO2R¹⁷; wherein R¹⁷ is alkyl. In another embodiment of Formula (Π), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. In another embodiment of Formula (II), A¹ is C(A³); A³ is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In another embodiment of Formula (Π), A¹ is C(A³); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 In another embodiment of Formula (II), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is SO2R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In another embodiment of Formula (Π), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is Η; E¹ is H; and Y¹ is Cl.,

In one embodiment of Formula (II), R¹ is R⁴ or R⁵. In one embodiment of Formula (II), R¹ is R⁴. In one embodiment of Formula (II), R¹ is R⁵, In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (II), R¹ is R⁴; and R⁴is cycloalkyl. In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalky l; wherein the cycloalkyl ring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodiment of Formula (II), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is

117 cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ is heterocycloalkyl. In another embodiment of Formula (Π), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R^S7 is R⁶⁰; R⁶⁰ is heterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(Rⁱ⁷)2. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2 In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2; R⁵⁷ is R⁶’, and R⁶¹ is alkyl which is unsubstituted. In another embodiment of Formula (Π), R^l is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R^S7)2, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which is unsubstituted. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of Formula (II), R* is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (Π), R^l is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycioalkyl ring is substituted as defined herein. In another embodiment of Formula (Π), R¹ is R⁴; and R⁴ is heterocycioalkyl; wherein the heterocycioalkyl ring is substituted with R⁵⁷. In another embodiment of Formula (II), R¹ is R⁴;

and R⁴ is heterocycioalkyl; wherein the heterocycioalkyl ring is piperidinyI, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the heterocycioalkyl ring is substituted with one or two or three or four or five more R⁵⁷; SO₂R⁵⁷,or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycioalkyl; wherein the heterocycioalkyl ring is piperidinyI, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is or R⁶¹; R⁶⁰ is cycloalkyl or heterocycioalkyl; and R⁶’ is alkyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycioalkyl; wherein the heterocycioalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycioalkyl, wherein the heterocycioalkyl is tetrahydropyranyl or oxetanyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycioalkyl; wherein the heterocycioalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl,

118 morpholinyl, or piperiziny I; ring is substituted with R⁵⁷; R⁵⁷ is Rⁱ⁰; R⁶⁰ is eye ioalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperiziny!, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyI ring is substituted 5 with one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶'; R⁶' is alkyl; and the alkyl is Cr alkyl, C2alkyl, or C3-alkyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; R^sl is alkyl; and the alkyl is Ci -alkyl, C2-alkyl, or C₃-alkyl;

wherein the Ci-alkyl, Cj-alkyl, or C_ralkyl are unsubstituted or substituted.

In one embodiment of Formula (II), R¹ is R⁵; and R⁵ is alkyl which is unsubstituted or substituted. In one embodiment of Formula (II), R¹ is R⁶; and R^s is alkyl which is unsubstituted or substituted with R⁷, OR⁷, N(R⁷)₂, or OH.

In one embodiment of Formula (II), R⁷ is R¹⁰ or R¹¹ which are unsubstituted or ] 5 substituted as defined herein. In another embodiment of Formula (II), R⁷ is Rⁱ⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R⁷ is R¹¹which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (II), R¹⁰ is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R^,a is heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl, piperizinyl, or pyrrol id inyl, which are unsubstituted or substituted as defined herein. In another embodiment of Formula (Π), R¹⁰ is tetrahydropyranyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R¹⁰ is morpholinyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R¹⁰ is cycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R^1D is cyclohexyl which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (II), R¹¹ is alkyl which is unsubstituted. In another embodiment of Formula (Π), R¹¹ is methyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (II), R¹' is alkyl, which is substituted as defined herein. In another embodiment of Formula (II), R¹¹ is alkyl, which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (II), which are 4-(4-((4’-chloro-l,r-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(335 ((dimethylamino)methy!)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyraii~4ylmethyl)amino)phenyl)sulfonyl)benzamide;

119

4-(4-((4'-chloro-l, 1 '-biphenyl-2-yljmethyljpiperazin-1 -y 1)-2-(3-(methy lam ino)phenoxy)-N-((3n itro-4-((tetrahydro-2H-py ran-4-y Imethy Ijam inojpheny Ijsul fony Ijbenzamide;

4-(4-((4'-ch 1 oro-1, Γ-bipheny 1-2-y I jmethyl jpiperazin-1 -yl)-2-(2-chlorophenoxy)-N-((3-nitro-4((tetrahy dro-2H-pyran-4-y I methy l)am i nojpheny Ijsulfony Ijbenzam ide;

4-( 4-((4'-chloro-1,1 ’-biphenyl -2 -yljmethy 1 jpiperazin-1 -y I j-2 -(3 -ch lorophenoxy j-N-((3 -n itro-4((tetrahydro-2 H-pyran-4-yl methy ljamino)pheny Ijsulfony Ijbenzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-I-yl)-2-(4-chiorophenoxy)-N-((3-nitro-4((tetrahydro-2 H-pyran-4-y Imethy 1 jaminojpheny Ijsu Ifony Ijbenzam ide;

4-(4-((4L_chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-nitrophenoxy)-N-((3-nitro-410 ((tetrahydro-2H-pyran-4-y Imethy Ijam inojpheny Ijsu Ifony Ijbenzam ide;

4-(4-((4'-chloro-1, r-biphenyl-2-y Ijmethyl jpiperazin-]-yl)-2-(3-(hydroxymethy))phenoxy)-N-((4((3-morpholin-4-y Ipropy Ijamino j-3-nitropheny Ijsulfony I jbenzam ide;

4-(4-((4'-chloro-l₃r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-chlorophenoxy)-N-((4-((3morphol in-4-y Ipropy l)am ino)-3 -nitropheny Ijsulfony Ijbenzamide;

4-(4-((4'-ch loro-Ι,Γ-bipheny 1-2-y I )methyl)piperazin-l-yI)-2-(2-chlorophenoxyj-N-((4-((3(d imethy lam inojpropy I jam ino j-3-nitropheny Ijsulfonyl jbenzam ide;

4-(4-((4'-chloro-1 ,Γ-biphenyl-2-yljmethy ljpiperazin-1 -y!j-2-(3-chlorophenoxy)-N-((4-((3morpholin-4-y Ipropy Ijamino j-3-nitropheny Ijsu Ifony Ijbenzamide;

4-(4-((4'-ch loro-Ι,Γ-bipheny 1-2-yljmethyl jpiperazin-l-ylj-2-(4-chlorophenoxyj-N-(( 4-((320 morpho I in-4-y Ipropy Ijamino )-3-nitropheny Ijsulfony Ijbenzamide;

4-(4-((4'-_chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-chlorophenoxy)-N-((4-((3(dimethy lam inojpropy I jamino j-3 -nitropheny Ijsulfony Ijbenzam ide;

4-(4-( (4 '-chloro-1,1 '-bi pheny 1-2 -yljmethyl jpiperazin-1 -y 1)-2 -(4-ch lorophenoxy )-N-((4-( (3 (d imethy lamino jpropy I jam ino j-3 -nitropheny Ijsul fony 1 jbenzam ide;

2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-IJ'-bipheny 1-2-yljmethy Ijpiperazin-1 -yl)-N-((3n it_ro-4-((tetrahydro-2H-pyran-4-y Imethy l)am inojpheny Ijsu Ifony Ijbenzam ide;

2-(4-aminophenoxy )-4-(4-( (4'-chloro-1,1 '-biphenyl-2-yl jmethyljpiperazin-l -yl)-N-((3-nitro-4((tetrahy dro-2 H-pyran-4-y Imethy 1 jam inojpheny Ijsu Ifony 1 jbenzam ide;

2-(3-aminophenoxy )-4-(4-( (4'-chloro-l, l'-biphenyl-2-yljmethy l)piperazin-l-yl)-N-((3-nitro-43 0 ((tetrah ydro-2 H-pyran-4-y Imethy 1 jam ino jpheny Ijsul fonyljbenzam ide;

4-(4-((4'-chloro- Ι,Γ-bipheny 1-2-y Ijmethyl jpiperazin-l-ylj-2-(3-methoxyphenoxy)-N-((3-nitro-4((tetrahydro-2 H-pyran-4-y I methy Ijaminojphenyljsu 1 fony 1 jbenzam ide;

4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-y Ijmethyl jpiperazin-1-y 1)-2-(3-(dime thy lamino)phenoxy)-N-((3nitro-4-((tetrahydro-2H-pyran-4-ylmethyljaminojphenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yljmethyljpiperazin-1-ylj-2-(3-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-yimethyljaminojphenyljsulfonyljbenzamide;

120

4-(4-((4'-chloro-l_&gt;l'-biphenyl-2-yI)methyl)piperazin-l-yl)-2-(2-(3-(dimethylamino)-3oxopropy l)phenoxy )-N-((3 -n itro-4-((tetrahydro-2H-py ran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-( (4'-ch loro-1, ] '-biphenyl -2-y I )methy l)piperazin-1 -y l)-2-(2-(2-(dimethy lam ino)-25 oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-( 4-((4'-chloro-1,1 '-biphenyl-2-y l)methyl)piperazin- l-yl)-2-(2-(3(dimethylamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-lJ ’-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-(2(dimethylamino)ethyI)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide;

4-(4-((4'-chloro-1,1 '-bipheny l-2-y 1 )methy [)piperazin-1 -y 1)-2-(2 ((d imethy Iamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethy l)amino)pheny l)su Ifony 1 )benzam ide;

4-(4-((4’-chl oro-1, ] '-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3(dimethylamino)propyl)amino)-3-nitrophenyI)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamide;

4-(4-((4’-ch loro-1, Γ-bi pheny 1-2-yl)methyl)pi perazin-1-y 1)-2-(3-(2,4-d imethy 1-1,3-th iazo 1-5yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

2-(2-ch lorophenoxy )-4-(4-((2-(4-ch loropheny l)-4,4-d i methylcyclohex- 1-en-lyl)methyl)piperazin-I-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

5 4-(4-( (2-(4-ch loropheny 1 )-4,4-dimethy Icyc lohex-1 -en-1 -y 1 )methy l)piperazin-1 -y 1)-2 -(3,5 dichlorophenoxy)-N-((4-((l-methylpiperidm-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-(3 -chlorophenoxy )-4-(4-( (2-(4-ch loropheny 1 )-4,4-dimethy Icyclohex-1 -en-1 yI)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

4-(4-((4'-chloro-4-(2-(dimethy[amino)ethoxy)-l,r-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(3ch lorophenoxy )-N-((4-((1 -methyl pi peridin-4-yl)amino)-3-n itropheny l)su Ifony I )benzam ide; 2-(2-chlorophenoxy )-4-(4-((4-( 4-chlorophenyl)-6,6-dimethy 1-5,6-dihydro-2H-pyran-3yl)methyl)piperazin-l-yl)-N-( (4-(( 1-methy lpiperidin-4-y l)amino)-3nitropheny l)su Ifony l)benzamide;

121

4-(4-((4'-chloro-l,l'-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-(2(d imethy lam ino)ethoxy Jphenoxy )-N-((3 -n itro-4-((tetrahy dro-2H-pyran-4ylmethyi)amino)phenyl)sulfonyl)benzamide;

2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-15 yl)methyl)piperazin-1-y I)-N-((4-((]-methy lpiperidin-4-y!)amino)-3nitrophenyl)sul fony l)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-diniethylcyclohex-l-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-isopropylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl)methyl)piperazin-l-yl)-N-((4-((l-methylpiperidin-4-yl)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyI)cyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-((4((l-methylpiperidin-4-yI)amino)-3-nitrophenyl)sulfonyl)benzamide;

4-(4-((2-(4-chloropheny 1)-4,4-d i methy Icycloh ex- 1-en-1-y l)methy l)piperazin-l -y 1)-2-(2.3d i fluoropheno xy)-N-((4 -((1 -m ethy lpiperidin-4-y 1 )amino)-3 -n itropheny l)su] fony l)benzam ide; 2-(3-bromophenoxy)-4-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yl)methyl)piperazin-l-yl)-N-((4-(( 1 -methy lpiperidin-4-y l)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl)methyI)piperazin-l-yl)-N-((4-((l-ethyIpiperidin-4-yl)amino)-3n itropheny l)sulfony l)benzam i de;

2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl)methyl)piperazin-l-yl)-N-((3-nitro-4-((l,2,2,6,6-pentamethylpiperidin-425 yl)amino)phenyl)sul fony l)benzam ide;

4-(4-((2-(4 -ch loropheny 1 )-4,4-d i methylcyclohex-1 -en-1 -y I )methy Qpiperazin-1 -y I )-2 -(2,3 di fluorophenoxy)-N-((3-n itro-4-(( I -tetrahydro-2H-pyran-4-ylpiperidin-4 yl)amino)phenyl)sulfonyl)benzamide;

4-(4-((2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 -en-1 -yl )methy I )piperazin-1 -y 1)-2-(2,3 30 difluorop henoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-n itropheny] )sulfonyl)benzam ide;

2-(4-atn ino-3-chlorophenoxy )-4-(4-((2-(4-ch loropheny 1)-4,4-dimethylcyc lohex-1-en-1yl)methyl)piperazin-l-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3nitrophenyl)sulfonyl)benzamide;

2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrol idin- 1-y lethy 1)-1, l'-bipheny 1-235 yl)methyl)piperazin-1 -yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

122

4-(4-((2-(4-chlorophenylJ-4,4-dimethylcyclohex-I-en-l-y!)methylJpiperazin-l-ylJ-2-(2,3dich lorophenoxy)-N-((4-((1-methy Ip ipen din-4-y IJamino )-3-n itropheny IJsulfony IJbenzam ide;

2-(2-chlorophenoxy )-4-(4-( (2-(4-chlorophenyl)cycIohept-l-en-l-y Ijmethy IJpiperazin-l-yl)-N-((4((l-methylpiperidin-4-yIJaminoJ-3-nitropheny IJsulfony] Jbenzamide;

4-( 4-((2-(4-ch loropheny I )-4,4-d i methy Icyclohex-1 -en-1 -y I Jmethy IJpiperazi n- l-ylJ-N-((4-((lmethy lpiperidin-4-y IJamin o J-3 -n itropheny! Jsulfony 1)-2-(3 -(tri fluoromethy I Jphenoxy)benzamide; 2-(2-chlorophenoxyJ-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly Ijmethy! Jpiperazin-l-yIJ-N-((4-(( l-methylpiperidin-4-yiJamino)-3((trifl uoromethy I Jsu 1 fony 1 Jpheny IJsulfony 1 Jbenzam ide;

4-(4-((2-(4-chloropheny!J-4,4-dimethylcyclohex-l-en-l-yi)methy IJpiperazin-!-yl)-2-(2,5dichlorophenoxyJ-N-((4-((l-methylpiperidin-4-ylJaminoJ-3-nitropheny!JsulfonylJbenzamide; 2-(2-chloro-4-fl uorophenoxy )-4-(4-((2 -(4-ch loropheny 1 J-4,4-d i methy !cyc lohex- 1-en-lylJmethyl)piperazin-l-yl)-N-((4-((l-methyIpiperidm-4-yl)aminoJ-3nitrophenyljsulfony I Jbenzamide;

2-(2-ch lorophenoxy )-4-(4-((2-(4-chlorophenyl J-4,4-d imethy Icy cl opent-l-en-1y Ijmethy I Jpiperazin-1 -y I J-N -((4-(( 1 -methy lpiperidin-4-y 1 Jam inoJ-3 nitrophenyl Jsulfony 1 Jbenzam ide;

4-(4-((2-(4-ch loropheny I J-4,4-d imethy Icyc lohex-1-en-l-yljmethyl Jpiperazin-l-yl)-2-(2-ch loro-3 (trifluoromethyl JphenoxyJ-N-((4-(( 1 -methy I pi perid in-4-y 1 Jam i no J-3 20 nitropheny IJsulfony IJbenzam ide;

2-(2-chlorophenoxyJ-4-(4-((2-(4-chIorophenylJ-4,4-dimethylcyclohex-l-en-lylJmethyl)piperazin-l-ylJ-N-((4-((l-cyclopropylpiperidm-4-ylJaminoJ-3nitrophenyljsulfonyljbenzamide;

4-(4-((2-(4-chloropheny 1 J-4,4-di methy Icyc lohex-1 -en-1 -y 1 Jmethy 1 Jp iperazi η-1 -y 1 J-2-(2,5 25 dichlorophenoxy )-N-((4-((3-morpholin-4-ylpropyIJaminoJ-3-nitrophenyl)suIfonyIJbenzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-ylJmethy I Jpiperazin-l-ylJ-2-(3-morpholin-4-ylphenoxyJ-N-((4((3-morpholin-4-yIpropy IJamino J-3-nitropheny IJsulfony I Jbenzam ide;

2-(3-(benzyloxy Jphenoxy J-4-(4-((4'-chloro-l,r-biphenyl-2-yljmethyl Jpiperazin-l-yl)-N-((3-nitro4-((tetrahydro-2H-pyran-4-y Imethy 1 Jam inojpheny I Jsulfony i Jbenzamide;

4-(4-((4’-chloro-Ι,Γ-bipheny 1-2-yljmethyl Jpiperazin-l-ylJ-2-(4-cy anophenoxyJ-N-((3-m'tro-4((tetrahydro-2H-py ran-4-y I methy IJaminoJpheny I Jsulfony IJbenzam ide;

4-(4-((4'-ch!oro-l, I '-biphenyl-2-yl)methyl)piperazin-l-ylJ-2-(4((d imethy lam inojmethy I Jphenoxy J-N-((3 -nitro-4-((tetrahydro-2H-pyran-4y Jmethy l)am inojpheny IJsulfony IJbenzam ide;

4-(4-((4'-chloro-1, l'-bipheny 1-2-yl)methyl)piperazin-l-yl)-2-(4-( I H-imidazol-l-yl Jphenoxy J-N((3-n itro-4-((tetrahydro-2H-pyran -4-y Imethy 1 Jam inojpheny i Jsulfony 1 Jbenzamide;

123

4-(4-((4'-chloro-l_ir-biphenyl-2-yl)methyl)piperazin-]-yl)-2-(3-nitrophenoxv)-N-((4-((tetrahydro2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzam ide;

tert-butyl 4-( 5-(4-((4'-chl oro-1,1 '-bipheny 1-2-yl)methyl)piperazin-1 -y 1)-2-((((3-nitro-4((tetrahydro-2 H-pyran-45 y Imethy 1 )am ino)phenyl )su Ifony I)amino)carbony l)phenoxy)benzy l(ethyl )carbamate;

tert-butyl 3-(5-(4-( (4'-chloro-l ,r-biphenyl-2-yl)methyI)piperazin-l-yl)-2-((((3-nitro-4((tetrahydro-2H-pyran-4y Imethy l)amino)phenyl)su Ifony l)am ino)carbony l)phenoxy )benzy l(ethy 1 )carbamate;

4-(4-((4’-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-((ethylamino)methyl)phetioxy)-N10 ((3-nitro-4-((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzam ide;

4-(4-( (4'-chloro-1,1'-bipheny 1-2-yl)methyl)piperazin-l-yl)-2-(3-((ethylamino Jmethy l)phenoxy)-N((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonylJbenzamide,'

2-(4-(acetylamino Jphenoxy )-4-(4-( (4 -chloro-1,1 '-bipheny l-2-yl)methy l)piperazin-1 -y 1 J-N-((3 nitro-4-((tetrahydro-2H-pyran-4-ylmethy]Jamino)phenyl)sulfonyl)benzamide;

tert-butyl 4-(5-(4-((4'-c h loro-Ι,Γ-bipheny 1-2-yl Jmethy ljpiperazin-l-y !J-2-((((3-ni tro-4((tetrahydro-2H-pyran-4y Imethy! Jam ino JphenylJsulfonylJaminoJcarbony I JphenoxyJphenylcarbamate;

2-(1, l'-b iphenyl-2-yloxy )-4-( 4-((4'-ch loro-1,1'-bipheny 1-2-yl)methy I )p iperazin-l-yl)-N-((3-nitro4-((tetrahydro-2 H-pyran-4 -y I methy l)am inojpheny I Jsulfony 1 Jbenzamide;

tert-butyl 3-(5-(4-((4'-chloro-l_fr-biphenyl-2-yl)methyl)piperazin-l-yl)-2-((((3-nitro-4((tetrahydro-2H-pyran-4y 1 methy I )amino)pheny l)su Ifony l)am ino)carbony I JphenoxyJphenylcarbamate;

2-(1,1 '-bi phenyI-3-yloxy)-4-(4-((4'-chl oro-1,1 '-biphenyl-2-ylJmethyl)piperazin-l -y!J-N-((3-nitro4-( (tetrahydro-2H-pyran-4-yl methy l)amino)pheny IJsul forty! Jbenzamide;

4-(4-((4'-chloro-1,1 ’-biphenyl-2-y l)methyl)piperazin-1 -y 1)-2-(4-(2(d imethy lam ino)ethy l)phenoxy)-N -((3 -n i tro-4-(( tetr ahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide;

2-(4-(benzyloxy)phenoxy)-4-(4-((4'-ch I oro-1,1 '-biphenyI-2-yl)methyl)piperazin-1 -yl)-N-((3-nitro4-((tetrahyd ro-2H-pyran-4-y 1 methy l)am ino)pheny I Jsulfony 1 jbenzamide;

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-morpho!in-4-ylphenoxy)-N-((3nitro-4 -((tetrahydro-2H-pyran-4-yImethy I Jam ino)ph eny l)sulfony 1 )benzamide;

tert-butyl 4-(3-(5-(4-((4’-chloro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin- 1-yl)-2-((((3-nitro-4((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)pi perazine-1 -carboxylate;

5 2-(3 -(benzy loxy )phenoxy )-4-(4-((4 -chi oro-1,1 '-b ipheny 1-2-yl )methy 1 )pi perazin-1 -yl)-N -((4-((3 (dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

124

2-(3-( benzyloxy Jphenoxy)-4-(4-((4'-chloro-1, l'-biphenyl-2-yljmethyl Jpiperazin-l-yl)-N-((4-((3morphol in-4-ylpropy I Jam ino )-3-nitrophenyl Jsulfony IJbenzamide;

4-(4-((4'-ch!oro-1,1 '-biphenyl-2-ylJmethylJpiperazin-1 -ylJ-2-(4-(2-morpholin-4ylethoxyJphenoxyJ-N-((3-nitro-4-((tetrahydro-2H-pyran-45 ylmethyljaminojphenyljsulfonyljbenzamide;

2-(4 -(benzy loxy)phenoxy)-4-(4-((4'-ch loro-1,1 '-bipheny 1-2-y I Jmethy 1 Jpiperazin-1 -y 1J-N -((4-((3 morpholm-4-ylpropylJamino)-3-nitrophenylJsulfonyl)benzamide;

tert-butyl 4-(4-(5-(4-((4'-chIoro-l,r-bipheny 1-2-yljmethyl Jpiperazin-1-y 1)-2-((((4-( (3-morphol in4-yipropyl)amino )-3 -nitrophenyl JsulfonylJamino JcarbonylJphenoxyJphenylJpi perazine-110 carboxylate;

4-(4-((4'-chloro-l_sr-biphenyl-2-ylJmethyl)piperazin-l-ylJ-N-(( 4-( (3-morpholin-4ylpropyl)amino)-3-nitrophenylJsu!fonylJ-2-(3-pyridin-4-ylphenoxy)benzamide;

4-(4-((4'-chloro-l, 1 '-biphenyl-2-yIJmethyl)piperazin-]-y]J-N-((4-((3-morpholin-4ylpropyI)ammoJ-3-nitrophenylJsulfonyl)-2-(4-pyridin-4-ylphenoxyJbenzamide;

4-(4-((4'-chloro-l, I '-bipheny 1-2-yljmethyljpiperazin-1 -ylJ-N-((4-((3-morpholin-4yl propyl Jam ino J-3 -n itrophenyljsu Ifony I J-2-(4-pyridin -3 -yl phenoxy Jbenzam ide;

4-(4-((4'-chloro-l₁l'-biphenyl-2-ylJmethyI)piperazin-l-yl)-2-(4-(2-(dimethylamino)-2oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyljaminojphenyljsulfony IJbenzamide;

4-(4-((4'-chlorobiphenyl-2-ylJmethyl)piperazin-l-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3morpho I inopropylaminoJ-3-nitrophenyIsu Ifony IJbenzamide;

4-(4-((4'-ch!orobiphenyl-2-yl)methylJpiperazin-]-ylJ-N-(4-(3-(dimethyIamino)propylaminoJ-3n i tro pheny 1 s u Ifony I J- 2 - (3 -(methy I carbamoy 1 Jp h e noxy Jben zam i d e;

4-(4-((4'-chl oro-1 ,l'-biphenyI-2-ylJmethyl Jpiperazin-I-ylJ-2-(3-(2-(d imethy laminoJ-225 oxoethoxyJphenoxyJ-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyljbenzamide;

4-(4-((4 '-chloro-1,1 '-bipheny 1-2-y 1 Jmethyljpiperazin-1 -y IJ-N-((4-( (3 (dimethy laminojpropy 1 Jamino)-3 -n i trophenyl Jsulfony 1 )-2-(3 (hydroxymethyljphenoxy)benzamide;

N-(4-((4-aminotetrahydro-2H-pyran-4-ylJmethylamino)-3-nitrophenylsulfonylJ-2-(3ch lorophenoxy)-4-(4-((2-(4-ch loropheny IJ-4,4-d imethy Icyc lohex-1-enyl Jmethy I Jpiperazin-1y IJbenzamide;

4-(4-(1 -(4'-ch lorobipheny l-2-y I Jethyl Jpiperazin-1 -ylJ-2-(2-chlorophenoxyJ-N-(3-nitro-4((tetrahydro-2H-pyran-4-ylJmethylaminoJphenylsulfonyIJbenzamide;

N- {[4- { 4- [(4'-chloro- ], 1 '-biphenyl-2 -yl Jmethy 1 j piperazin-1 -y 1} -2-(3,5dichlorophenoxyjpheny] [sulfony l}-4-[(l-methylpiperidin-4-ylJamino]-3-nitrobenzamide;

125

4-(4- {[2-(4-chlorophenyI)-4,4-dimethylcyclohex-1 -en-l-yl]methyl}piperazin-1 -yl)-2-(3fluorophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4- {[2 -(4-ch loropheny I )-4,4-d i methy Icyclohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1)-2-(3 fluorophenoxy )-N-( {3 -nitro-4- [(1 -tetrahydro-2H-pyran-4-y lpiperidin-45 yl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny])-4,4-dimethylcyclohex- 1-en-1-y l]methy I} piperazin-1 -yl)-2-(3fluorophenoxy )-N-( {4-((3 -morphol in-4-y I propyl )am ino]-3 -nitrophenyl} su Ifony l)benzam ide; 2-(2-chIorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-yIpiperidin-410 yl)amino]phenyl}sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-1-en-1yl]methyl} piperazin-1-y l)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3n itropheny!} sulfonyl)benzamide;

2-(2-ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icycl ohex-1 -en-1 15 yl]methyl} piperazin-1-yl)-N-({4-[(l-cyclopentylpiperidin-4-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy I} piperazin-1-y 1)-2-(4fluorophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl} sulfony l)benzamide;

2-(3 -ch 1 orophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4 -dimethy Icyc lohex-1 -en-1 20 yl]methyl}piperazin-l-yl)-N-({4-[(l-cyclopropylpiperidin-4-yl)amino]-3nitropheny I} sulfony l)benzam ide;

2-(2-chIoro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycIohex-1 -en-1y I] methy I} piperazin-l-yl)-N-({4-((3-morphol in-4-ylpropyl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1-en-1-yl]methyl) piperazin-l-yl)-N-( {4-((1cyclopropy Ipiperid in-4-yl)amino]-3-nitrophenyl} sulfony 1)-2 -(2,3-difluorophenoxy)benzamide; 4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex- 1-en- l-yl]methyl} piperazin- 1-y 1)-2-(2fluorophenoxy)-N-( {4-((1 -methy Ipi perid in-4 -y I )amino]-3 -n itropheny 1} su I fony l)benzam ide;

4-( 4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex- 1-en- l-yl]methyl}piperazin- 1-y l)-N-({4-[(l30 cyclopropy lpiperidin-4-yl)amino] -3 -nitrophenyl} sulfony 1)-2-(2 -fluorophenoxy )benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl] methyl} pi perazin-1-y 1)-2-(2fluorophenoxy )-N-( {3-nitro-4-[( 1-tetrahydro-2H-pyran-4-y lpiperidin-4y l)am ino]pheny I} su lfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-(23 5 fluorophenoxy )-N-( {4-((3 -morphol in-4-y Ipropy l)am i no]-3 -n itropheny 1} su 1 fony l)benzamide;

126

4-( 4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1-en-1-yijmethyl} piperazin-l-yl)-2-(2fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl} sulfony l)benzamide; 2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly IJmethyl} piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2 H-pyran-4-y lpiperidin-45 yl)ammojphenyl[sulfonyl)benzamide;

2-(3 -chlorophenoxy )-4-(4- {[2-(4-ch lorophenyl )-4,4-di methy Icyc lohex-1 - e n -1 yijmethyl [piperazin-l-yl)-N-({4-[(3-morpholin-4-ylpropyl)ainino]-3nitrophenyljsu Ifony l)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-l-yijmethyl} piperazin-1-y 1)-2-(310 fluorophenoxy )-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1 )-4,4-d imethy Icyc lohex-1 -en -1 yl]methyl}piperazin-l-yI)-N-({4-[(l-cyclopentylpiperidin-4-yl)aminoJ-3nitrophenyl}sulfonyl)benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l15 yijmethyl} piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-y l)amino]-3[(trifluoromethyl)sulfonyl]phenyl[sulfonyl)benzamide;

4-(4- {[2 -(4-ch loropheny 1 )-4,4-d imethy Icyclohex-1 -en-1 -y 1 ] methy 1} piperazin-1 -y l)-N-( {4- [(1 cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl} sulfony 1)-2-(3-fl uorophenoxy)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-yijmethyl} piperazin-l-yl)-N-({4-[(l20 cyclopenlylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d i methy Icyc lohex-1-en-l-yijmethyl} piperazin-l-yl)-N-({4-[(1cycIopentylpiperidin-4-yl)amino]-3-nitropheny I [sulfony 1)-2-( 2-fluorophenoxy)benzam ide;

4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-l-yijmethyl [piperazin-1-y 1)-2-(2,3difluorophenoxy )-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl[ sulfony l)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1-en-l-yijmethyl [piperazin-1-y 1)-2-(2,3difluorophenoxy )-N-[(3-nitro-4-{[l-(thien-3-ylmethyI)piperidin-4yljam ino) pheny l)su Ifony l]benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl[piperazin-I-yl)-N-[(4-{[3(dimethylamino)propyl]amino[-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex- 1-en-l -yl] methy 1} piperazin-1 -y 1)-N- [(4- {[3 (dimethylamino)propyl]amino}-3-nitrophenyl)sulfonylJ-2-(3-fluorophenoxy)benzamide;

4-(4- {[2 -(4-ch lorophenyl)-4,4-d imethy Icyc lohex- 1-en-l -yl] methy I} piperazin-1 -y I )-N-[(4- {[3 (d imethy lamino)propyl] am ino [-3-nitropheny I )su Ifony l]-2-(4-fluorophenoxy)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-di methy Icyclohex-1-en-1-yijmethyl [piperazin-1-y I )-2-(2,335 dif1uorophenoxy)-N-[(4-{[l-(2-fluoroethyl)piperidin-4-yl]amino}-3n itropheny l)su Ifony 1] benzamide;

127

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]metliyl}piperazin-]-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3nitTOpheny I} su Ifony l)benzam ide;

2-(3-ch lorophenoxy)-4-(4- {[2-(4-chloropheny 1)-4,4 -dimethy Icyclohex-1 -en-1 5 y 1 ]methy 1} piperazin-1 -yl)-N-[(4- {[3 -(dimethylam ino)propy l]am ino} -3 nitrophenyl)sulfonyl] benzamide;

2-(3-chlorophenoxy)-4-(4- {[2-(4-chl oropheny 1)-4,4-dimethy Icyclohex-1 -en-1 y fjmethy I} p iperazin-1 -y 1)-N -[(4- ([3-(4 -methy Ip iperazi η-1 -y l)propy l]am ino} -3 nitrophenyl)suifonyl]benzamide;

2-(3-chlorophenoxy )-4-(4-{[4-(4-chloropheny 1)-6,6-d imethy 1-5,6-dihydro-2H-pyran-3yl]methyl} piperazin-1-yl)-N-({4-[(l-methy lpiperidin-4-yl)amino]-3n itropheny I} su Ifonyl jbenzam ide;

4-(4-{[4-(4-chlorophenyI)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyI}piperazin-I-yl)-2(2,3-difluorophenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-315 nitrophenyl}sulfonyl)benzamide;

N-( {4-[( 1 -al ly Ip iperidin-4-y l)amino]-3 -n itropheny 1} su 1 fony 1 )-4 -(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-l-en-l-yl]methyl} piperazin-1-yl)-2-(2,3-difluorophenoxy )benzamide;

2-(3 -chloro-2-fl uorophenoxy )-4 -(4- {[2-(4 -ch loropheny I )-4,4-d imethy leyc lohex-1 -en-1 yl]methyl} piperazin-]-yl)-N-({4-[(l-methylpiperidin-4-y l)amino]-320 nitrophenyl }sulfonyl)benzamide;

2-(3-chloro-2-f]uorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc!ohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3nitropheny 1} su Ifony I)benzam ide;

2-(3 -ch loro-2-fluorophenoxy )-4-(4- {[2-(4-chlorophenyl)-4,4-d imethy Icyclohex-1 -en-1 2 5 y IJmethy 1} piperazin-1 -y 1 )-N- ((3 -n itro-4- [(3-py rro 1 i d in -1 y Ipropy l)amino] phenyl} sulfonyl )benzam ide;

2-(3-chloro-2-fluorophenoxy )-4-(4-( [2-(4-chIorophenyl)-4,4-d imethylcyclohex-l-en-1yl]methyl} piperazin-l-yl)-N-( {4-[(2-morpholin-4-ylethyl)amino]-3nitrophenyl}sulfonyl)benzamide;

0 2-(2-chloro-6-fl uorophenoxy )-4-(4- {[2-(4-ch loropheny I )-4,4-d imethy Icyclohex-1 -en-1 yl] methy 1} piperazin-1 -yl)-N-({4-[( 1 -methy lpiperidin-4-y l)amino] -3 nitropheny I} su Ifony l)benzamide;

2-(2-ch loro-6-fl uorophenoxy )-4-(4-( [2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-435 yl)amino]phenyl}sulfonyl)benzamide;

128

2-(3 -chlorophenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1-en-Iy l]methyl} piperazin-1 -y l)-N-[(4- {[(1 -methylpiperidin-4-y I )methyl]am ino} -3 n itropheny l)sulfonyl] benzamide;

4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-1-yljmethyl) piperazin-l-yI)-2-(2,35 difluorophenoxy)-N-[(4-{[(l-niethylpiperidin-4-yl)methyl]amino}-3n itropheny 1 )su Ifony l]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-1-yljmethyl) piperazin-1-yl)-2-[3(methoxymethoxy )-2-methy Iphenoxy ]-N-({4-[( I -methy Ipiperidi n-4-y I )amino]-3 nitrophenyl }su Ifony l)benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-I-yl]methyl)piperazin-l-yl)-2-(3-hydroxy2-methylphenoxy)-N-({4-[(l-methylpiperidm-4-yl)amino]-3-nitrophenyl} sulfony l)benzamide; 2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3yljmethyl) piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yI)amino]-3nitrophenyl)sulfonyl)benzamide;

4-(4-{[4-(4-ch loropheny 1)-6,6-dimethy 1-5,6-dihydro-2H-pyran-3-yljmethyl) piperazin-1-y 1)-2-(3iodophenoxy )-N-({4-[(1-methy 1 pi peridin-4-yl)amino]-3-nitrophenyl)sul fony l)benzam ide; 2-(3-chlorophenoxy )-4-(4-( [2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-en-lyl]methy!) piperazin-l-yl)-N-[(4-{[l-(2-hydroxyethyl)piperidin-4-y]]amino)-3nitrophenyl)sulfbnyl]benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icy c lohex-1 -en-1 y l]methy I} pi perazin-1 -y l)-N -[(3 -n itro-4- {[ I -(2-pheny lethy 1 )piperid in-4yl]amino)phenyl)sulfonyl]benzamide;

4-(4- {(2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en- 1-y 1] methyl} piperazin-1 -yl)-2-(3,4dichlorophenoxy)-N-( {4-((1-methyIpiperidin-4-yl)aminoJ-3-nitrophenyl}sulfonyl)benzamide;

2 -(2-ch loro-3,5 -di fl uorophenoxy )-4-(4- {[2-(4-chloropheny I )-4,4-d imethy icy c lohex- 1-en-1 yl J methy 1) piperazin-1 -y i)-N-( {4-(( I -methy Ip iperid in-4-yl)am ino] -3 nitrophenyl} sulfonyl)benzamide;

4-(4- {[ 2-(4-ch loropheny I )-4,4-d im ethy Icyclohex-1 -en-1 -y 1] methy I} p i perazin-1 -yl)-2-(3methoxyphenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl)sulfonyI)benzamide;

4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1-en-1-yljmethyl} piperazin-1-y 1)-2-(3(hydroxymethyl)phenoxy]-N-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl) sulfony I )benzam ide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly I] methyl) piperazin-l-yl)-N-({4-[(1,4-dimethy lpiperidin-4-yl)aminoJ-335 nitrophenyl} sulfbnyl)benzamide;

129

2-(3-chlorophenoxy)-4-(4-{[2-(4-clilorophenyl)-4,4-dimethylcyclohex-l-en-]yl]methyl}piperazin-l-yl)-N-({4-[(l_J4-dimethylpiperidin-4-yl)amino]-3n itropheny 1} su Ifony 1 )benzamide;

2-(3 -chlorophenoxy)-4-(4-{[2-(4-ch loropheny1)-4,4-d imethyIcyclohex- 1-en-1 5 yl]methyl}piperazin-]-yl)-N-{[4-({l-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}amino)-3nitrophenyl]sulfonyl} benzamide;

2-(2-ch loro-3 -hy droxyphenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en -1 yl]methyl}piperazin-]-yl)-N-({4-[(]-methylpiperidin-4-yl)aminoj-3nitrophenyl}sulfonyl)benzamide;

2-(3-ch lorophenoxy )-4-(4-{[2-(4-chlorophenyI)-4,4-dimethy Icyclohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-[(3-nitro-4-{[l-(3-phenylpropyl)piperidin-4yl]amino}phenyl)sulfonyl]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethylcyclohex-1 -en-1 yl]methyl} piperazin-1-y l)-N-[(4-{[l-(2-methoxyethyl)piperidin-4-yl]amino)-315 n itropheny l)sulfonyl]benzam ide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-[(l-ethylpiperidin-4-y])amino]-3nitrophenyl)sulfonyl)benzamide;

2-(3 -chlorophenoxy)-4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-I -en-1 20 yl] m ethyl} piperazin-1 -y] )-N-( {4- [(1 -isopropy Ipiperid in-4-y 1 )am ino]-3 nitrophenyl} su Ifony l)benzam ide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethylcycloh ex-1 -en-1 -y I] methyl} piperazin-l-yl)-2-(3hydroxyphenoxy)-N-({4-[(l-methylpiperidin-4-yl)amino]-3-nitrophenyl}su]fonyl)benzamide; 2-(2-chloro-3-fl uorophenoxy)-4-( 4-{[2-(4-ch loropheny 1)-4,4-dimethylcyc lohex-1-en-l25 yl]methyl} piperazin-l-yl)-N-({4-[(l-methy Ipiperid in-4-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(2 -chloro-3 -fluorophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex- 1-en-lyl]methyl}piperazm-l-yI)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4y 1 )am ino] pheny I} sul fony l)benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)-N-[(4-{ [3-(dimethylamino)propyl]amino}-3nitrophenyl)sulfonyl]benzamide;

4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-l-en-1-yl]methyl} piperazin-l-yl)-2-(2methoxyphenoxy)-N-({4-[(l-methylpipendin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyi)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-(2methy Iphenoxy)-N-( {4 - [ (1 -methy 1 piperid in-4-yl )am i n o ]-3 -nitrophenyl} sulfonyl )benzamide;

130

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex- l-en-l -y 1 ] methy 1} piperazin-1 -y 1)-2-(3 methy Iphenoxy )-N-( {4- [(1 -methylpiperid in-4-yl)amino]-3 -n itropheny 1} sulfony I )benzam ide;

2-(2-chlorophenoxy )-4-(4- {[6-(4-ch loropheny I)-1,3 -benzodioxo 1-5-y l]methyl} piperazi η-1 -yl)-N({4-[(l-methylpiperidm-4-yl)amino]-3-nitrophenyl|suIfbnyI)benzamide;

2-(2-chlorophenoxy)-4-(4- {[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1y IJmethy I} pi perazin-l-yl)-N-({4-[(4-methy Ipiperazin-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3yljmethyl) piperazin-1-yl)-N-( {4-[(4-methy Ipiperazin-1-yl)amino]-310 nitrophenyl }su I fonyl)benzam ide;

4-(4.{[4-(4-chlorophenyl)-6,6-dimethyl-5_J6-dihydro-2H-pyran-3-yl]methyl}piperazin-l-yl)-2(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-l-yl)amino]-3n itropheny 1} su Ifonyl )benzam ide;

2-(3 -chlorophenoxy )-4-(4 -{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex- l-en-l 15 y|]methyl}piperazin-l-yl)-N-[(4-{[l-(cyclopropylmethyl)piperidm-4-ylJamino}-3n itropheny l)sulfony I] benzamide;

2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl) piperazin-l-yi)-N-[(4-{[l-(cyclopropylmethyl)piperidin-4-yl]amino}-3nitrophenyl)sulfony!]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly IJmethy 1} piperazin-1 -y l)-N- {[4-( {1 - [2-(dimethy lamino)-2-oxoethy !]piperidin-4-y 1} am ino)-3 nitrophenyl]sulfonyl}benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-[(4-{[I-(2-morpholin-4-ylethyl)piperidin-4-yl]animo}-325 nitrophenyl )sulfonyl] benzamide;

N-[(4- {[(4-am inotetrahydro-2 H-pyran-4-yl)methyi] amino} -3-nitrophenyl)su lfonyl]-2-(2chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl|piperazin-lyl)benzamide;

2-(2-chlorophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 3 0 y 1] methyl} piperazin-1 -y l)-N -[(4- {[(4-hydroxy-l -methylpiperidin-4 -yl)methy IJamino} -3 n itropheny l)sulfonyl] benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-‘N-[(4-{[(3S)-l-methylpyrtolidin-3-ylJamino}-3nitrophenyl)sul fony IJbenzam ide;

131

2-(3 -c hlorophenoxy )-4-(4- {[2 -(4-ch loropheny I )-4,4-dimethy Icyc! ohex- 1-en-lyl]methyl}piperazin-l-yl)-N-[(4-{((3R)-l-methylpyrrol!din-3-yI]amino}-3nitrophenyl)sul fony I] benzamide;

4-(4- {[2-(4-ch loropheny 1 )-4,4-d i methy leyclohex-1 -en-1 -yl] methy 1} pi perazin-1 -y 1)-N -({4-[( 1 5 methy lpiperidin-4-yl)amino]-3-nitrophenyl} sulfony 1)-2-(3-( 1 H-pyrrol-2-yl)phenoxy]benzamide;

4-(4-{[2-(4-chloropheny I )-4,4-dimethy Icyc lohex-l-en-l-yl]methy I} piperazin-1-y 1)-2-(3fluorophenoxy)-N-[(4-{[(4-hydroxy-l-methylpiperidin-4-yl)methyl]amino}-3nitropheny l)sulfony l]benzamide;

2-(3 -ch lorophenoxy )-4-(4 - {(2-( 4-ch loropheny 1)-4,4-dimethy leyclohex-1-en-1 10 y ] ]methy I} pi perazin-l-yl)-N-({4-[(4-methyl piperazin-l-yl)amino]-3n itropheny 1} su Ifony I )benzam ide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-[(4-{[4-(dimethylamino)cyclohexy!]amino}-3n itropheny l)sulfony 1 ]benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl} piperazin-l-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3nitrophenyl)sulfonyl]benzamide;

Tran s-2-(3-ch lorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy leyclohex-1-en-1yl]methy I} piperazin-l-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-320 nitrophenyl} sulfony l)benzam ide;

4. {4-[ 1-( 4’-chloro-1, Γ-b i pheny 1-2-yl)ethyl] piperazin-l-y!}-2-(2-ch lorophenoxy )-N-( {4-[(1methylpiperidin-4-yl)amino]-3-n itropheny 1} sulfony l)benzamide;

2-(2-ch loro-4-hydroxyphenoxy )-4-(4- {[2-(4 -ch loropheny I )-4,4-d imethy leyclohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-325 nitrophenyl} sulfony l)benzamide;

2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-({4-((4-methylpiperazin-l-yl)amino]-3nitrophenyl} sulfony I )benzamide;

2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l30 yl]methyl}piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3[(trifluoromethy l)sulfony l]pheny 1} su Ifony 1 )benzam ide;

2-(5-(4-((2-(4-chloropheny 1)-4,4-dimethylcyclohex-l-enyl)methyl)piperazin-l-yl)-2-(4-(1methy 1 piperidin-4-y lamino )-3 -nitrophenyl su Ifony Icarbamoy I )phenoxy)-N,N-d imethy Ibenzamide; 2-(2-chIoro-4- hydroxyphenoxy )-4-(4- {[2-(4-chloropheny 1 )-4,4-d imethy Icycl ohex-1 -en-1 35 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

132

2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4_J4-dimethylcyclohex-l-en-lyl]methYl}piperaztn-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

2-[3-(acety lam ino)phenoxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icy c lohex-1-en-l5 yl]methyl} piperazin-l-yl)-N-( {3-nitro-4-[(l-tetrah ydro-2H-pyran-4-y lpiperidin-4yl)amino}phenyl}sulfony!)benzamide;

2-(3-chlorophenoxy )-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1 yl]methyl} piperazin-1 -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-(4-am ino-3-chlorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-1yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydra-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-(2-chlorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-lyl] methyl} piperazin-1-y l)-N-{ [4-( {[4-(hydroxymethy I )tetrahydro-2H-pyran-4-yl]methyl} amino)15 3-nitrophenyl]sulfonyl} benzamide;

2-(3 -ch lorophenoxy )-4-(4- {[2-(4-chloropheny 1)-4,4-d imethy leyc lohex-1 -en-1 y l]methy 1} piperazin-l-yl)-N-{ [4-( morpholin-4-y lam ino)-3-nitrophenyl] sulfonyl [benzamide;

2-(2-ch lorophenoxy )-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1-en-1y 1 ] met h y I} piperazin-1 -y l)-N- [(3 -n itro-4- {[3 -(3 -oxopiperazin-1 20 y 1 )propy I ]am ino} pheny l)sulfonyl ] benzamide;

2-(3-amino-5-chlorophenoxy )-4-(4-{[2-(4-ch loropheny I )-4,4-dimethy Icyclohex-1-en-1yl]methy 1} pi perazin-1 -y I )-N-( {3 -n itro-4-[(tetrahy dro-2 H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(44 [2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1-y I] methyl} piperazin-l-y!)-N-({ 3-nitro-42 5 [ (tetrah ydro-2H-pyran-4-y Imethy 1 )amino] pheny 1} sulfony 1)-2 - [2-( I H-pyrazo 1-4yl)phenoxy] benzamide;

- [2-(2-aminopyrid in-3-y 1 )phenoxy] -4-(4- {[2-(4-ch 1 oropheny l)-4,4-d imethy Icyclohex-1 -en-1 yl]methyl} piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1 )-4,4-d imethy Icyclohex-l-en-l-yl]methyl} piperazin-1-y I )-N-({ 3-nitro-4[(tetrahydro-2 H-pyran-4-y Imethyl )am ino]pheny I} sul fony 1)-2-(2-( 1 H-pyrazol-5 yl)phenoxy]benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

In another aspect, the present invention provides compounds of Formula (II!)

133

<img file="MY179077A_D0009.tif" />

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, wherein A^!, B¹, D¹, E¹, Y^l, Z², L¹, and Z³ are as described herein for Formula (I), n is 0, 1, 2, or 3;

describing the number of additional substituents on R²⁶, and R¹⁰⁰ is as described for substituents on R²⁶, and at least one R¹⁰² is a substituent as described for substituents on R⁴² and R^42A, and the remainder are H.

In one embodiment of Formula (III), A¹ is N. In another embodiment of Formula (III), A¹is C(A²). In another embodiment of Formula (III), A¹ is C(A²); and A² is H.

In one embodiment of Formula (III), B¹ is OR¹, or NHR¹. In another embodiment of

Formula (III), A¹ is C(A²); A² is H; and B¹ is NHR¹. In another embodiment of Formula (III), A¹is C(A²); A² is H; and B^l is OR¹.

In one embodiment of Formula (III), D¹ is H. In another embodiment of Formula (III), A¹ is C(A²); A² is Η; B¹ is NHR¹; and D¹ is H. In another embodiment of Formula (III), A¹ is 15 C(A²); A² is Η; B¹ is OR¹; and D¹ is H.

In one embodiment of Formula (1Π), E¹ is H. In another embodiment of Formula (III), A¹is C(A²); A² is H; B^l is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is H; and E’ is H.

In one embodiment of Formula (III), Y¹ is H, CN, NO2, F, Cl, Br, CF3, R¹⁷, or SO2R¹⁷. In 20 another embodiment of Formula (ΠΙ), Y¹ is NO₂. In another embodiment of Formula (III), Y¹ is

Cl. In another embodiment of Formula (III), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (III), Y¹ is SO2R¹⁷; wherein R¹⁷ is alkyl. In another embodiment of Formula (III), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl, In another embodiment of Formula (III), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 or SO2R¹⁷; wherein R¹⁷ is alkyl or 25 alkynyl. In another embodiment of Formula (III), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 In another embodiment of Formula (III), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is

134

Η; Ε¹ is Η; and Υ¹ is SO₂R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In another embodiment of Formula (III), A¹ is C(A²); A² is Η; B¹ is OR¹; D^l is Η; E¹ is H; and Y¹ is Cl.

In one embodiment of Formula (III), R¹ is R⁴ or R^s. In one embodiment of Formula (III), R¹ is R⁴. In one embodiment of Formula (III), R¹ is R⁵. In one embodiment of Formula (ΠΙ), R¹ is

R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (III), R^l is R⁴; and

R⁴ is cycloalkyl. In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with R⁵⁷, NHR⁵⁷, orN(R⁵⁷)₂. In another embodiment of Formula (III), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R^w. In another embodiment of Formula (III), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R^M; and R⁶⁰ is heterocycloalkyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R^6D is heterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl or piperazinyl, In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(R^!7)₂. In another embodiment of Formula (ΙΠ), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(Rⁱ⁷)2, In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2, Rⁱ⁷ is R⁶', and R⁶¹ is alkyl which is unsubstituted. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which is unsubstituted. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷, In another embodiment of Formula (ΠΙ), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of

Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (III), R¹ is R⁴;

and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted as defined herein. In another embodiment of Formula (ΙΠ), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the

135 heterocycloalkyl ring is substituted with Rⁱ⁷. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ is heterocycloalky-1; wherein the heterocycloalkyl ring is piperidinyl, pynolinyl, morpholinyl, or piperizinyl; and wherein the heterocycloalkyl ring is substituted with one or two or three or four or five more R⁵⁷; SO₂Rⁱ⁷,or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of

Formula (III), R^l is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with Rⁱ⁷; R⁵⁷ is R^so or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R ⁷; R is R⁶⁰; R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl or oxetanyL In another embodiment of Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R ;R is R ; R is alkyl; and the alkyl is C_ralkyl, C_ralkyl, orC₃-alkyl. In another embodiment of Formula (III), R¹ is R⁴;

R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pynolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R^S7; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C_ralkyl, C₂-alkyl, or C₃-alkyI; wherein the C_ralkyl, C_:-alkyl, or C₃-aIkyl are unsubstituted or substituted.

In one embodiment of Formula (III), R¹ is R⁵; and R⁸ is alkyl which is unsubstituted or substituted. In one embodiment of Formula (III), R¹ is R⁸; and R^s is alkyl which is unsubstituted or substituted with R⁷, OR⁷, NfR⁷^, or OH.

In one embodiment of Formula (III), R⁷ is R¹⁰ or R¹¹ which are unsubstituted or substituted as defined herein. In another embodiment of Formula (III), R⁷ is R¹⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (ΠΙ), R⁷ is R^uwhich is unsubstituted or substituted as defined herein.

In one embodiment of Formula (III), R^,D is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (III), R¹⁰ is heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment 35 of Formula (III), R¹⁰ is tetrahydro furanyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted or substituted as defined herein. In another

138

4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy Icyclohex- 1-en-l -yl] methy 1} piperazin-1 -y 1)-N- [(4- {[1(cyclopropylmethyl)piperidin-4-yl]amίno}-3-nitrophenyl)sulfonyl]-2-[(6_J7-difluoro-lH-mdol·5yl)oxy]benzamide;

4-(4- {[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 -en-1 -yl]methyl} piperazin-1 -yl)-2-[(6-f1uoro5 1 H-indoI-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino] phenyl} sulfony 1 )benzam ide;

4-(4-{[2-(4-ch loropheny 1 )-4,4-d imethy Icyclohex-1-en-l-yl]methyl} piperazin-1-y 1)-2-[(6,7d ifluoro-1 H-indo 1-5-y I)oxy]-N - [(3 -nitro-4- { [3 -(3 -oxopiperazin-1 y l)propy 1 ]am ino} pheny l)sulfony 1] benzamide;

4-(4-{[2-(4-chlorophenyl)-4₎4-dimethylcyclohex-l-en-l-yl]methy I} piperazin-l-yI)-2-[(6-fluoro1 H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-l-tetrahydro-2H-pyran-4-ylethyI)amino]-3nitropheny 1} sulfony l)benzamide;

- 4-(4- {[2-(4-chIorophenyI)-4,4-dimethylcyclohex-1 -en-1 -yl] methy 1} piperazin-1 -y 1)-2- [(6-fluoro]H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-315 nitrophenyl] sulfonyl} benzamide;

2-[(6-chlorQ-l H-indol-5-yl)oxy]-4-( 4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-lyl] methy 1} piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-yl pi peridin-4yl)amino]phenyi}sulfonyl)benzamide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl} piperazin-1-y 1)-2-((6,720 difluoro-1 H-indol-5 -y l)oxy ]-N-( { 3 -nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-((6-chloro-lH-indo 1-5-yl)oxy]-4-(4-{[2-(4-chloropheny I )-4,4-d imethy Icy cl oh ex-1-en-ly I] methy I} piperazin-1-y 1)-N-({4-[(4-methy Ip i perazin-1-y l)amino]-3i nitrophenyl}sulfonyl)benzamide;

,, 25 4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1-yl] methyl} piperazin-1 -yl)-2-[(6-fluorolH-indoI-5-yl)oxy]-N-[(3-nitro-4-{[l-(l,3-thiazol-4-ylmethyl)piperidin-4yi] amino} phenyl )su Ifony l]benzamide;

N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)su Ifony l]-4-(4-{ [2-(4chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-i-yl)-2-[(6-fluoro-l H-indol-530 y])oxy]benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-1-en-i-yl] methyl} piperazin-1-y l)-2-[(6-fluoro1 H-indol- 5 -y 1 )oxy] -N-[(4- {[(3 S,4R)-3-hydroxy-1 -(1,3 -thiazol-4-y Imethy 1 )piperid in-4-y I] am ino} 3-nitropheny l)sulfonyl]benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-d imethy Icyclohex-1 -en-1 -y I] methy 1} piperazin-1 -y 1)-2- [(6-fluoro3 5 1 H-indol-5 -yl)oxy] -N-{[3 -n itro-4-(tetrahydro-2H-pyran-4-y lamino)phenyl] su Ifony 1} benzamide;

140

2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyIcyclohex-l-en-lyl] methy 1} piperazin-1 -yI)-N- {[4-( 1,4-dioxan-2-y lmethoxy)-3 -nitrophenyl ] sulfonyl} benzam ide; 2-[(6-ch loro-1 H-indol-5-y 1 )oxy]-4-(4- {[2-(4-chIoroph enyl )-4,4-dimethy Icy c 1 ohex-1 -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(l,4-dioxan-2-ylmethyl)amino]-35 nitrophenyl} sulfonyl)benzamide;

4-(4-{[2-( 4-ch lorop heny 1 )-4,4-dimethy Icyc lohex-l-en-l-yl]methyl}piperazin-l-yl)-N-( {4-[(1,4dioxan-2-y Imethy l)amino]-3-nitrophenyl} sulfonyl )-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide; Trans-2-[(6-ch loro-lH-indol-5-y!)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icy clo hex-1-en-lyl]methyl}piperazin-l-yl)-N-({4-[(4-morpholin-4-ylcyclohexyI)amino]-310 nitrophenyl) su Ifony l)benzamide;

Trans-2-[(6-chloro-lH-indol-5-yl)oxy]-4-(4-{[4-(4-chloropheny 1)-6.6-dimethy 1-5,6-dihydro-2Hpyran-3 -y 1] methy I} p iperazin-1 -y l)-N-( {4- [(4-morphol in-4-y Icyclohexy 1 )am ino]-3 nitrophenyl} su Ifony I)benzamide;

4-(4-{[4-(4-chloropheny I )-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-1-y 1)-2-((615 fluoro- Ϊ H-indol-5-yl)oxy]-N-( {4- [(4-morpholin-4-ylcyclohexy 1 )amino]-3 nitrophenyl }sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl )-4,4-dimethy Icyclohex-1 -en-1 -yl]methyl} piperazin-1 -yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[4-(4-chlorophenyl)-6,6-dimethy 1-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-1-y 1)-2-(( 6fluoro-1 H-indol-5-yl)oxy]-N-( {4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[4-(4-chloropheny 1)-6,6-dimethy 1-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-l-yl)-N{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-lH-indol-525 yl)oxy]benzamide;

2-{[3-(2-aminoethyl)-1 H-indol-5-yl]oxy )-4-(4-{[2-(4-chloropheny I )-4,4-di methylcyclohex-1-enI-yl] methyl} piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-{[3-(2-aminoethyl)-lH-indol-5-yl]axy}-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en30 1-yl]methyl} piperazin-l-yI)-N-( {4-[(4-methylpiperazm-l-yl)amino]-3nitrophenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-l-yl]methyl}piperazin-1-y l)-N-{[5-cyano6-(tetrahydro-2H-pyran-4-yImethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-lH-indol-5yl)oxy]benzamide;

Ml

4-(4- {[2-( 4-chlorophenyl )-4,4-dimethy Icyc lohex-1 -en-1 -y l]methy 1} piperazin-1 -yl)-N-{[5-ch!oro6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl] sulfonyl}-2-[(6-fluoro-l H-indo 1-5yl)oxy]benzamide;

4-(4- {[2-(4-chlorophenyl)-4,4-dimethy Icyclohex-1 -en-1 -y IJmethy 1} pi perazin-1 -y 1)-N- {[5 -cy ano5 6-( l,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro- lH-indol-5-yl)oxy]benzamide;

N-{[5-bromo-6-( 1,4-d ioxan-2-y Imethoxy )pyridin-3 -y l]suifony 1} -4-(4- {[2-(4-ch lorophenyl)-4,4dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide; Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyI)aniino]pyridin-3-yl}sulfonyl)-4-(4-{ [2-(4chloro pheny 1)-4,4-d imethy Icyclohex-1-en-1-y]]methy I} piperazin -i-yl )-2-[(6-fluoro-1 H-indo 1-510 yl)oxy]benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 -yl] methy 1} piperazin-1 -y l)-N-( {5-cyano6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su]fony[)-2-[(6-fluoro-]H-indol-5yl)oxy]benzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy I eye lohex-1 -en-1 -y I] methy 1} piperazin-1 -y l)-N-{ [5 -cyan o15 6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-lH-indol-5-yl)oxy]benzamide;

Trans-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yl]methy I} piperazin-1 -y 1)-2-[(6fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3nitrophenyl}sulfonyl)benzamide;

N-({5-brorno-6-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridm-3-yl}sulfonyl)-4-(420 {[2-(4-ch loropheny 1)-4,4-dimethy 1 eye lohex-1 -en-1 -y I] methy 1} p iperazin-1 -y l)-2-[(6-fluoro-1Hindol-5-yl)oxy]benzamide;

Trans-2-[(6-chloro-l H-indoI-5-yl)oxy]-4-(4-{[5-(4-chIorophenyI)-2,3,6,7-tetrahydrooxepin-4yl]methyl} piperazin-l-yl)~N-({4-[(4-morpholin-4-ylcycIohexyl)amino]-3[(trifluoromethyl )sulfonyl]phenyl}sulfonyl)benzamide;

Trans-2-[(6-chIoro-lH-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyI)-2₎3,6,7-tetrahydrooxepin-4y l]methy 1} piperazin-1 -yI)-N-( {4-[(4-morphol in-4-ylcyclohexy l)amino] -3 nitrophenyl} su lfonyl)benzam ide;

4-(4- {[4-( 4-ch loropheny 1)-6,6-d imethy 1-5,6-dihydro-2 H-pyran-3 -y l]methy 1} piperazin-1 -y 1)-2- [(6 fluoro-lH-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-l-yl)amino]-330 nitrophenyl} su Ifony l)benzamide;

4-(4- {[2-(4-ch 1 orophenyl )-4,4-d imethy Icyc lohex-1 -en-1 -y 1] methy 1} p iperazi n-1 -y 1 )-2-[(6-fluorolH-indol-5-yl)oxy]-N-({4-[(4-morpholm-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide; 4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -yl] methyl} piperazin-1 -yl)-2-[(6-fluorolH-indoi-5-yI)oxy]-N-[(4-{[l-(methyIsulfonyl)piperidin-4-yI]amino}-335 nitrophenyl)sulfonyl]benzamide;

142

4-(4- {[ 2 - (4-ch 1 oropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y 1] methy 1} piperazin-1 -y 1)-N- {[5 ethynyl-6-(tetrahydro-2H-pyran-4-vImethoxy)pyridin-3-y IJsulfony l}-2-[(6-fluoro-lH-indol-5yl)oxy ] benzam ide;

4-(4-{[4-(4-chlorophenyl )-6,6-dimethy 1-5,6-dihydro-2H-pyran-3-y Ijmethy IJpiperazin-1-yl)-N5 {(5 -ethyny l-6-(tetrahydro-2H-py ran-4-y lmethoxy)pyrid tn-3 -y IJsulfony 1} -2-[(6-fluoro-1H-indo 1-5yl )oxy Jbenzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-di methy Icyclohex-1-en-l-yljmethyl Jpiperazin-l-yl)-N-({ 5-cyano6-((1 -tetrahy dro-2H-pyran-4-y lpiperidin-4-y l)oxy]pyridin-3 -y 1} su 1 fony 1)-2-((6-fluoro-1 H-indo 15-yl)oxy] benzamide;

N-( { 5 -chloro-6- [(4-fluorotetrahydro-2H-pyran-4-y l)methoxyJpyridin-3 -y 1} su Ifony 1 )-4-(4- {[2-(4 chlorophenyI)-4,4-dimethylcydohex-l-en-l -yljmethyl} piperazin-I -y 1)-2-[(6-fluoro- lH-indol-5yljoxy Jbenzam ide;

4-(4-{[2-(4-chlorDphenyl)-4₁4-dimethy Icyc lohex-1-en-l-yljmethyl Jpiperazin-l-yl)-N-( {4-[(1cyclopropylpiperidin-4-yl)amino]-3-nitrophenylJsulfonyl)-2-[(6-fiuoro-IH-indol-515 yl)oxyjbenzamide;

4-(4- {[2-(4-chl oropheny 1 )-4,4-d imethy Icyclohex- 1-en-l -y Ijmethy IJ piperazi η-1 -yl)-N-({4-[(4ethyImorpholin-3-yI)methoxy]-3-nitrophenyl}sulfonyI)-2-[(6-fluoro-lH-indol-5yl)oxy]benzamide;

4-(4- {[2-(4-ch loropheny 1 H^-dimethy Icyclohex-1 -en-1 -y 1J methy IJ piperazin-1 -y 1)-2 - [(6-fluoro20 lH-mdol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-l-tetrahydro-2H-pyran-4-ylpiperidin-3yljaminojphenyljsulfonyljbenzamide;

4-(4- {[2-(4-chloropheny 1 )-4,4-d i m ethylcyclohex- 1-en-l -yljmethyl} p iperazin-1 -y 1 )-N-({4-[(1,1 dioxidothiomorphol in-4-yl)am ino]-3-nitropheny 1} sulfonyl )-2-((6-fluoro- lH-indol-5yl)oxy]benzam ide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-l-yljmethyl} piperazin-I-yl)-2-[(6-fluorolH-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3ylmethyl)amino]phenyl}sulfonyl)benzamide;

Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}suIfonyl)-4-(4-{[2-(4chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-[(6-fluoro-lH-indol-530 yl)oxyj benzamide;

Trans-4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyclohex- 1-en-l -yljmethyl} piperazin-1 -yl)-N-[(4{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-lH-indol-5y 1 )oxy ] benzami de;

Trans-4-(4-{[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1-en-l-yljmethyl} piperazin-1-y 1)-2-((635 fluoro-lH-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;

143

Trans-4-(4- {[2-(4-c hl oropheny 1)-4,4-d imethy Icyc lohex-1 -en -1 -y 1] methy 1} pi perazin- l-yl)-2-[(6fluoro-1 H-indoI-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1 yl)cyclohexyl]amino) phenyl)su Ifony I] benzam ide;

4-(4-{ [2-(4-chlorophenyl)-4,4-di methyl cyclohex-1 -en-1 -yljmethyl} piperazin-1 -y l)-2-[(6-fluoro5 lH-mdol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyI]ammo}-3nitrophenyl)sulfonyl]benzamide;

T rans-4-(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1 -en-1 -y l]methy 1} piperazin-1 -y 1)-2- [(6fluoro-1 H-indol-5-y l)oxy] -N-[(4-{[(4-hydroxycyc lohexy l)methy l]am ino} -3 π itropheny l)sulfony IJbenzam ide;

4-(4-{[2-(4-ch 1 oropheny 1)-4,4-d imethy Icy c lohex-1 -en-1 -y I] methy 1} piperazin-1 -y I)-N-( {4-[( 1 eye 1 opropyl-4-fl uoropiperid in-4-y I )methoxy]-3 -n itropheny 1} sulfony 1)-2 -[(6-fl uoro-1 H-indoI-5ζ yl)oxy]benzamide;

4-(4- {[2-(4-chloropheny 1)-4,4-dimethylcycIohex-1 -en-1 -y l]methyl} piperazin-1 -y 1)-N- {[4-( {(3 R)l-[2-fluoro-l-(fluoromethyl)ethyl]pynOlidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro15 lH-indol-5-yl)oxy]benzamide;

N-({5-chloro-6-[(4-f]uorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4chi oropheny 1 )-6,6-d imethy 1-5, 6-d ihydro-2H-pyran-3 -yljmethy 1} piperazin-1 -y l)-2-[(6-fl uoro-1Hindo 1-5-yl)oxy] benzamide;

N-( {5 -chloro-6-[(4,4-difluorocyc lohexy 1 )methoxy]pyrid in-3-y1}su1 fony 1)-4-(4- {[4-(420 chlorophenyl )-6,6-d imethy 1-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-l-yl)-2-[(6-fluoro-lHindol-5-yl)oxy]benzamide;

4-(4-{[2-(4-chIorophenyl)-4,4-dimethylcyclohex-i-en-l-yl]methyl}piperazin-l-yl)-N-[(4-{[(4,4difluorocyclohexyl)niethyl]aniino}-3-nitrophenyl)sulfonyI]-2-[(6-fIuoro-IH-!ndol-5Y¹ yl)oxy] benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

In another aspect, the present invention provides compounds of Formula (IV)

144

<img file="MY179077A_D0010.tif" />

<img file="MY179077A_D0011.tif" />

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are as described herein for Formula (I), n is 0, 1, 2, or 3;

describing the number of additional substituents on R²⁶, and R¹⁰⁰ is as described for substituents on R²⁶, and at least one R¹⁰² is a substituent as described for substituents on R⁴² and R^42A, and the remainder are H.

In one embodiment of Formula (IV), A¹ is N. In another embodiment of Formula (IV), A¹is C(A²). In another embodiment of Formula (IV), A¹ is C(A²); and A² is H,

In one embodiment of Formula (TV), B¹ is OR¹, or NHR¹. In another embodiment of

Formula (IV), A¹ is C(A²); A² is H; and B¹ is NHR¹, In another embodiment of Formula (IV), A¹is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (IV), D¹ is H. In another embodiment of Formula (IV), A¹ is C(A²); A² is Η; B¹ is NHR¹; and D¹ is H. In another embodiment of Formula (IV), A¹ is 15 C(A²); A² is Η; B¹ is OR¹; and D¹ is H.

In one embodiment of Formula (IV), E¹ is H. In another embodiment of Formula (IV), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹is C(A²); A² is Η; B¹ is OR¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (IV), Y¹ is H, CN, NO2) F, Cl, Br, CF3, R¹⁷, or SO2R¹⁷. In 20 another embodiment of Formula (IV), Y¹ is NO2. In another embodiment of Formula (IV), Y¹ is Cl. In another embodiment of Formula (IV), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (IV), Y¹ is SO2R¹⁷; wherein R¹⁷ is alkyl. In another embodiment of Formula (IV), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. In another embodiment of Formula (IV), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO2 or SO₂R¹⁷; wherein R¹⁷ is alkyl or 25 alkynyl. In another embodiment of Formula (IV), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is

145

H; and Υ¹ is Ν0; In another embodiment of Formula (TV), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹is Η; E¹ is H; and Y¹ is SO2R^!7, wherein R^[7is alkyl substituted with three F, In another embodiment of Formula (IV), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is Η; E¹ is H; and Y¹ is Cl.

In one embodiment of Formula (IV), R^l is R⁴ or R⁵. In one embodiment of Formula (IV), 5 R¹ is R⁴. In one embodiment of Formula (IV), R¹ is R⁵. In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (IV), R’ is R⁴; and R⁴ is cycloalkyl. In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloaikyl.

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (TV), R¹ is R⁴;

and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with Rⁱ⁷, NHR⁵⁷, or N(R^S7)i. In another embodiment of Formula (IV). R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ is heterocycloaikyl. In another embodiment of Formula (IV), R^l is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloaikyl; wherein the heterocycloaikyl ring is morpholiny] or piperazinyl. In another embodiment of Formula (IV), R^l20 is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalky]; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷}2. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2, R⁵⁷ is R⁶', and R⁶¹ is alkyl which is unsubstituted. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R^so is cycloalkyl which is unsubstituted. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of Formula (TV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloaikyl which is unsubstituted.

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloaikyl; wherein R⁴ is 35 unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R^l is R⁴; and R⁴ is heterocycloaikyl; wherein the heterocycloaikyl ring is substituted as defined herein. In

146 another embodiment of Formula (TV), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted with Rⁱ⁷. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the heterocycloalkyl ring is substituted with one or two 5 or three or four or five more R⁵⁷; S0₂R⁵⁷,or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of

Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl;

wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl or oxetanyl, In another embodiment of Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with Rⁱ⁷; Rⁱ⁷ is R⁶⁰; R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyciopropyl or cyclopentyl. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶’; R⁶’ is alkyl;

and the alkyl is Ci-alkyl, C₂-alkyl, or C₃-aIkyl. In another embodiment of Formula (IV), R¹ is R⁴;

R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R⁵⁷; R⁵⁷ is R®¹; R⁶¹ is alkyl; and the alkyl is C_ralkyl, C₂-alkyl, or C₃-aIkyl; wherein the Cj-alkyl, Cj-alkyl, or C₃-alkyl are unsubstituted or 25 substituted.

In one embodiment of Formula (IV), R¹ is R^s; and R⁵ is alkyl which is unsubstituted or substituted. In one embodiment of Formula (IV), R¹ is R⁵; and R^s is alkyl which is unsubstituted or substituted with R⁷, OR⁷, N(R⁷)₂, or OH,

In one embodiment of Formula (IV), R⁷ is R¹⁰ or R¹¹ which are unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R⁷ is R¹⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R⁷ is R¹¹which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (IV), R^1D is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R¹⁰ is 35 heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl,

147 piperizinyl, or pyrrolidinyl, which are unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R¹⁰ is tetrahydropyranyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (TV), R¹⁰ is morpholinyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R¹⁰ is cycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (IV), R¹⁰ is cyclohexyl which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (IV), R’¹ is alkyl which is unsubstituted. In another embodiment of Formula (IV), R¹¹ is methyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (TV), R¹¹ is alkyl, which is substituted as defined herein. In another embodiment of Formula (IV), R¹¹ is alkyd, which is substituted with OR¹³, Rⁱ²is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (TV), which are 4-( 4-((4'-ch loro-1,1 '-biphenyi-2-yl)methyl)piperazm-l -yl)-N-( (4-((3(dimethylamino)propyl)amino)-3-nitrophenyl)sul fony 1)-2-((1 -methyl-lH-indol-415 yl)oxy)benzamide;

4-(4-((2-(4 -ch loropheny l)-4.4-d i methylcyclohex-! -en-1 -y l)methy l)piperazin-1 -y 1)-2-((3 -methyl]H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitropheny I )su Ifony I)benzam ide; 4-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyclohex- 1-en-1-y l)methyl)piperazin- 1-y 1)-2-((3-methy IlH-indol-4-yl)oxy)-N-( (4-((] -methylpiperidin-4-yI)am ino)-3-n itropheny l)su Ifony l)benzamide;

4-(4-((4'-chloro-1,1 ’-biphenyl-2-yl)niethyl)piperazm-1 -y 1)-2-(( 1 -methyl-1 H-indol-4-yl)oxy)-N((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

tert-buty 1 4-(5 -(4- {[2-(4-chloropheny 1)-4,4-dimethy Icyc 1 ohex-1 -en-1 -y 1] methy 1} piperazin- 1 -y 1 )2-{[( {4-[(]-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl} phenoxy)- 1Hindole-1 -carboxylate;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethylcycIohex-1 -en-1 -y I]methy I} piperazin-1 -y 1)-2 - [(6-fluoro] H-indol-4-y 1 )oxy] -N-( {4-[( 1 -methylpiperidin-4-y l)am ino]-3 -nitrophenyl} sulfony l)benzam ide; 4-(4- {[2-(4-chloropheny 1)-4,4-dimethylcyclohex-1 -en-1 -yl]methyl) piperazin-1 -y !)-2-[(6-fl uoroIH-indoI“4-yl)oxy]-N-({3-nitro-4-[(I-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-( {1,3 -bis [(4-methy I piperazin-1 -yl)methyl]-1H- indo 1-4-yl} oxy)-4-(4 - {[2-(4-ch lorophenyl)-4,4dimethylcyclohex-l-en-l-yl]methyl} piperazin-l-yl)-N-[(4-{[3-(dimethylamino)propyi]amino}-3nitrophenyi)sulfonyl] benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-1-yl ] methyl) piperazin-1-y l)-N-[(4-{ [3(d imethylamino)propy l]amino} -3 -n itropheny I)sulfonyl]-2-({3 -[(4-methy Ipiperazin- ] -y 1 )methy 1] 35 lH-indol-4-y]}oxy)benzamide;

148

4-(4-{[2-(4-chloropheny IJ-4,4-dimethylcyclohex-l-en-1-yl] methy I} piperazin-l-yl)-N-({3-nitro-4[(1 -tetrahydro-2H-pyran-4-ylpjperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-l Hindol-4-yl]oxy Jbenzamide;

4-( 4-{[2-(4-chlorophenylj-4.4-dimethy Icyclohex-1-en-l-yl]methylj piperazin-l-yl)-2-[(6-fluoro5 1 H-indol-4-yl)oxy]-N-[(3-nitro-4-{ [3 -(3 -oxopiperazin-1y 1 jpropyl] am ino} phenyl Jsulfony 1 Jbenzamide;

2-[(3-chloro-lH-indol-4-ylJoxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethylcyclohex-l -en-1yl]methylJpiperazin-l-ylj-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethyl )am ino] phenyl Jsulfony IJbenzamide;

4-(4- {[2-(4-ch I oropheny I )-4,4-di methy Icyc lohex-1 -en-1 -y 1 ] methy I} piperazi n-1 -y 1J-2- [(6-fluoro1 H-indoI-4-y Ijoxy] -N-( {4-[(2-methoxyethy I jam ino]-3 -n itropheny 1} sulfonyl jbenzam ide;

( 2-((3-chloro- lH-indol-4-yl )oxy]-4-(4-{ [2-(4-chlorophenylJ-4,4-d imethy Icyc lohex- 1-en-l yl]methyl}piperazin-l-ylj-N-({4-[(4-methyIpiperazin-l-yl)amino]-3nitrophenyljsulfonyljbenzamide;

4-(4-{[2-( 4-ch loropheny 1)-4,4 -d imethy Icyc lohex- 1-en-l -yl] methy I) pi perazin-1-yl )-2-({3-(3(d i methy lam inojpropy 1] -1H- indol-4-y 1} oxy j-N -({3 -nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]pheny I Jsulfony I jbenzamide;

4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icy clohex-1 -en -1 -y 1] met hy 1} piperazin- 1 -y 1)-2-( {3 - [3 (dirnethylamino)propyl]-]H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-l-yljamino]-320 nitrophenyljsulfonyljbenzamide; and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

V

149

In another aspect, the present invention provides compounds of Formula (V)

<img file="MY179077A_D0012.tif" />

(V) and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z⁵ are as described herein for Formula (I), n is 0, 1, 2, or 3; describing the number of additional substituents on R²⁶, and R^,o° is as described for substituents on R²⁶, and at least one of R¹⁰³ or R¹⁰⁴ is a substituent as described for substituents on R⁴² and R^42a and the remainder are H,

In one embodiment of Formula (V), R¹⁰⁴ is NH₂ or NHR⁵⁰. In another embodiment of

Formula (V), R'⁰⁴ is NH₂.

In one embodiment of Formula (V), A¹ isN. In another embodiment of Formula (V), A¹is C(A²), In another embodiment of Formula (V), A¹ is C(A²); and A² is H.

In one embodiment of Formula (V), B¹ is OR¹, or NHR¹. In another embodiment of Formula (V), A¹ is C(A²); A² is H; and B¹ is NHR¹. In another embodiment of Formula (V), A¹ is

C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (V), D¹ is H. In another embodiment of Formula (V), A¹is C(A²); A² is Η; B¹ is NHR¹; and D^l is H. In another embodiment of Formula (V), A¹ is C(A²); A² is Η; B¹ is OR¹; and D^l is H.

In one embodiment of Formula (V), E¹ is H. In another embodiment of Formula (V), A¹ is C(A²); A² is H; B^l is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (V), Y¹ is H, CN, NO2, F, Cl, Br, CF3, R¹⁷, or SO:R¹⁷. In another embodiment of Formula (V), Y¹ is NO2. In another embodiment of Formula (V), Y¹ is Cl. In another embodiment of Formula (V), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (V), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl In another embodiment of Formula (V), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. In another embodiment of Formula (V), A¹ is

150

C(A²); A¹ is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO3 or SO3R¹⁷; wherein R^1T is alkyl or alkynyl. In another embodiment of Formula (V), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y’ is NO2 In another embodiment of Formula (V), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is SO₂R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In another embodiment 5 of Formula (V), A’ is C(A²); A² is Η; B¹ is OR¹; D¹ is Η; E¹ is H; and Y¹ is Cl..

In one embodiment of Formula (Y), R¹ is R⁴ or R⁵. In one embodiment of Formula (V), R¹ is R⁴. In one embodiment of Formula (V), R¹ is R⁵. In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (V), R¹ is R⁴; and R⁴is cycloalkyl. In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl.

j 0 In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is ? substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodiment of Formula (V), R¹ is R⁴; and R⁴15 is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ is heterocycloalkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In another ·* embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is j: cyclohexyl; and wherein the cyclohexyl ring is substituted with N(Rⁱ⁷)₂ In another embodiment of 25 Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NfR⁵⁷^, R⁵⁷ is R⁶¹, and R is alkyl which is unsubstituted. In another embodiment of Formula (V), R^l is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which is unsubstituted. In another embodiment of Formula (V), R¹ is 30 R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

151

In one embodiment of Formula (V), R^l is R⁴; and R⁴ is heterocycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein, In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted as defined herein. In another embodiment of Formula (V), R^l is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted with R⁵⁷, In another embodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the heterocycloalkyl ring is substituted with one or two or three or four or five more R⁵⁷; SO₂R⁵⁷,or OH, and R⁵⁷ is R⁶⁰ or R⁶'. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalky I; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl. or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; Rⁱ⁷ is R⁶⁰ or _R6L _r60 is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with Rⁱ⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl or oxetanyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl. and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five Rⁱ⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is Cj-alkyl, C₂alkyl, or Ca-alkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; R^S1 is alkyl; and the alkyl is Ci-alkyl, Cj-alkyl, or C₃-alkyI; wherein the Ci-alkyl, C₃-alkyl, or C₃-aIkyl are unsubstituted or substituted.

In one embodiment of Formula (V), R¹ is R⁵; and R⁵ is alkyl which is unsubstituted or substituted. In one embodiment of Formula (V). R¹ is R⁵; and R⁵ is alkyl which is unsubstituted or 30 substituted with R⁷, OR⁷, N(R⁷)z, or OH.

In one embodiment of Formula (V), R⁷ is R¹⁰ or R¹¹ which are unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R⁷ is R¹⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R⁷ is R¹¹which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (V), R¹⁰ is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹⁰ is

152 heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹⁰ is tetrahydro furanyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted or substituted as defined herein, in another embodiment of Formula (V), R^ia is tetrahydropyranyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹⁰ is morpholinyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹⁰ is cycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹⁰ is cyclohexyl which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (V), R¹¹ is alkyl which is unsubstituted. In another embodiment of Formula (V), R¹¹ is methyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (V), R¹¹ is alkyl, which is substituted as defined herein. In another embodiment of Formula (V), R¹¹ is alkyl, which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (V), which are

2-(6-aminopyridin-3-ylJ-4-(4-{[2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en-lyljmethyl }piperazin-l-yl)-N-({3-nitro-4-[(l-tetrahydro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyljbenzamide;

2-[(6-aminopyridin-3-yl)oxyJ-4-(4-{[2-(4-chlorophenylJ-4,4-dimethylcycIohex-l-en-)y I Jmethy 1} p iperazin-1 -y l)-N -({3 -n itro-4- [(I -tetrahydro-2H-pyran-4-y lpiperidin-4- y I JaminoJ phenyl} sulfonyljbenzamide;

tert-buty I 5-(5 -(4- {[2-(4-ch 1 oropheny 1)-4,4-d i methyIcyc lohex-1 -en-1 -yl] methy 1} piperazin-1 -yI J2- {[({3 -n itro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl} sulfonyl )amino]carbonyl) phenoxy )pyridin-2-ylcarbamate;

tert-buty I 4-(5-(4- {[2-(4-ch loropheny I )-4,4-d i methyIcyc lohex-1 -en-1 -y 1] methy 1} piperazin-1 -yI J25 2- {[({3 -n itro-4-[( 1 -tetrahy dro-2H-pyran-4-ylpiperidin-4yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;

2-[(6-am inopyridin-3 -y l)oxy] -4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex- 1 -en-1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(2-am inopyrid in-4-yl)oxy]-4-(4-{ [2-(4-chloropheny 1)-4,4-d imethy Icyclohex-1-en-1y 1] methy 1} pi perazi n- ] -y 1J-N -( {3 -nitro-4- [(1 -tetrahydro-2H- pyran-4-y 1 p i pe rid in-4yljamino]phenyl}sulfony IJbenzamide;

2-[(5-bromopyridin-3-ylJoxy]-4-(4-{[2-(4-chlorophenylJ-4,4-dimethylcyclohex-l-en-ly IJmethyl} piperazin-1 -yl )-N-( {3-n itro-4-[(tetrahy dro-2 H-pyran-435 ylmethyljamino]phenyl}sulfonyl)benzamide;

153 tert-butyl 5-(5-(4-{[2-(4-chlorophenylJ-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-ylJ2- {[(]3 -nitro-4-[(tetrahy dro-2 H-pyran-4y Imethy 1 Jam ino]pheny I} su Ifony 1 Jam ino]carbony 1} phenoxy Jpy rid in-3 -yl carbamate;

2-[(5-am inopyridin-3 -y IJoxy] -4-(4- {[2-(4-ch loropheny I J-4,4-d imethy Icyc lohex-1 -en-1 5 y I] methy 1 Jpiperazin-1 -y 1 J-N-( {3 -nitro-4-[(tetrahy dro-2 H-pyran-4y Imethy ljamino]phenyl)su Ifony IJbenzam ide;

tert-butyl 4-(5-(4-{[2-(4-chlorophenyIJ-4,4-dimethy Icyclohex-l-en-l-yl]methyl} piperazin-1-ylJ2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy I Jamino]pheny I }sulfonyljamino]carbony I} phenoxy )pyridin-2-ylcarbamate;

2-[(2-aminopyridin-4-ylJoxy]-4-(4-][2-(4-chlorophenyl)-4₁4-dimethylcyclohex-l-en-lyl]methyl} piperazin-1-ylJ-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyljamino]phenyl] sulfonyljbenzamide;

4-(4- {[2-(4 -chlorophenyl J-4,4-d imethy Icyclohex-1 -en-1 -y l]methy 1} piperazin-1 -y I J-2-[(6hydroxypyridin-3-ylJoxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-415 y I methyl Jam ino] phenyl} sul fony I Jbenzamide;

2-{[6-( benzyloxyjpyrid in-3-yl] oxy]-4-(4-] [2-(4-chloropheny lJ-4,4-dimethy Icyclohex-1 -en-1 yl]methyl}piperazin-I-ylJ-’N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyljbenzamide;

2-[(6-amino-5-fluoropyri din-3-ylJoxy]-4-(4-] [2-(4-chloropheny 1 J-4,4-dimethy Icyclohex-1-en-l2 0 y 1] methy 1} piperazin-1 -y 1 J-N-( ] 3 -nitro-4-[(tetrahydro-2H-pyran-4y Im ethyl Jam ino] phenyl] sulfonyl Jbenzamide;

2-[(6-amino-5-ch loropyridin-3 -y 1 Joxy]-4-(4- ] [2 -(4-ch loropheny 1 J-4,4-dimethy Icyclohex- 1-en-ly 1 ]methy I} piperazin-1 -y I J-N-( ] 3 -nitro-4-[(tetrahydro-2H-pyran-4ylmethyljamino]phenyl} sulfonyl Jbenzamide;

T rans-2- [(6-am ino-5-chloropyrid in-3 -y IJoxy ]-4-(4- {[2-(4-ch loropheny I )-4,4-d imethy Icyclohex-1 en-I-yl]methyI}piperazin-l-ylJ-N-({4-[(4-morpholin-4-ylcyclohexylJamino]-3nitrophenyl} sulfonyljbenzamide;

2-[(6-am ino-5 -ch 1 oropyr idin-3 -y IJoxy] -4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 yl]methyI}piperazin-l-yl)-N-({4-[(4-fluorotetrahydro-2H-pyTan-4-yl)methoxy]-330 nitrophenyl} sulfonyljbenzamide;

2-[( 6-am ino-5 -ch loropyridin-3 -y IJoxy] -4-(4- {[2-(4 -c h loropheny 1 J-4,4-d imethy Icy c lohex-1 -en-1 yl]methyl} piperazin-l-yl)-N-( ]4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyljsulfonyljbenzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-][2-(4-chlorophenylJ~4,4-dimethylcyclohex-l-en-l35 yl]methyl}piperazin-l-ylJ-N-{[4-(l,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl Jbenzamide;

154

Trans-2-[(6-am ino-5-chloropyrid in-3-yl)oxy]-4-(4-{[2-(4-chloropheny I )-4,4-dimethy Icyclohex-1en-l-yl]methyl}piperazin-l-yl)-N-[(4-{[(4-methoxycyclohexy])methyl]amino}-3nitrophenyl)sulfony I] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l5 y 1] methyl} piperazin-1 -y 1 )-N-({4- [(1,4-dioxan-2 -y Imethy l)am ino] -3 nitrophenyl} sulfony l)benzamide;

2-[(6-am ino-5-chloropy ridin-3 -yl)oxy] -4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyclohex- 1-en-lyl]methyl}piperazin-l-yl)-N-({4-[(3-morpholm-4-yIpropyl)amino]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-y l)oxy]-4-(4-{[2-(4-chlorophenyI)-4,4-dimethy Icyclohex-1-en-1yljmethyl} piperazin-l-yl)-N-({ 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]pyridin-3-yl}sulfonYl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l15 yl]methyl} piperazin-1 -yl)benzamide;

2-[(6-amino-5-brom opyrid in-3-y I )oxy]-4-(4-{[2-(4-ch loropheny I )-4,4-dimethy Icyclohex-1 -en-1 y]]methyl}piperazin-l-y])-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzaroide;

2-am ino-5-(5-(4-{[2-(4-ch loropheny 1)-4,4-dimetliy Icyc lohex-1-en-1 -yl]methyl}piperazin-I-y 1)-220 {[( {3-n itro-4- [(tetrahydro-2 H-pyran-4 ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl} phenoxy )nicotinamide;

2-[(6-am ino-5 -cyanopyridin-3 -y l)oxy]-4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-1 -en-1 yl]methyl} piperazin-1 -yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

5 2-[(6-am ino-5 -ch loropyridin-3 -yl)oxy] -4-(4- {[2-(4-chloropheny 1 )-4,4-dimethy Icyclohex-1 -en-lyl] methyl} pi perazin- 1-y l)-N-[(4-{[(3 R)-1-(2,2 -di fluoroethyi)pyrrolidin-3-yl]amino}-3nitrophenyl)sul fony l]benzam ide;

2- [(6-amino-5 -chloropyridin-3 -y 1 )oxy]-4-(4- {[2-(4-ch 1 oropheny 1 )-4,4-di methylcyc lohex-! -en-1 yl]methyl}piperazin-l-yl)-N-({4-[(l-methylpiperidin-4-yl)amino]-330 [(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;

2- {[6-(acety lam ino)pyridm-3 -yl]oxy} -4-(4- {[2 -(4-ch loropheny 1)-4,4-dimethy Icy clohex- ] -en -1 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

4-(4-{[2-(4-chloropheny 1)-4,4-d imethy Icyc lohex-l-en-l-yl]methyl}piperazm-1-y 1)-2-( {63 5 [(methylsu Ifony l)am ino] pyridin-3 -y I} oxy)-N-( {3 -n itro-4- [(tetrahydro-2 H-pyran-4ylmethyl)amino]phenyl}sulfonyl)benzamide;

155

2-[(6-am ino-5 -ch loropyridin-3 -y l)oxy]-4-(4- {[2-(4-chloropheny 1)-4,4-d imethy Icy c lohex-I-en-1y IJmethy 1} p iperazin-1 -y l)-N -({4 - [ (1 -cyclopropy Ipiperid in-4-y l)am ino] -3 nitrophenyl} sulfonyl)benzamide;

2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l5 yljmethyl} piperazin-l-yl)-N-({4-[(4-methylpiperazin-l-yl)amino]-3nitrophenyl} sulfonyl)benzamide;

-[(6-amino-5 -bromopyrid in-3 -yl)oxy] -4-(4- {[2 -(4-ch loropheny 1)-4,4-dimethy Icyclohex-1 -en-1 y l]methyl} piperazin-l-yl)-N-({ 4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3n itropheny 1} su Ifony l)benzam ide;

2- [(6-am ino-5 -bromopyrid in-3 -y l)oxy]-4-(4- {[2-(4-chlorophenyl )-4,4-d imethy Icyclohex-1 -en-1 yl]methyl}piperazin-l-yI)-N-({4-[(l_J4-dioxan-2-yImethyl)amino]-3nitrophenyl}sulfonyl)benzamide;

2-[(6-am ino-5-methy Ipyridin-3-yI)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1-en-1 yljmethyl} piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-415 yl methy I )amino]pheny I} su Ifony l)benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-d imethy Icyc lohex-1-en-lyljmethyl }piperazin-l-yl)-N-[(4-{[(4-f]uorotetrahydro-2H-pyran-4-yl)methyl]amino}-3nitrophenyl)sulfonyl]benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-I20 yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(l-oxetan-3-ylpiperidin-4yl)amino]phenyl}sulfonyl)benzamide;

2-[(6-am ino-5- isopropy Ipyrid in-3 -y 1 )oxy] -4-(4- {[2-(4-chloropheny I )-4,4-dimethy Icyclohex-1 -en1 -yl] methyl} piperazin-1 -yl)-N-( {3-nitro-4-[(tetrahydro-2H-pyran-4ylmethy l)amino] phenyl} su Ifony l)benzamide;

2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1en-1 -y I] methy 1} piperazin-1 -y l)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4 y lmethyl)am i nojpheny 1} su 1 fony l)benzam i de;

T rans-2-[(6-amino-5-bromopyrid in-3 -y 1 )oxy]-4 -(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 en- l-yl]methyl} piperazin- 1-y I)-N-[(4-{ [(4-methoxycyc lohexyl)methy l]amino} -33 0 nitrophenyl )sulfonyl jbenzamide;

2-[(6-amino-5 -ch loropyri d in-3 -yl)oxy]-4-(4- {[2-(4-ch loropheny 1 )-4,4-dimethy 1 eye 1 ohex-1 -en-1 yljmethyl} piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3nitropheny I )sulfony I] benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-ch I oropheny 1)-4,4-dimethy Icyc lohex-1 -en-1 35 yljmethyl} piperazin-l-yl)-N-[(4-{[(3R)-l-cyclopropylpyrrolidin-3-yl]amino}-3nitrophenyl)sulfonyl]benzamide;

156

2-[(6-am ino-5-ch Ioropyridin-3-y I )oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d imethy Icyc lohex-1-en-1y Ijmethyl }piperazin-l-yl)-N-{ [4-( {4-fluoro-l-[2-fluoro-1-( fluoromethy l)ethyl]piperidin-4yl}methoxyj-3-nitroplienyl]sulfonyl}benzamide;

tert-butyl 6-bromo-4-( 5-(4- {[2-(4-ch 1 oropheny 1)-4,4-dimethyIcyclohex-1 -en-1 5 yljmethyl} piperazin-1 -y 1)-2- {[({3 -n itro-4- [(tetrahydro-2 H-pyran-4y Imethy I jam inojpheny I} sul fony Ijam ino]carbonylj phen oxy )pyridin-2-ylcarbamate;

tert-butyl 4-(5-(4-((2-(4-chIoropheny 1)-4,4-d imethyIcyclohex-1-eny I )methyl)piperazin-l-y 1)-2-(3π itro-4-((tetrahy dro-2H-pyran-4-yl )methy lam inojpheny Isulfony Icarbamoy Ijphenoxy jpyridine2,6-diyidicarbamate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-1-yljmethyl Jpiperazin-l-yl)-2-{ [6(cyclopropylammo)pyndin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyljamino]phenyl}sulfonyl)benzamide;

Trans-4-(4-{[2-(4-chlorophenylj-4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-2-({6[(2,2-difluoroethyljamino]pyridin-3-yl}oxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-315 nitropheny Ijsu Ifony Ijbenzam ide;

4-(4-{[2-(4-chlorophenyl j-4,4-d imethy Icyc lohex-1-en-1-yljmethy 1 Jpiperazin-1-y I j-2-( (6-((2,2difluoroethyl)amino]pyridin-3-yl}oxyj-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfony Ijbenzamide;

2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,420 dimethy!cyclohex-l-en-1-yljmethyl} piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4y!methyl)amino]phenyl}sulfony Ijbenzamide;

-[(6-amino-5-ch loropyridin-3 -y Ijoxy ]-4-(4- {[2-(4-c h loropheny 1)-4,4-dimethy Icy cloh ex- 1 -en-1 y I ] methy I} pi perazi η-1 -y 1 )-N-( {4 - [ ({4-[ 2 - fl uoro-1 -(fluoromethy I jethyI]morpholin-2yl}methy])ammc]-3-nitrophenyl}sulfonyl)benzamide;

2- [(2-am ino-6-bromopyridin-4-y Ijoxy ]-4-(4- {[2-(4-chloropheny 1 )-4,4-d imethy Icy cl ohex-1 -en-1 yljmethyl} p iperazin-1 -y I )-N -({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyljamino]phenyl J sulfonyl jbenzamide;

4-(4-{[2-(4-ch loropheny! j-4,4-dimethy 1 cyclohex-1 -en-1 -yljmethyl} piperazin- l-yl)-2-[(2,6diaminopyridin-4-yl)oxy]-N-({3-n!tro-4-[(tetrahydro-2H-pyran-430 y[methyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyljmethyl} piperazin-1 -ylj-N-{(3-nitro-4-(tetrahydro-2H-pyran-4yl methoxy jpheny Ijsulfony I} benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-

5 yl Jmethyl} pi perazin-1 -y 1 )-N- {[4-( {(3 Rj-1 -[2-fluoro-1 -(fl uoromethy Ijethy 1 ] piperid in-3 - yl}amino)-3-nitrophenyI]sulfonyl Jbenzamide;

157 tert-butyl 5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethy Icyclohex- 1-en-1 yl]methyl} piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl} sulfony l)amino]carbony I} phenoxy )pyridin-2-ylcarbamate;

4-( 4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-l-yl] methyl} piperazin-l-yl)-N-( {3-nitro-45 [(tetrahydro-2H-pyran-4-yImethyl)amino] phenyl} sulfonyI)-2-({6-((2,2,2trifluoroethyl)ammo]pyridin-3-yl}oxy)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyI)-4,4-dimethylcyclohex-l-en-lyl]methyl}piperazin-l-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3n itropheny I )sulfonyl]benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chloropheny!)-6,6-dimethyl-5,6-dihydro-2Hpyran-3-y I] methy I} piperazin-1 -y I )-N-( {3 -nitro-4 - [(tetrahydro-2H-pyran -4ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-ch loropyridin-3-yl)oxy]-4-(4-{[2-(4-chloropheny 1)-4,4-dimethy Icyclohex-1-en-lyl] methy 1} piperazin-1 -y I )-N-( {3 -nitro-4-[(tetrahydrofuran-3 15 ylmethyl)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4yl)methoxy]pyridin-3-yl}sulfonyI)-4-(4-{ [4-( 4-chloropheny 1)-6,6-dimethyl-5,6-dihydro-2Hpyran-3-y IJmethyl} piperazin-1 -yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-( {9-(4-chloropheny 1)-3-[2-fluoro-1 20 (f!uoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl} methy l)piperazin-l-yl]-N-({3-nitro-4[(tetrahydro-2H-pyran-4-yimethyl)amino]phenyl} sulfony] (benzamide;

2- [(6-am ino-5-ch loropyridin-3 -yl )oxy] -4-(4- {[9-(4-chl oropheny 1)-3- i sopropy 1-3 azaspiro[5.5]undec-8-en-8-yl]methyl} piperazin-1-y l)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino] phenyl} sulfony !)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[]-(N,N-dimethylglycyl)-4fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyI]-4-(4-{[2-(4-chlorophenyl)-4,4d imethy Icyc 1 ohex-1 -en-1 -yl] methy]} piperazin-1 -y l)benzamide;

2-[(6-am ino-5 -chloropyridin-3 -y l)oxy] -4-(4- {[2-(4-ch loropheny 1)-4,4-dimethy Icy clo hex- 1 -en-1yljmethyl} piperazin- l-yl)-N-{ [4-({(3R)-l-[2-fluoro-1 -(fluoro methyl )ethyl]pyrrol id in-330 yl}amino)-3-nitrophenyl]suIfonyi} benzamide;

2- [(2-am ino-5- brom opyridin-4-y l)oxy ]-4-(4- {[2-(4-ch loropheny 1 )-4,4 -d imethy Icyclohex- ]-en-lyl]methyl}piperazin-l-yl)-'N-({3-nitro-4-[(tetrahydro-2H-pyran-4y Imethy l)amino]phenyl}sulfonyl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l’ yl]methyl}piperazin-l-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3nitrophenyl)sulfbnyl] benzamide;

158

2-[(6-ammo-5-chloropyridin-3-yl)oxy]-4-[4-({4^,-chloro-3-[2-(dimethylamino)ethoxy]-l,1 bipheny 1-2-y 1} methy I )pi perazi η-1 -y l]-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl[sulfonyl)benzamide;

2-[(6-am ino-5 -ch loropyridin-3 -y l)oxy] -N- {[ 5-chloro-6-( {(3 R)-1 -[2-fluoro-1 5 (fl uoromethyl)ethyl]pyrro lid in-3-yl[ methoxy )pyridin-3-yl] sulfony I [-4-(4-{[2-(4-ch loropheny I)4,4-dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)benzamide;

2-[(6-am ino-5-chloropyridin-3-yl)oxy]-N-((5-ch loro-6-{[(3 R)-l-(2,2-difluoroethyl)pyrrol id in-3yl] methoxy [pyri din-3-yl)su Ifony i]-4-(4-{[2-(4-ch loropheny [)-4,4-dimethy Icy clohex-1-en-lyl]methyl}piperazin-l-yl)benzamide;

Trans-2-[(6-amino-5-chioropyridin-3-yl)oxy]-4-(4-{ [2-(4-ch loropheny !)-4,4-d imethy Icy clohex-!en-l-yl]methyl[ piperazin-l-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3n itrophenyl)su 1 fony 1] benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-lyl]methyl[ piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin15 3 -y I [sulfonyl [benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[l-(2,2-difluoroethyl)-4-fluoropiperidin4-y 1] methoxy [pyrid in-3-yl)sul fony l]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-lyl]methyl}piperazin-l-yl)benzamide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-420 yl)methoxy]phenyl}sulfbnyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-ly 1] methyl [piperazin-1-yl)benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-ch loropheny 1)-4,4-dimethy Icyc lohex-1-en-lyl]methyl[ piperazin-1-yl)-N-{[6-({4-fluoro-l-[2-fluoro-l-(fluoromethyl)ethyl]piperidin-4y I [ methoxy )-5 -(tri fiuoromethyl )pyrid in-3 -y 1 ] su Ifony 1} benzam ide;

2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4difluorocyclohexyl)methoxy]pyridin-3-yl [sulfony 1)-4-(4-{[2-(4-chloropheny 1)-4,4dimethylcycl ohex-]-en-l-yl]methyl[ pi perazin-l-yl)benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

159

In another aspect, the present invention provides compounds of Formula (VI)

<img file="MY179077A_D0013.tif" />

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, wherein A¹, B^l, D\ E¹, Y¹, Z³, L¹, and Z³ are as described herein for Formula (I), n is 0, 1,2, or 3; describing the number of additional substituents on R³⁶, and R¹⁰⁰ is as described for substituents on R³⁶, and at least one R¹⁰³ is a substituent as described for substituents on R⁴³ and R^43A, and the remainder are H.

In one embodiment of Formula (VI), A' is N, In another embodiment of Formula (VI), A¹10 is C(A³). In another embodiment of Formula (VI), A¹ is C(A²); and A³ is H.

In one embodiment of Formula (VI), B¹ is OR¹, or NHR¹. in another embodiment of Formula (VI), A¹ is C(A³); A³ is H; and B¹ is NHR¹. In another embodiment of Formula (VI), A¹is C(A²); A³ is H; and B¹ is OR¹.

In one embodiment of Formula (VI), D¹ is H. In another embodiment of Formula (VI), 15 A¹ is C(A³); A³ is Η; B¹ is NHR^j; and D¹ is H. In another embodiment of Formula (VI), A¹ is

C(A³); A³ is Η; B¹ is OR¹; and D¹ is H.

In one embodiment of Formula (VI), E¹ is H. in another embodiment of Formula (VI), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (I), A¹is C(A²); A² is Η; B¹ is OR¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (VI), Y¹ is H, CN, NO_2i F, Cl, Br, CFj, R¹⁷, or SO;R¹⁷. In another embodiment of Formula (VI), Y¹ is NO2. In another embodiment of Formula (VI), Y is Cl. In another embodiment of Formula (VI), Y¹ is SO2R¹⁷; wherein R¹⁷ is as defined herein. In another embodiment of Formula (VI), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. In another embodiment of Formula (VI), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. In another embodiment of Formula (VI), A¹ is

C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In another embodiment of Formula (VI), A¹ is C(A²); A² is Η; B¹ is NHR¹; D¹ is Η; E¹ is

160

H; and Υ¹ is ΝΟ2 In another embodiment of Formula (VI), A* is C(A²); A² is Η; B¹ is NHR¹; D¹is Η; E¹ is H; and Y^l is SO2R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In another embodiment of Formula (VI), A¹ is C(A²); A² is Η; B¹ is OR¹; D¹ is Η; E¹ is H; and Y¹ is Cl, In one embodiment of Formula (VI), R¹ is R⁴ or R⁵. In one embodiment of Formula (VI), 5 R¹ is R⁴. In one embodiment of Formula (VI), R¹ is R⁵. In one embodiment of Formula (VI), R^! is

R⁴; and R⁴ is cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (VI), R¹ is R⁴, and R⁴ is cycloalkyl. In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein R⁴ is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹ is R⁴;

and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted as defined herein. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴is cycloalky]; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ is heterocycloalkyl. In another embodiment of Formula (VI), R^l is R⁴; R⁴ is cycloalkyl; wherein the cycloalky I ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is heterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is substituted with N(R^S7)2. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NfR⁵⁷):. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)2, R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with N(Rⁱ⁷)₂₎ R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which is unsubstituted. In another embodiment of Formula (VI), R^l is R⁴; and R⁴ is cycloalkyl; wherein the cycloalky I ring is substituted with NHR⁵⁷. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷ In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R^fi0, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein R⁴ is 35 unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted as defined herein. In

161 another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is substituted with R⁵⁷. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the heterocycloalkyl ring is substituted with one or two 5 or three or four or five more R^S7; SO₂R⁵⁷,or OH. and R⁵⁷ is R⁶⁰ or R^ei. In another embodiment of

Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with Rⁱ⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl, In another embodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl;

wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring ts substituted with R⁵⁷; R^S7 is _R60. _r60 is heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl or oxetanyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein the 15 piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with Rⁱ⁷; Rⁱ⁷ is R^6C; R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five Rⁱ⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl;

and the alkyl is C)-alkyl, C₂-alkyl, or C₃-alkyl, In another embodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; R^fil is alkyl; and the alkyl is Cjalkyl, C₂-alkyl, or C₃-aIkyl; wherein the C]-alky I, C₂-alkyl, or C₃-alkyl are unsubstituted or substituted.

In one embodiment of Formula (VI), R¹ is R^s; and R⁵ is alky! which is unsubstituted or substituted. In one embodiment of Formula (VI), R¹ is R⁵; and R^s is alkyl which is unsubstituted or substituted with R⁷, OR⁷, N(R⁷)₂, or OH.

In one embodiment of Formula (VI). R⁷ is R¹⁰ or R¹¹ which are unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R⁷ is R¹⁰ which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R⁷ is R^uwhich is unsubstituted or substituted as defined herein.

In one embodiment of Formula (VI), R¹⁰ is cycloalkyl or heterocycloalkyl which are unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹⁰ is 35 heterocycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹⁰ is tetrahydro furanyl, tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl,

162 piperizinyl, or pyrrolidinyl, which are unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R^,u is tetrahydropyranyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹⁰ is morpholinyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R^!0 is cycloalkyl which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹⁰ is cyclohexyl which is unsubstituted or substituted as defined herein.

In one embodiment of Formula (VI), R¹¹ is alkyl which is unsubstituted. In another embodiment of Formula (VI), R¹¹ is methyl, which is unsubstituted or substituted as defined herein. In another embodiment of Formula (VI), R¹¹ is alkyl, which is substituted as defined herein. In another embodiment of Formula (VI), R¹¹ is alkyl, which is substituted with OR¹², R¹²is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (VI), which are

4-(4- {[2-(4-ch loropheny 1)-4,4-d imethy Icyclohex-1 -en-1 -y I] methy I} piperazin-1 -y 1 )-2-[(4-chlorolH-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-415 ylmethyl)amino]phenyl}sulfonyl)benzamide;

and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.

Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmune disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseases during which anti-apoptotic Bcl-2 proteins are expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I),

Still another embodiment pertains to methods of treating disease in a patient during which anti-apoptotic Bcl-2 proteins are expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, 35 colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-ceil origin, melanoma, myelogenous leukemia,

163 myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer, brain cancer, 5 breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically 10 effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseases during which are expressed anti-apoptotic Bcl-2 proteins, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic 15 agent.

Still another embodiment pertains to methods of treating disease in a patient during which are expressed anti-apoptotic Bcl-2 proteins, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic 20 agent.

Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, 25 myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, 35 prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula

164 (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds having Formula (1) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobroinide, hydroiodide, lactobionate. lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds and prodrugs thereof are contemplated as being embraced by this invention. Basic addition salts of the compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.

The compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrastemally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (1) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight, Single dose compositions contain these amounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without an excipient. Excipients include, for example, encapsulating materials or additives such as absorption 35 accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants,

165 perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.

Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1.3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, com starch, com oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, 10 potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydro furfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered 15 ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, com oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example, chloro fluorohydrocarbons, ethanol, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (1) to be administered parenterally include, for example, 1,3-butanediol, castor oil, com oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

Compounds having Formula Q) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, 30 antivirals, aurora kinase inhibitors, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (BiSpecific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat 35 shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics,

166 kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA’s, 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 chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (P13K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiqutin ligase inhibitors, and the like, and in combination with one or more of these agents .

BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells, The T-cell then attacks the target cancer cell. Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (V.R. Sutton, D.L. Vaux and J.A. Trapani. J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2-Fribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3'-ends of a given strand. For example, siRNAs targeting Mcl-1 have been shown to enhance the activity of ABT263, (i.e., N-(4-(4-((2-(4-chloropheny 1)-5,5-d imethy 1-1-eye iohex-l-en-l-yl)methyl)piperazin-l- yi)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3((trifluoromethyl)sulfony])benzenesulfonamide) or ABT-737 (i.e., N-(4-(4-((4'-chloro(l,rbipheny l)-2-y I )methy 1 )piperazi η-1 -y l)benzoy I )-4-((( 1 R)-3 -(d imethy lam ino)-1 ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9), 3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen

167 binding sites and are generally not naturally occurring antibodies. The term “multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site. Multispecific DVDs include DVD binding proteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine, VNP 4010IM), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like,

Antimetabolites include ALIMTA® (pemetrexed di sodium, LY231514, MTA),

5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabi ne, deferoxamine, doxifluridine, eflomithine, EICAR (5-ethynyl-1 -β -D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR* (gemcitabine), hydroxyurea, ALKERAN®(melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-l, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

168

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora Aspecific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IP 1-194, IP 1-565, N-(4-(4-((4'chloro( Ι,Γ-bipheny 1)-2-yljmethyl Jpiperazin-1-y IJbenzoy 1)-4-((( 1RJ-3-(dimethyl amino J-1 ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideJ (ABT-737J, N-(4-(4-((2-(4ch loropheny 1)-5,5-dimethy 1-1 -cyclohex-l-en-I-yl)methylJpiperazin-l-ylJbenzoyl)-4-(((lRJ-3(morpholin-4-yl J-1-((phenylsulfanyl Jmethy I Jpropy I Jamino)-310 ((trifluoromethyljsulfonyljbenzenesulfonamide (ABT-263J, GX-070 (obatoclaxj and the like. Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinibj and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202,

R-roscovitineJ, ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxibj, BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celecoxibj, COX-189 (lumiracoxibj, CT-3, DERAMAXX® (deracoxibj, JTE-522, 4-methyl-2-(3_ί4-dimethylρhenylJ-l-(4-sulfamoylphenyl·lH-pyΓτole), MK663 (etoricoxibj, NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614,

VIOXX® (rofecoxibj and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immuno liposomes, EGF-vaccine, EMD7200, ERBITUX® (cetuximabJ, HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinibj and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinibj, OMN1TARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafamibj, GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like,

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, ] 7-DMAG, geldanamycin, IP 1-504, KOS-953, MYCOGRAB* (human recombinant antibody to HSP-90J, NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like,

Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC-0152,

LCL-I61, LBW-242 and the like.

169

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, antiCD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (eg., DR4 and DR5) such as Apomab, conatumumab, ETR2ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCBO18424 and the like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AM1GES1C® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORJL* (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147,

CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder,

CO.) and Chiron, (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™ (vandetanib, ZD-6474), and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET®

170 (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycaroptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-l/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGFIR-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and JI, GA 101, ofatumumab, ABT-806 (mAb-806), ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specific antibodies and C-met specific antibodies, and the like.

Hormonal therapies include ARJMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetroreiix), degarelix, deslorelin, DESOPAN®' (trilostane), dexamethasone, DROGENIL* (flutamide), EVISTA® (raloxifene), AFEMA™ (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAX1S™ (abarelix), prednisone, PROPEC1A® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant),

VETORYL* (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EBI089, CB1093), lexacalcitrol (KHI060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG30 014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.

Examples of immunologicals include interferons and other immune-enhancing agents.

Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta,

171 interferon gamma-la, ACTIMMUNE® (interferon gamma-lb) or interferon gamma-nl, combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-a), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, deni leukin, epratuzumab, 5 GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (antiCTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFGl), PROVENGE®(sipuleucel-T), sargaramostim, sizofdan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN* (immunotherapeutic, Lotus Pharmaceuticals), Z-l 00 (Specific Substance of Maruyama (SSM)), WF-10 (Tetrachlorodeeaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to 15 direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the 20 like.

Purine analogs include LANV1S® (thioguanine) and PURI-NETHOL® (mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), 25 vinflunine, ZK-EPO (synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, 30 teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (famesyl transferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglab in, L-asparaginase, atamestane (1 -methy 1-3,17-dione-androsta-l ,4diene), AV AGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab),

172 cachectin or cachexia (tumor necrosis factor), canvaxin (vaccine), CEA VAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN* (hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™ (cyproterone acetate), combrestatm A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), enil uracil, EVIZON™ (squalamine lactate), DIMERIC INE® (T4N5 liposome lotion), discodermolide, DX-8951 f (exatecan mesylate), enzastaurin, EPO906 (epithilone B),

GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-a, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafamib, 5,ΙΟΙ 5 methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT®(AE-941),

NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine), ORATHECIN™ (rubitecan), OS1DEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERA TOPE® (STn-KLH), thymitaq (2-amino-3,4dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoIine dihydrochloride), TNFERADE™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),

VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (antialphavbetaS antibody), XCYTRIN® (motexafin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as binders to and inhibitors of anti-apoptotic Be 1-2 proteins was performed using the Time Resolved-Fluorescence Resonance

173

Energy Transfer (TR-FRET) Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No. PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwise specified. Peptide synthesis reagents including di isopropylethyl amine (DIEA), dichloromethane (DCM), N-methyIpyrrolidone (NMP), 2-( 1 H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluroniuni hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained from Applied Biosystems, Inc. (ABI), Foster City, CA or American Bioanalytical, Natick, MA. Preloaded 9-Fluoreny Imethy loxy carbonyl (Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc10 Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH, FmocHis(Trt)-OH, Fmoc-ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, FmocAsn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec, San Jose, CA. The peptide synthesis resin (Fmoc-Rink amide MBHA resin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego, CA. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS) was obtained from Anaspec.

Tri fluoroacetic acid (TFA) was obtained from Oakwood Products, West Columbia, SC. Thioanisole, phenol, tri isopropylsilane (TIS), 3,6-dioxa-l,8-octanedithiol (DODT) and isopropanol were obtained from Aldrich Chemical Co., Milwaukee, WI. Matrix-assisted laser 20 desorption ionization mass-spectra (MALDI-MS) were recorded on an Applied Biosystems

Voyager DE-PRO MS). Electrospray mass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp., San Jose, CA) in both positive and negative ion mode.

General Procedure For Solid-Phase Peptide Synthesis (SPPSJ

Peptides were synthesized with, at most, 250 pmol preloaded Wang resin/vessel on an

ABI 433 A peptide synthesizer using 250 pmol scale Fastmoc™ coupling cycles. Preloaded cartridges containing 1 mmol standard Fmoc-amino acids, except for the position of attachment of the fluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge, were used with conductivity feedback monitoring. N-terminal acetylation was accomplished by using 1 mmol acetic acid in a cartridge under standard coupling conditions.

Removal Of 4-Methyltrityl (Mtt) From Lysine

The resin from the synthesizer was washed thrice with dichloromethane and kept wet. 150 mL of 95:4:1 dichloromethane:triisopropylsilane:trif1uoroacetic acid was flowed through the resin bed over 30 minutes. The mixture turned deep yellow then faded to pale yellow. 100 mL of N,N-dimethylformamide was flowed through the bed over 15 minutes. The resin was then washed 35 thrice with Ν,Ν-dimethylformamide and filtered, Ninhydrin tests showed a strong signal for primary amine.

174

Resin Labeling With 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/N,Ndimethylformamide and stirred or shaken at ambient temperature overnight. When complete, the resin was drained, washed thrice with N,N-dimethyIformamide, thrice with (lx DCM and lx 5 methanol) and dried to provide an orange resin that was negative by ninhydrin test.

General Procedure For Cleavage And Deprotection Of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambient temperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). The resin was removed by filtration and rinsing twice with TFA.

The TFA was evaporated from the filtrates, and product was precipitated with ether (10 mL/Ο. I g resin), recovered by centrifugation, washed twice with ether (10 mL/0.1 g resin) and dried to give (. the crude peptide.

General Procedure For Purification Of Peptides

The crude peptides were purified on a Gilson preparative HPLC system running

Unipoint® analysis software (Gilson, Inc., Middleton, WI) on a radial compression column containing two 25 x 100 mm segments packed with Delta-Pak™ Cl 8 15 pm particles with 100 A pore size and eluted with one of the gradient methods listed below, One to two milliliters of crude peptide solution (10 mg/mL in 90% DMSO/water) was purified per injection. The peaks containing the produces) from each run were pooled and lyophilized. All preparative runs were run at 20 mL/min with eluents as buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure For Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series system with a diodearray detector and a Hewlett-Packard 1046A fluorescence detector running HPLC 3D ChemStation software version A.03,04 (Hewlett-Packard, Palo Alto, CA) on a 4.6 x 250 mm

YMC column packed with ODS-AQ 5 pm particles with a 120 A pore size and eluted with one of the gradient methods listed below after preequilibrating at the starting conditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water and buffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

F-Bak: Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:

2)INR-NH₂

Fmoc-Rink amide MBHA resin was extended using the general peptide synthesis procedure to provide the protected resin-bound peptide (1.020 g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved and deprotected as described hereinabove to provide the crude product as an orange solid (0.37 g). This product was purified by RP-HPLC. Fractions across the main peak were tested by analytical RP-HPLC, and the pure fractions were isolated and

175 lyophilized, with the major peak providing the title compound (0.0802 g) as a yellow solid; MALDLMS m/z = 2137.1 [(M+H)*].

Alternative Synthesis o/Peptide Probe F-Bak: Acetyl-(SEQ ID NO: 1 )GQVGRQLAI1GDK(6FAM)-(SEQ ID NO:2)INR-NH₂

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHA resin (Novabiochem) on an Applied Biosystems 433A automated peptide synthesizer running Fastmoc™ coupling cycles using pre-loaded 1 mmol amino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine, where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge. The N-terminal acetyl group was incorporated by putting 1 mmol acetic acid in a 10 cartridge and coupling as described hereinabove, Selective removal of the 4-methyltrityl group was accomplished with a solution of 95:4:1 DCM:T1S:TFA (v/v/v) flowed through the resin over 15 minutes, followed by quenching with a flow of dimethyIformamide. Single-isomer 6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1% DIEA in N,Ndimethylformamide and confirmed complete by ninhydrin testing. The peptide was cleaved from 15 the resin and side-chains deprotected by treating with 80:5:5:5:2.5:2.5 TFA/water/phenol/ thioan iso le/triisopropy I silane: 3,6-dioxa-l,8-octanedithiol (v/v/v/v/v/v), and the crude peptide was recovered by precipitation with diethyl ether. The crude peptide was purified by reverse-phase high-performance liquid chromatography, and its purity and identity were confirmed by analytical reverse-phase high-performance liquid chromatography and matrix-assisted laser-desorption mass-spectrometry (m/z = 2137.1 ((M+H)⁺)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay Representative compounds were serially diluted in dimethyl sulfoxide (DMSO) starting at 50 μΜ (2χ starting concentration; 10% DMSO) and 10 μΕ were transferred into a 384-well plate. Then 10 μΕ of a protein/probe/antibody mix was added to each well at final concentrations listed in TABLE 1. The samples are then mixed on a shaker for 1 minute and incubated for an additional 3 hours at room temperature. For each assay, the probe/antibody and protein/probe/antibody were included on each assay plate as negative and positive controls, respectively. Fluorescence was measured on the Envision (Perkin Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody) emission filters. Inhibition constants (Ki) are shown in TABLE 2 below and were determined using Wang’s equation (Wang Z.-X. An Exact Mathematical Expression For Describing Competitive Binding Of Two Different Ligands To A Protein Molecule. FEBS Lett. 1995,360:111-4).

TABLE 1. Protein, Probe And Antibody Used For TR-FRET Assays

<td> Protein</td><td> Probe</td><td> Protein</td><td> Probe</td><td> Antibody</td><td> Antibody</td>

176

<td></td><td></td><td> (nM)</td><td> (nM)</td><td></td><td> (nM)</td>

<td> GST-Bcl-2</td><td> F-Bak Peptide Probe Acetyl-(SEQ ID NO: 1 GQVGRQLAI1GDK(6FAM) SEQ ID NO: 2 INR-amide)</td><td> 1</td><td> 100</td><td> Tb-anti-GST</td><td> 1</td>

6-FAM = 6- carboxyfluorescein,; Tb = terbium; GST = glutathione S-transferase

The samples were then mixed on a shaker for 1 minute and incubated for an additional 3 hours at room temperature. For each assay, the probe/antibody and protein/probe/antibody were included on each assay plate as negative and positive controls, respectively. Fluorescence was measured on the Envision (Perkin Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody) emission filters.

Inhibition constants (IQ for compounds according to the invention are shown in TABLE 2 below. Where the K, for a compound is represented as “&gt;” (greater than) a certain numerical value, it is intended to mean that the binding affinity value is greater than the limits of detection of the assay used. Where the Kj for a compound is represented as (less than) a certain numerical value, it is intended to mean that the binding affinity value is lower than the limit of detection of the assay used.

Sr

TABLE 2, TR-FRET Bcl-2 Binding Ki (μΜ)

<td> Example No,</td><td> TR-FRET Binding: Bcl-2 Ki (μΜ)</td><td> Example No.</td><td> TR-FRET Binding: Bcl-2 Ki (μΜ)</td>

<td> I</td><td> 0.008354</td><td> 207</td><td> 0.000074</td>

<td> 2</td><td> 0.031467</td><td> 208</td><td> 0,000261</td>

<td> 3</td><td> 0.000827</td><td> 209</td><td> &lt;0.000010</td>

<td> 4</td><td> 0.002474</td><td> 210</td><td> 0.00002</td>

<td> 5</td><td> 0.000746</td><td> 211</td><td> 0.001338</td>

<td> 6</td><td> 0.000787</td><td> 212</td><td> 0.000375</td>

<td> 7</td><td> 0.002592</td><td> 213</td><td> 0,000031</td>

<td> 8</td><td> 0.003451</td><td> 214</td><td> 0.000221</td>

<td> 9</td><td> 0.000754</td><td> 215</td><td> 0.002954</td>

<td> 10</td><td> 0.00072</td><td> 216</td><td> 0.000027</td>

<td> 11</td><td> 0.000171</td><td> 217</td><td> 0.000174</td>

<td> 12</td><td> 0.000331</td><td> 218</td><td> 0.000175</td>

<td> 13</td><td> 0.001621</td><td> 219</td><td> 0.014857</td>

177

<td> 14</td><td> 0.000079</td><td> 220</td><td> 0.000127</td>

<td> 15</td><td> 0.000586</td><td> 221</td><td> 0.000227</td>

<td> 16</td><td> 0.003039</td><td> 222</td><td> &gt;1.195000</td>

<td> 17</td><td> 0.005578</td><td> 223</td><td> 0.010911</td>

<td> 18</td><td> 0.002487</td><td> 224</td><td> 0,005603</td>

<td> 19</td><td> 0.001679</td><td> 225</td><td> 0.003283</td>

<td> 20</td><td> 0.003965</td><td> 226</td><td> 0.007586</td>

<td> 21</td><td> 0.014054</td><td> 227</td><td> 0.000174</td>

<td> 22</td><td> 0.005455</td><td> 229</td><td> 0.001085</td>

<td> 23</td><td> 0.00827</td><td> 230</td><td> 0.002833</td>

<td> 24</td><td> 0.014984</td><td> 231</td><td> 0.036946</td>

<td> 25</td><td> 0.001501</td><td> 232</td><td> 0.001047</td>

<td> 26</td><td> 0.000511</td><td> 233</td><td> 0.000037</td>

<td> 27</td><td> 0,002212</td><td> 234</td><td> 0.000099</td>

<td> 28</td><td> 0.001326</td><td> 235</td><td> 0.000039</td>

<td> 29</td><td> 0.000903</td><td> 236</td><td> 0.000071</td>

<td> 30</td><td> 0.00007]</td><td> 237</td><td> 0.000197</td>

<td> 31</td><td> 0.002007</td><td> 238</td><td> 0.000124</td>

<td> 32</td><td> 0.001584</td><td> 239</td><td> 0.000105</td>

<td> 33</td><td> 0.007173</td><td> 240</td><td> 0.000912</td>

<td> 34</td><td> 0.000049</td><td> 241</td><td> 0.000141</td>

<td> 35</td><td> 0.000022</td><td> 242</td><td> 0.000092</td>

<td> 36</td><td> 0.00007</td><td> 243</td><td> 0.000069</td>

<td> 37</td><td> 0.000005</td><td> 244</td><td> 0.001734</td>

<td> 38</td><td> 0.000013</td><td> 245</td><td> 0.00048</td>

<td> 39</td><td> 0.000019</td><td> 246</td><td> 0.000065</td>

<td> 40</td><td> 0.000019</td><td> 247</td><td> 0.000039</td>

<td> 41</td><td> 0.000027</td><td> 248</td><td> 0.000051</td>

<td> 42</td><td> 0.00003</td><td> 249</td><td> 0.000168</td>

<td> 43</td><td> 0.000034</td><td> 250</td><td> 0.000672</td>

<td> 44</td><td> 0.000036</td><td> 251</td><td> 0.000435</td>

<td> 45</td><td> 0.000047</td><td> 252</td><td> 0.001147</td>

<td> 46</td><td> 0,000047</td><td> 253</td><td> 0.00005</td>

<td> 47</td><td> 0.00005</td><td> 254</td><td> 0.000119</td>

<td> 48</td><td> 0,000053</td><td> 255</td><td> 0.007013</td>

178

<td> 49</td><td> 0.000062</td><td> 256</td><td> 0.000105</td>

<td> 50</td><td> 0.000062</td><td> 257</td><td> 0.000097</td>

<td> 51</td><td> 0.000066</td><td> 258</td><td> 0.000083</td>

<td> 52</td><td> 0.000072</td><td> 259</td><td> 0.000165</td>

<td> 53</td><td> 0.000077</td><td> 260</td><td> 0.011834</td>

<td> 54</td><td> 0.000082</td><td> 261</td><td> 0.000186</td>

<td> 55</td><td> 0.00009</td><td> 262</td><td> 0.000276</td>

<td> 56</td><td> 0.000106</td><td> 263</td><td> 0.00011</td>

<td> 57</td><td> 0.000147</td><td> 264</td><td> 0.000068</td>

<td> 58</td><td> 0.000155</td><td> 265</td><td> 0.000363</td>

<td> 59</td><td> 0.000184</td><td> 266</td><td> 0.00081</td>

<td> 60</td><td> 0.000187</td><td> 267</td><td> 0.028426</td>

<td> 61</td><td> 0.00022</td><td> 268</td><td> 0.000042</td>

<td> 62</td><td> 0.000227</td><td> 269</td><td> 0.000469</td>

<td> 63</td><td> 0.000438</td><td> 270</td><td> &gt;1.195000</td>

<td> 64</td><td> 0.000458</td><td> 271</td><td> 0.001908</td>

<td> 65</td><td> 0.00052</td><td> 272</td><td> 0.00124</td>

<td> 66</td><td> 0.000592</td><td> 273</td><td> 0.000516</td>

<td> 67</td><td> 0.000807</td><td> 274</td><td> 0.000936</td>

<td> 68</td><td> 0.005934</td><td> 275</td><td> 0.000081</td>

<td> 69</td><td> 0.008246</td><td> 276</td><td> 0.000199</td>

<td> 70</td><td> 0.020421</td><td> 277</td><td> 0.000017</td>

<td> 71</td><td> 0.031597</td><td> 278</td><td> 0.039967</td>

<td> 72</td><td> 0.031666</td><td> 279</td><td> 0.001703</td>

<td> 73</td><td> 0.03226</td><td> 280</td><td> 0.00755</td>

<td> 74</td><td> 0.18943</td><td> 281</td><td> 0.000111</td>

<td> 75</td><td> 0.076832</td><td> 282</td><td> 0.001012</td>

<td> 76</td><td> 0.2395</td><td> 283</td><td> 0.01721</td>

<td> 77</td><td> 0.45052</td><td> 284</td><td> 0.079348</td>

<td> 78</td><td> &gt;1.195000</td><td> 285</td><td> 0.000037</td>

<td> 79</td><td> 0.099826</td><td> 286</td><td> 0.003181</td>

<td> 80</td><td> 0.14872</td><td> 287</td><td> 0.000131</td>

<td> 81</td><td> 0.031048</td><td> 288</td><td> 0.000017</td>

<td> 82</td><td> 0.51156</td><td> 289</td><td> &lt;0.000010</td>

<td> 83</td><td> &gt;1.195000</td><td> 290</td><td> 0.000251</td>

179

<td> 84</td><td> 0.013654</td><td> 291</td><td> 0.000273</td>

<td> 85</td><td> 0.005626</td><td> 292</td><td> 0.000191</td>

<td> 86</td><td> 0.005263</td><td> 293</td><td> 0.000233</td>

<td> 87</td><td> 0.26427</td><td> 294</td><td> 0.000127</td>

<td> 88</td><td> &gt;1.195000</td><td> 295</td><td> 0.000077</td>

<td> 89</td><td> 0.006111</td><td> 296</td><td> &lt;0.000010</td>

<td> 90</td><td> 0.010626</td><td> 297</td><td> &lt;0.000010</td>

<td> 91</td><td> &gt;1.195000</td><td> 298</td><td> 0.000054</td>

<td> 92</td><td> 0.002569</td><td> 299</td><td> 0.051687</td>

<td> 93</td><td> 0.01683</td><td> 300</td><td> 0.013659</td>

<td> 94</td><td> 0.56121</td><td> 301</td><td> 0.000113</td>

<td> 95</td><td> 0.000428</td><td> 302</td><td> &lt;0.000010</td>

<td> 96</td><td> &gt;1.195000</td><td> 303</td><td> 0.000092</td>

<td> 97</td><td> 0.14659</td><td> 304</td><td> 0.000822</td>

<td> 98</td><td> 0.000959</td><td> 305</td><td> 0.000146</td>

<td> 99</td><td> 0.071364</td><td> 306</td><td> 0.000671</td>

<td> 100</td><td> 0.11299</td><td> 307</td><td> 0.000524</td>

<td> 101</td><td> 0.6695</td><td> 308</td><td> 0.00004</td>

<td> 102</td><td> 0.043518</td><td> 309</td><td> 0.00069</td>

<td> 103</td><td> 0.006755</td><td> 310</td><td> 0.000155</td>

<td> 104</td><td> 0.002321</td><td> 311</td><td> 0.000185</td>

<td> 105</td><td> 0.003567</td><td> 312</td><td> 0.000531</td>

<td> 106</td><td> 0.21452</td><td> 313</td><td> &lt;0.000010</td>

<td> 107</td><td> 0.000331</td><td> 314</td><td> 0.003094</td>

<td> 108</td><td> nd</td><td> 315</td><td> 0.004555</td>

<td> 109</td><td> 0.000237</td><td> 316</td><td> 0.000058</td>

<td> 110</td><td> 0.000039</td><td> 317</td><td> 0.000205</td>

<td> 111</td><td> 0.01744</td><td> 318</td><td> &lt;0.000010</td>

<td> 112</td><td> 0.000042</td><td> 319</td><td> 0.000198</td>

<td> 113</td><td> 0.000032</td><td> 320</td><td> 0.000028</td>

<td> 114</td><td> 0.000036</td><td> 321</td><td> 0.000029</td>

<td> 115</td><td> 0.000042</td><td> 322</td><td> 0.00453</td>

<td> 116</td><td> 0.000123</td><td> 323</td><td> 0.003484</td>

<td> 117</td><td> 0.000072</td><td> 324</td><td> &lt;0.000010</td>

<td> 118</td><td> 0.000151</td><td> 325</td><td> 0.000183</td>

180

<td> 119</td><td> 0.000156</td><td> 326</td><td> 0.000037</td>

<td> 120</td><td> 0.000214</td><td> 327</td><td> 0.000212</td>

<td> 121</td><td> 0.000081</td><td> 328</td><td> 0.000068</td>

<td> 122</td><td> &lt;0.000001</td><td> 329</td><td> 0.000108</td>

<td> 123</td><td> 0.00011</td><td> 330</td><td> &lt;0.000010</td>

<td> 124</td><td> 0.000033</td><td> 331</td><td> 0,000238</td>

<td> 125</td><td> 0.000075</td><td> 332</td><td> 0.000034</td>

<td> 126</td><td> 0.000068</td><td> 333</td><td> 0.000107</td>

<td> 127</td><td> 0.00003</td><td> 334</td><td> 0,000197</td>

<td> 128</td><td> 0.000064</td><td> 335</td><td> &lt;0.000010</td>

<td> 129</td><td> 0.000107</td><td> 336</td><td> &lt;0.000010</td>

<td> 130</td><td> 0.000067</td><td> 337</td><td> 0.000049</td>

<td> 131</td><td> 0.000066</td><td> 338</td><td> &lt;0.000010</td>

<td> 132</td><td> 0.00021]</td><td> 339</td><td> 0,000057</td>

<td> 133</td><td> 0.000055</td><td> 340</td><td> 0.000385</td>

<td> 134</td><td> 0.000181</td><td> 341</td><td> 0.000017</td>

<td> 135</td><td> 0.000068</td><td> 342</td><td> 0.003340</td>

<td> 136</td><td> 0.000177</td><td> 343</td><td> 0.000009</td>

<td> 137</td><td> 0.000021</td><td> 344</td><td> 0.000042</td>

<td> 138</td><td> 0.000016</td><td> 345</td><td> 0.000005</td>

<td> 139</td><td> 0.000125</td><td> 346</td><td> &lt;0.000010</td>

<td> 140</td><td> 0.000223</td><td> 347</td><td> 0.000377</td>

<td> 141</td><td> 0.000482</td><td> 348</td><td> 0,003779</td>

<td> 142</td><td> 0.000071</td><td> 349</td><td> 0,000019</td>

<td> 143</td><td> 0.000053</td><td> 350</td><td> &lt;0,000010</td>

<td> 144</td><td> 0.000028</td><td> 351</td><td> 0.002843</td>

<td> 145</td><td> 0.000057</td><td> 352</td><td> 0.000079</td>

<td> 146</td><td> 0.00004</td><td> 353</td><td> 0.000016</td>

<td> 147</td><td> 0.000127</td><td> 354</td><td> 0.000114</td>

<td> 148</td><td> 0.000106</td><td> 355</td><td> 0.009567</td>

<td> 149</td><td> 0.00003</td><td> 356</td><td> 0,002822</td>

<td> 150</td><td> 0.000759</td><td> 357</td><td> 0.000177</td>

<td> 151</td><td> 0.006935</td><td> 358</td><td> 0.000062</td>

<td> 152</td><td> 0.018589</td><td> 359</td><td> 0,000110</td>

<td> 154</td><td> 0.000012</td><td> 360</td><td> 0.000050</td>

181

<td> 155</td><td> 0.000062</td><td> 361</td><td> 0.000015</td>

<td> 156</td><td> 0.000035</td><td> 362</td><td> 0.000033</td>

<td> 157</td><td> 0.00072</td><td> 363</td><td> &lt;0.000010</td>

<td> 158</td><td> 0.000619</td><td> 364</td><td> 0.000014</td>

<td> 159</td><td> 0.000526</td><td> 365</td><td> 0.004551</td>

<td> 160</td><td> 0.000028</td><td> 366</td><td> 0.006052</td>

<td> 161</td><td> 0.000031</td><td> 367</td><td> 0.000012</td>

<td> 162</td><td> 0,000048</td><td> 368</td><td> &lt;0.000010</td>

<td> 163</td><td> 0.000686</td><td> 369</td><td> 0.000014</td>

<td> 164</td><td> 0.000056</td><td> 370</td><td> &lt;0.000010</td>

<td> 165</td><td> 0.00012</td><td> 371</td><td> &lt;0.000010</td>

<td> 166</td><td> 0.000082</td><td> 372</td><td> 0.014978</td>

<td> 167</td><td> 0.001345</td><td> 373</td><td> 1.195000</td>

<td> 168</td><td> 0.028343</td><td> 374</td><td> 0.005337</td>

<td> 169</td><td> 0.000498</td><td> 375</td><td> 0.327810</td>

<td> 170</td><td> 0.000036</td><td> 376</td><td> 0.057705</td>

<td> 171</td><td> 0.000066</td><td> 377</td><td> 0.002323</td>

<td> 172</td><td> 0.000549</td><td> 378</td><td> &lt;0.000010</td>

<td> 173</td><td> 0.000019</td><td> 379</td><td> 0.017948</td>

<td> 174</td><td> 0.000037</td><td> 380</td><td> 0.008274</td>

<td> 175</td><td> 0.000046</td><td> 381</td><td> 0.000020</td>

<td> 176</td><td> 0.00024</td><td> 382</td><td> 0.000114</td>

<td> 177</td><td> 0.000037</td><td> 383</td><td> 0.427490</td>

<td> 178</td><td> 0.000175</td><td> 384</td><td> 0.006233</td>

<td> 179</td><td> 0.000036</td><td> 385</td><td> 0.049293</td>

<td> 180</td><td> 0.000112</td><td> 386</td><td> &lt;0.000010</td>

<td> 181</td><td> 0.000119</td><td> 387</td><td> &lt;0.000010</td>

<td> 182</td><td> 0.000172</td><td> 388</td><td> 0.000020</td>

<td> 183</td><td> 0.00253</td><td> 389</td><td> &lt;0.000010</td>

<td> 184</td><td> 0.000155</td><td> 390</td><td> &lt;0.000010</td>

<td> 185</td><td> 0.000083</td><td> 391</td><td> &lt;0,000010</td>

<td> 186</td><td> 0.000035</td><td> 392</td><td> &lt;0.000010</td>

<td> 187</td><td> 0,000054</td><td> 393</td><td> &lt;0.000010</td>

<td> 188</td><td> 0.000073</td><td> 394</td><td> 0,000018</td>

<td> 189</td><td> 0.000036</td><td> 395</td><td> 0.000077</td>

182

<td> 190</td><td> 0.000077</td><td> 396</td><td> &lt;0.000010</td>

<td> 191</td><td> 0.000552</td><td> 397</td><td> 0.000137</td>

<td> 192</td><td> 0.000024</td><td> 398</td><td> 0.000175</td>

<td> 193</td><td> 0.000064</td><td> 399</td><td> &lt;0.000010</td>

<td> 194</td><td> 0.000317</td><td> 400</td><td> 0.000082</td>

<td> 195</td><td> 0.000684</td><td> 401</td><td> 0.000035</td>

<td> 197</td><td> 0.00022</td><td> 402</td><td> 0.000039</td>

<td> 198</td><td> &lt;0.000010</td><td> 403</td><td> 0,002136</td>

<td> 199</td><td> 0,000244</td><td> 404</td><td> 0.000069</td>

<td> 200</td><td> 0,000081</td><td> 405</td><td> 0.000354</td>

<td> 201</td><td> 0.00001</td><td> 406</td><td> 0.000166</td>

<td> 202</td><td> 0.020043</td><td> 407</td><td> 0.000946</td>

<td> 203</td><td> 0.000084</td><td> 408</td><td> 0.001160</td>

<td> 204</td><td> 0.000075</td><td> 409</td><td> 0.000686</td>

<td> 205</td><td> 0,000153</td><td> 410</td><td> &lt;0.000010</td>

<td> 206</td><td> 0.000037</td><td> 411</td><td> 0.021291</td>

The inhibition constant (K,) is the dissociation constant of an enzyme-inhibitor complex or a protein/small molecule complex, wherein the small molecule is inhibiting binding of one protein to another protein. So a large K, value indicates a low binding affinity and a small K 20 value indicates a high binding affinity.

The data in TABLE 2 shows inhibition constants for the inhibition of a Bak BH3 peptide probe to Bcl-2 protein and indicate that compounds according to the invention have high binding affinities for anti-apoptotic Bcl-2 protein. The compounds are therefore expected to have utility in treatment of diseases during which anti-apoptotic Bcl-2 protein is expressed,

It is expected that, because compounds having Formula I bind to Bcl-2, they would also have utility as binders to anti-apoptotic proteins having close structural homology to Bcl-2, such as, for example, anti-apoptotic Bcl-X_L, Bcl-w, Mcl-1 and Bfl-l/AI proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal 30 cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer spleen cancer, and the like is described in commonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCT US ³⁵ 2004/37911, published as WO 2005/024636.

183

Involvement of Bcl-2 proteins in immune and autoimmune diseases is described in Current Allergy and Asthma Reports 2003, 3, 378-384; British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418,

Involvement of Bcl-2 proteins in arthritis is disclosed in commonly-owned United States

Provisional Patent Application Serial No. 60/988,479,

Involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in commonly-owned United States Patent Application Serial No, 11/941,196.

Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system. Cancers include, but are not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt’s lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endothel iosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and nonsmall cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pineal oma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung

184 carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrbm’s macroglobulinemia, testicular tumors, uterine cancer, Wilms’ tumor and the like.

It is also expected that compounds having Formula (I) would inhibit growth of cells expressing Bcl-2 proteins derived from a pediatric cancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing’s family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm’s tumor, pediatric favorable histology Wilm’s tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia, acute or chronic immune disease associated with organ transplantation,

Addison's disease, allergic diseases, alopecia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritisjuvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoprotemia, acquired immunodeficiency-related diseases, acute immune disease associated with organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, adult (acute) respiratory distress syndrome, AIDS dementia complex, alcoholic cirrhosis, alcohol-induced liver injury, alcoholinduced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-1- antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis associated lung disease, anterior horn cell degeneration, antibody mediated cytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, atrophic autoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), autoimmune mediated

185 hypoglycaemia, autoimmune neutropaenia, autoimmune thrombocytopaenia, autoimmune thyroid disease, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bronchiolitis obliterans, bundle branch block, bums, cachexia, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, 5 cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chlamydia, choleosatatis, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immune disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary disease (COPD), 10 chronic salicylate intoxication, colorectal common varied immunodeficiency (common variable hypogammaglobulinaemia), conjunctivitis, connective tissue disease associated interstitial lung disease, contact dermatitis, Coombs positive haemolytic anaemia, cor pulmonale, CreutzfeldtJakob disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Crohn's disease, dementia 15 pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma, dermatologic conditions, dermatomyositis/polymyositis associated lung disease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus, Diffuse Lewy body disease, dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, Down's Syndrome in middle age, drug-induced interstitial 20 lung disease, drug-induced hepatitis, drug-induced movement disorders induced by drugs which block CNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, female 25 infertility, fibrosis, fibrotic lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis, glomerular nephritis, glomerulonephritides, Goodpasture's syndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty arthritis, graft rejection of any organ or tissue, graft versus host disease, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, group B streptococci (GBS) infection. Grave's disease, haemosiderosis 30 associated lung disease, hairy cell leukemia, hairy cell leukemia. Hallerrorden-Spatz disease,

Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombo lytic thrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIV infection/HTV neuropathy, Hodgkin's disease, 35 hypoparathyroidism, Huntington's chorea, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders,

186 hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic leucopaenia, idiopathic pulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver disease, infantile spinal muscular atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonitis, 5 iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile pernicious anaemia, juvenile rheumatoid arthritis juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, linear IgA disease, lipidema, liver transplant rejection, Lyme disease, lymphederma, lymphocytic infiltrative lung disease, malaria, male infertility idiopathic or

NOS, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, mixed connective tissue disease associated lung disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas ShiDrager and Machado-Joseph), myalgic encephalitis/Royal Free Disease, myasthenia gravis, microscopic vasculitis of the kidneys, mycobacterium avium intrace llulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, Nonalcoholic Steatohepatitis, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, organ transplant rejection, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian failure, pancreas transplant rejection, parasitic diseases, parathyroid transplant rejection, Parkinson's disease, pelvic inflammatory disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis car ini i pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-Mi cardiotomy syndrome, postinfectious interstitial lung disease, premature ovarian failure, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, Progressive supranucleo Palsy, psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy, pulmonary hypertension secondary to connective tissue disease, pulmonary manifestation of polyarteritis nodosa, post-inflammatory interstitial lung disease, radiation fibrosis, radiation therapy, Raynaud’s phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, Reiter's disease, renal disease NOS, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoid arthritis associated interstitial lung disease, rheumatoid spondylitis, sarcoidosis.

187

Schmidt's syndrome, scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell anemia, Sjogren's disease associated lung disease, Sjbrgren's syndrome, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinal 5 ataxia, spinocerebellar degenerations, spondyloarthropathy, spondyloarthopathy, sporadic, polyglandular deficiency type I sporadic, polyglandular deficiency type II, Still's disease, streptococcal myositis, stroke, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, sympathetic ophthalmia, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic lupus erythematosus-associated lung disease, systemic sclerosis, systemic sclerosis-associated interstitial lung disease, T-cell or FAB ALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th] Type mediated diseases, thromboangitis obliterans, thrombocytopenia, thyroiditis, toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), type

B insulin resistance with acanthosis nigricans, type III hypersensitivity reactions, type IV hypersensitivity, ulcerative colitic arthropathy, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins, vasculitis, vasculitic diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, vitiligo acute liver disease, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wegener's granulomatosis, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, yersinia and salmonella-associated arthropathy and the like.

Schemes and Experimental

The following abbreviations have the meanings indicated. ADDP means l,l'-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQDjzPHAL, K₃Fe(CN)₆, K_;CO_3l and KiSOi; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHAL means hydroquinidine 1,4-phthalazinediyl diethyl ether; DBD means l,8-diazabicyclo[5,4.0]undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means di isopropylethylamine; DMAP means Ν,Ν-dimethylaminopyridine; DMF means

N,N-dimethylformamide; dmpe means ],2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means l,4-bis(diphenylphosphino)-butane; dppe means 1,2bis(diphenylphosphino)ethane; dppf means l,l'-bis(diphenylphosphino)ferrocene; dppm means l,l-bis(diphenylphosphino)methane; EDAC HC1 means l-(3-dimethylaminopropyl)-3ethyl carbodi imide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means 0-(735 azabenzotriazol-l-yl)-N,N'N’N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH₃ means macroporous

188 trietliylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methyIpyrrolidine; PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to be the most useful 5 and readily understood description of procedures and conceptual aspects of this invention.

Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary,

SCHEME I

<img file="MY179077A_D0014.tif" />

Compounds of Formula (4) can be prepared as shown in SCHEME I, and can be used as described in SCHEME 8 to prepare compounds of Formula (I), which are representative of the compounds of the present invention. Compounds of Formula (1) wherein R is alkyl, can be converted to compounds of Formula (2) using ZY’MgX¹, wherein X¹ is a halide, in a solvent such as but not limited to ether or tetrahydro furan. Compounds of Formula (3) can be prepared from compounds of Formula (2) using a strong base such as NaH and R^S7X², wherein X² is a halide and R⁵⁷ is as described herein. Compounds of Formula (3), when treated with aqueous

NaOH or LiOH, will provide compounds of Formula (4).

SCHEME 2

<img file="MY179077A_D0015.tif" />

_R37A

O^z³ (6)

<img file="MY179077A_D0016.tif" />

<img file="MY179077A_D0017.tif" />

As shown tn SCHEME 2, compounds of Formula (5) can be reacted with compounds of Formula (6) and a reducing agent to provide compounds of Formula (7). Examples of reducing 25 agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,

189 polymer supported cyanoborohydride, and the like. The reaction is typically performed in a solvent such as but not limited to methanol, tetrahydrofuran, and dichloromethane or mixtures thereof. Compounds of Formula (8) can be prepared from compounds of Formula (7) as described in SCHEME 1, and can be used as described in SCHEME 8 to prepare compounds of Formula (I).

SCHEME 3

Br

<img file="MY179077A_D0018.tif" />

Compounds of Formula (9), when reacted with a compound a Formula (10) wherein X is a halide or triflate, and a base will provide a compound of Formula (11). Bases useful in the reaction include triethylamine, di isopropylethylamine and the like. Compounds of Formula (13), wherein Y is as described herein for substituents on Z³, can be prepared from compounds of Formula (11) and compounds of Formula (12) using Suzuki coupling conditions known to those skilled in the art and readily available in the literature. Compounds of Formula (14) can be prepared from compounds of Formula (13) as described in SCHEME 1, and can be used as described in SCHEME 8 to prepare compounds of Formula (1).

190

SCHEME 4

<img file="MY179077A_D0019.tif" />

<img file="MY179077A_D0020.tif" />

(20) (2D

As shown in SCHEME 4, compounds of Formula (17) can be prepared from compounds of Formula (15) and compounds of Formula (16), wherein R is alkyl and R³⁸ is as described herein, using Suzuki coupling conditions known to those skilled in the art and readily available in the literature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as L1AIH4 in a solvent such as but not limited to diethyl ether or THF. Compounds ofFormula (19) can be prepared from compounds ofFormula (18) using DessMartin periodinane or Swem oxidation conditions known to those skilled in the art and readily available in the literature. Compounds of Formula (19) can be reacted with a compound of Formula (5) and a reducing agent to provide compounds ofFormula (20), Examples of reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, polymer supported cyanoborohydride, and the like. The reaction is typically performed in a solvent such as but not limited to methanol, tetrahydrofiiran, 1,2-dichloroethane, and dichloromethane or mixtures thereof. Compounds ofFormula (21) can be prepared from compounds ofFormula (20) as described in SCHEME 1, and can be used as described in SCHEME 8 to prepare compounds ofFormula (I),

191

SCHEMES

<img file="MY179077A_D0021.tif" />

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, may be converted to compounds of Formula (23) by reacting the former, wherein X¹ is Cl, Br, I, or 5 CF3SO3-, and compounds of Formula R⁴¹-OH and a catalyst, with or without a first base.

Examples of catalysts include copper(I) trifluoromethanesulfonate toluene complex, PdCl₂, Pd(OAc)₂, and Pd₂(dba)₃. Examples of first bases include triethylamine, N,Ndi isopropylethylamine, Cs₂CO₃, Na₂CO3, K3PO4, and mixtures thereof,

Compounds of Formula (22) may also be converted to compounds of Formula (23) by 10 reacting the former, when X¹ is Cl, F, or NO2, and compounds of Formula R^4,-OH with a first base. Examples of first bases include tri ethylamine, Ν,Ν-dtisopropyl ethylamine, Cs2CO3, Na₂CO₃, K3PO4, and mixtures thereof,

SCHEME 6

<img file="MY179077A_D0022.tif" />

Compounds of Formula (18) can be reacted with mesyl chloride and a base such as but not limited to tri ethyl amine, followed by N-t-butoxycarbonylpiperazine, to provide compounds of Formula (24). Compounds of Formula (25) can be prepared by reacting compounds of Formula

192 (24) with triethylsilane and trifluoroacetic acid. Compounds of Formula (25) can be reacted with compounds of Formula (26) and HK2PO4 to provide compounds of Formula (27) in a solvent such as but not limited to dimethylsulfoxide. Compounds of Formula (28) can be prepared from compounds of Formula (27) as described in SCHEME 1, and can be used as described in

SCHEME 8 to prepare compounds of Formula (I).

.SCHEME 7

<img file="MY179077A_D0023.tif" />

As shown in SCHEME 7, compounds of Formula (1) can be reacted with an appropriate tri phenylphosphonium bromide of Formula (29) and a base such as but not limited to sodium hydride or n-butyllithium to provide compounds of Formula (30). The reaction is typically performed in a solvent such as THF or DMSO. Compounds of Formula (31) can be prepared from compounds of Formula (30) as described in SCHEME 1, and can be used as described in

SCHEME 8 to prepare compounds of Formula (I).

SCHEME 8

Ο O E¹

S' A (32)

0,,0 E¹

II

H₂N

D¹ A¹ B¹ (33)

W, (0), (14), (21), (28), (31), or (38)

<img file="MY179077A_D0024.tif" />

_zia f 1 n'^SA^Yh A!

_D1^A¹ B¹

<img file="MY179077A_D0025.tif" />

As shown in SCHEME 8, compounds of Formula (32), which can be prepared as described herein, may be converted to compounds of Formula (33) by reacting the former with ammonia. Compounds of Formula (33) may be converted to compounds of Formula (1) by reacting the former and compounds of Formula (4), (8), (14), (21), (28), (31), or (38) and a coupling agent, with or without a first base. Examples of coupling agents include 1 -ethyl-3-[3(dimethylamino)propyl]-carbodiimide hydrochloride, 1,1'-carbonyldiimidazole, and benzotriazoll-yl-oxytripyrrolidinophosphonium hexafluorophosphate. Examples of first bases include triethylamine, Ν,Ν-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

SCHEME 9

193

<img file="MY179077A_D0026.tif" />

Compounds of Formula (33), prepared as described in SCHEME 8, may also be converted to compounds of Formula (I) by reacting the former and compounds of Formula (34) and a first base. Examples of first bases include but are not limited to sodium hydride, triethylamine, Ν,Ν-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

SCHEME 10

<img file="MY179077A_D0027.tif" />

(37)

<img file="MY179077A_D0028.tif" />

<img file="MY179077A_D0029.tif" />

(38)

As shown in SCHEME 10, compounds of Formula (35), wherein L is a bond, alkyl, O, S, S(O), S(O)₂, NH, etc., can be reacted with compounds of Formula (36), to provide compounds of

Formula (37). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to dimethyl sulfoxide, and may require the use of a base such as but not limited to potassium phosphate, potassium carbonate, and the like. Compounds of Formula (38) can be prepared from compounds of Formula (37) as described in SCHEME 1, and can be used as described in SCHEME 8 to prepare compounds of Formula (I).

194

SCHEME 11

<img file="MY179077A_D0030.tif" />

(40) (41)

Compounds of Formula (39), wherein Y is as described herein for substituents on Z³, can be prepared from compounds of Formula (39A) wherein X is a halide or inflate, and Y-B(OH)₂5 using Suzuki coupling conditions known to those skilled in the art and readily available in the literature. Compounds of Formula (39) can be reacted with tert-butyl piperazine-l-carboxylate and a reducing agent such as sodium triacetoxyborohydride to provide compounds of Formula (40). The reaction is typically performed in a solvent such as but not limited to methylene chloride. Compounds of Formula (41) can be prepared from compounds of Formula (40) by reacting the latter with R^{15 * i7 * * 20}X, wherein X is a halide, and NaH in a solvent such as N,Ndimethylformamide, and then the resulting material can be treated with triethyl silane and tri fluoroacetic acid in dichloromethane. Compounds of Formula (41) can be used as described in Scheme 10 wherein L'-Z³ is as shown in Formula (41).

SCHEME 12

<img file="MY179077A_D0031.tif" />

₁₅ (42) (43)

As shown in SCHEME 12, substituted piperazin-2-ones wherein R^S7 is alkyl, can be reacted with compounds of Formula (6) and a reducing agent such as sodium triacetoxyborohydride in dichloromethane to provide compounds of Formula (42). Compounds of

Formula (42) can be reduced to compounds of Formula (43) using a reducing agent such as but not limited to lithium aluminum hydride in a solvent such as but not limited to tetrahydrofuran. Compounds of Formula (43) can be used as described in Scheme 10 wherein L’-Z³ is as shown in Formula (43).

The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The

195 exemplified compounds were named using ACD/ChemSketch Version 5.06 (05 June 2001, Advanced Chemistry Development Inc,,Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

EXAMPLE 1

4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide

EXAMPLE 1A tert-butyl 4-((4'-chlorobipheny 1-2-yl)methyl)piperazine-l-carboxylate 4'-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl piperazine-l-carboxylate (4,23 g) and sodium triacetoxyborohydride (5.61 g) in CH2CI2 (60 mL) were stirred for 24 hours. The mixture was treated with methanol and poured into ether, The extract was washed with water and 15 brine and concentrated. The concentrate was chromatographed on silica gel with 2-25% ethyl acetate/hexanes.

EXAMPLE IB l-((4'-chlorobiphenyl-2-yl)methyl)piperazine

EXAMPLE i A (3.0 g) and triethylsilane (1 mL) were stirred in dichloromethane (30 mL) and trifluoroacetic acid (30 mL) for 2 hours. The mixture was concentrated, taken up in ether and concentrated again.

EXAMPLE IC methyl 2-bromo-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yi)benzoate

Methyl 2-bromo-4-fluorobenzoate (3 g), EXAMPLE IB (4.43 g), and K₂CO₃ (3.56 g) were stirred in DMSO (35 mL) at 125°C for 24 hours. The mixture was cooled, taken up in ethyl acetate (500 mL), washed with water and brine, dried over Na2SO&lt;i, filtered and concentrated. The concentrate was chromatographed on silica gel with 5-25% ethyl acetate/hexanes.

EXAMPLE ID

-((dimethy lamino)methy l)phenol 3-HydroxybenzaIdehyde (1,0 g), 2M dimethylamine in THF (5 mL), and sodium triacetoxyborohydride (2 g) in CHjCh (10 mL) were stirred for 24 hours. The mixture was treated 35 with methanol and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.

196

EXAMPLE IE methyl 4-(4-((4'-chlorobipheny 1-2-yl)methyl )piperazin- 1-y 1)-2-(3 ((dimethy lam ino)methy l)phenoxy)benzoate

EXAMPLE IC (400 mg), EXAMPLE ID (260 mg), Cs₂CO₃ (570 mg), 1-naphthoic acid 5 (2.96 g), copper (I) triflate-toluene complex (245 mg), ethyl acetate (9 μι), and 4A sieves (30 mg) in toluene (2 mL) was stirred at 105°C for 24 hours. The mixture was cooled and taken up in ethyl acetate (100 mL) and water (40 mL). The layers were separated and the extract was washed twice with Na₂CO₃ solution and brine, dried, and concentrated. The concentrate was chromatographed on silica gel with 25-50% ethyl acetate/hexanes.

EXAMPLE IF

4-(4-((4’-chIorobiphenyl-2-yl)methyI)piperazin-l-yl)-2-(3((dimethylam ino)methy l)phenoxy)benzoic acid

EXAMPLE IE (750 mg) was stirred in 25 mL 2; 1 dioxane/ΙΜ NaOH at 80°C for 4 hours. The solution was cooled and adjusted to pH 4 with NaH₂PO₄ solution and concentrated HC1, and extracted with ethyl acetate. The extract was washed with brine, dried (Na₂SO₄), and concentrated.

EXAMPLE IG

0 3-nitro-4-((tetrahydro-2 H-pyran-4-y l)methy Iamino)benzenesu Ifonam ide

4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl)methylamme (L14 g), and triethylamine (1 g) were stirred in THF (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH₂PO₄ solution and brine, and dried (Na₂SO₄), filtered and concentrated. The product was triturated from ethyl acetate.

197

EXAMPLE 1H 4-(4-((4’-chloro-l,]'-biphenyl-2-yl)methyl)piperazin-1 -y 1)-2-(3 ((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethyl )amino)phenyl)sulfony 1 Jbenzam ide

EXAMPLE IF (128 mg), EXAMPLE 1G (73 mg), 1-ethy 1-3-(3-(d imethy lam ino)propy 1)carbodiimide hydrochloride (88 mg), and 4-dimethylaminopyridine (28 mg) were stirred in CHjCL (3 mL) for 24 hours. The mixture was cooled and chromatographed on silica gel with 010% methanol/ethyl acetate. 'H NMR (300MHz, DMSO-d₆) 5 11.15 (br s, ] H), 8.63 (dd, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.44-7.53 (m, 5H), 7.36 (m, 3H), 7.22 (m, 3H), 7.01 (s, 1H), 6.92 (d, 10 IH), 6.78 (d, 1H), 6.44 (s, 1H), 4,17 (m, 2H), 3.86 (dd, 2H), 3.33 (m, 6H), 3.16 (m, 4H), 2.66 (s, 6H), 2.37 (br s, 4H), 1.91 (m, 1 Η), 1.63 (d, 2H), 1.29 (m, 2H).

EXAMPLE 2

4-(4-((4'-ch loro-1, T-bipheny 1-2-yl )methyl ipiperazin- 1-y 1)-2 -(3-(methy lam ino)phenoxy)-N -((315 nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyI)sulfonyl)benzamide

EXAMPLE 2A

3-(methylamino)phenol

Ethylamine was bubbled into a solution of 4-hydroxybenzaldehyde (2.0 g) and sodium 20 tri acetoxy boro hydride (5.2 g) in CHiCL (60 mL) for ] hour, and the mixture was stoppered and stirred for 24 hours. IM NaOH solution was added (10 mL), and di-tert-butyl dicarbonate (3.57 g) and triethylamine (2.28 mL) were then added and the mixture was stirred for 24 hours. The solution was cooled and adjusted to pH 4 with NaH₂PO₄ solution and concentrated HC1, and extracted with ethyl acetate. The extract was washed with brine, dried (NajSOJ, and concentrated. The concentrate was chromatographed on silica gel with 20% ethyl acetate/hexanes.

EXAMPLE 2B methyl 4-(4-((4 '-ch Iorobiphenyl-2-yl)methyl ipiperazin- ] -y 1)-2-(3 (methylamino)phenoxy)benzoate ³θ EXAMPLE IC (457 mg), EXAMPLE 2A (225 mg), cesium carbonate (595 mg), copper(i) triflate toluene complex (41 mg), and ethyl acetate (0.016 mL) in toluene (5 mL) were stirred at 110’C for 72 hours. The mixture was cooled and chromatographed on silica gel with 525% ethyl acetate/hexanes.

³⁵ EXAMPLE 2C

4-(4-((4'-chlorobiphenyl-2-yl)methy])piperazin-1-y 1)-2-(3-(methylamino)phenoxy)benzoic acid

198

This EXAMPLE was prepared by substituting EXAMPLE 2B for EXAMPLE 1E in EXAMPLE IF.

EXAMPLE 2D

4-( 4-((4'-ch loro-1, Γ-b iphenyl-2 -yljmethyl )piperazin-1 -y 1)-2-(3 -(methy lamino)phenoxy)-N-( (3 n itro-4-((tetrahydro-2H-pyran-4-y 1 methy Ijaminojpheny 1 jsulfony Ijbenzam ide

This EXAMPLE was prepared by substituting EXAMPLE 2C for EXAMPLE IF in EXAMPLE IG. *H NMR (500MHz, DMSO-cL) 8 11.60 (brs, 1H), 8.37 (s, 1H), 7.69 (d, IH), 7.58 (d, IH), 7.47 (m, 5H), 7.38 (m,3H), 7.24 (m, IH), 6.95 (d, IH),6.89(dd, 1H), 6.61 (d, 1H),6.26 10 (s, IH), 6.13 (d, IH), 5.97(s, IH), 5.92 (d, 1 Hj, 5.59 (brs, IH), 3.84 (dd, 2Hj, 3.37 (m, 6H), 3.03 (m, 4H), 2.89 (m, 2H), 2.59 (br s, 3H), 2.36 (br s, 4H), 1.91 (m, IH), 1.62 (d, 2H), 1.24 (m, 2H).

EXAMPLE 3

4-(4-( (2-(4-ch loropheny 1 )-4,4-d i methy Icyc lohex- 1-en-l -y Ijmethy 1 )piperazin-1 -yl)-2-((2-methy 1 15 lH-indol-5-yljoxy)-N-((4-((]-methylpiperidin-4-yl)aminoj-3-nitrophenyl)sulfonyl)benzamide

EXAMPLE 3A ethyl 4-fluoro-2-(2-methyl-1 H-indol-5-yloxy)benzoate

Ethyl 2.4-di fluorobenzoate (1.14 g), K₃PO₄ (1.30 g) and 2-methyl-5-indolol (0.90 g) were 20 stirred at 110°C in diglyme (12 mL) for 24 hours, The mixture was cooled and poured into ether. The solution was washed three times with IM NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.

199

EXAMPLE 3 B methyl 4,4-d imethy l-2-(trifluoromethylsulfonyloxy)cyc lohex-1 -enecarboxylate

To a suspension of hexane-washed NaH (17 g) in dichloromethane (700 mL) was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0°C, After stirring for 30 minutes, the mixture was cooled to -78°C and trifluoroacetic anhydride (40 mL) was added. The mixture was wanned to room temperature and stirred for 24 hours. The extract was washed with brine, dried and concentrated.

EXAMPLE 3C methyl 2-(4-chlorophenyi)-4,4-dimethylcyclohex-l-enecarboxylate

EXAMPLE 3B (62.15g), 4-chlorophenyIboronic acid (32.24 g), CsF (64 g) and ( tetrakis(triphenylphosphine)palladium(0) (2g) in 2:1 dimethoxyethane /methanol (600 mL) were heated to 70°C for 24 hours. The mixture was concentrated. Ether was added, and the mixture was filtered and concentrated,

EXAMPLE 3D (2-(4-ch loropheny! )-4,4-dimethy Icyclohex-1 -enyl)methanol

To a mixture of LiBFL (13g), EXAMPLE 3C (53.8 g) and ether (400 mL), methanol (25 mL) was added slowly by syringe. The mixture was stirred at room temperature for 24 hours. The mixture was quenched with 1N HC1 with ice-cooling. The mixture was diluted with water and extracted by ether (3x 100mL). The extracts were dried, and concentrated. The concentrate was chromatographed on silica gel with 0-30% ethyl acetate/hexanes.

^r EXAMPLE 3 E tert-butyl 4-((2-(4-chloropheny])-4,4-dimethylcydohex-l-enyl)methyl)piperazine-l-carboxylate

Mesyl chloride (7.5 mL) was added via syringe to EXAMPLE 3D (29.3 g) and triethylamine (30 mL) in CHiClj (500 mL) at 0°C, and the mixture was stirred for 1 minute. N-tbutoxycarbonylpiperazine (25 g) was added and the mixture was stirred at room temperature for 24 hours. The suspension was washed with brine, dried, and concentrated. The concentrate was chromatographed on silica gel with 10-20% ethyl acetate/hexanes.

200

EXAMPLE 3F

-((2-(4-chloropheny 1)-4,4-dimethy Icyc 1 ohex-1 -eny 1 )methy 1 Jpiperazine This EXAMPLE was prepared by substituting EXAMPLE 3E for EXAMPLE 1A tn EXAMPLE IB.

EXAMPLE 3G ethyl 4-(4-((2-(4-chloropheny 1)-4,4-dimethyIcyclohex- l-enyl)methyI Jpiperazin-1-y 1)-2-(2methyl-1 H-indol-5-yloxy)benzoate

EXAMPLE 3F (1008 mg), EXAMPLE 3A (900 mg), and HK₂PO₄ (550 mg) were stirred 10 in DMSO (7 mL) at 140°C for 24 hours. The mixture was diluted with ethyl acetate, washed three times with water, washed with brine, dried, and concentrated, The concentrate was chromatographed on silica gel with 30% ethyl acetate/hexanes.

EXAMPLE 3 H

4-(4-((2-(4-chloropheny 1)-4,4-dimethy Icyc lohex-1 -enyljmethy I Jpiperazin-1 -yl)-2-(2-methy Μ Hindol-5-yloxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 3G for EXAMPLE 1E in EXAMPLE IF.

EXAMPLES!

4-( I -methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 4-amino-N-methylpiperidine for 3-(Nmorpholinyl)-l-propylamine in EXAMPLE 4A.

EXAMPLE 3 J

4-(4-((2-(4-chlorophenyl)-4,4-dimethy]cyclohex-l-en-l-yl)methyl)piperazin-l-yl)-2-((2-methyl1 H-indol-5-y I JoxyJ-N-((4-((1-methy lpiperidin-4-yl Jam ino )-3-nitrophenyl Jsulfony IJbenzamide This EXAMPLE was prepared by substituting EXAMPLE 3H for EXAMPLE IF and EXAMPLE 3J for EXAMPLE IG in EXAMPLE 1H. ’H NMR (300MHz, DMSO-d₆J δ 10.98 (s, 30 1H), 10.50 (brs, 1H), 8.55 (dd, 1H), 8.17 (d, lH),7.88(dd, 1H), 7.51 (d, 1H), 7.34 (d, 2HJ, 7.24 (d, 1H), 7.14 (d, 1H), 7.05 (d, 2HJ, 7.00 (d, 1H), 6.72 (d, 1H), 6.55 (d, 1H), 6.08 (d, 2H), 3.85 (m, 1H), 3,45 (m, 4HJ, 2.98 (br s, 4H), 2,85 (m, 2HJ, 2.71 (br s, 2H), 2.63 (s, 2H), 2.38 (s, 2H), 2.15 (m, 6HJ, 1.95 (m, 4HJ, 1.80 (m, 2HJ, 1.38 (m, 2H), 0,92 (s, 6HJ,

EXAMPLE 4

201

4-(4-((2-(4 -ch 1 oropheny 1)-4,4-d imethy leyclohex-1 -en-1 -y l)methy 1 )piperazin-1 -y 1)-2 -((2-methy 11 H-indol-5-y l)oxy)-N-((4-((3 -morpho I in-4-y Ipropy l)am ino )-3 -nitrophenyl)sulfony l)benzami de

EXAMPLE 4A

4-(3 -morphol inopropy lamino)-3 -n itrobenzenesul fonamide

4-Fluoro-3-nitrobenzenesulfonamide (550 mg), 3-(N-morpholinyl)-l-propylamine (1,00 g), and tri ethylamine (1 g) were stirred in THF (30 mL) for 24 hours. The mixture was diluted with ethyl acetate, washed with NaHiPCL solution and brine, and dried (NaiSCL), filtered and concentrated. The product was triturated from ethyl acetate.

EXAMPLE 4B

4-(4 -((2-(4-ch loropheny 1 )-4,4-d imethy Icycl ohex-1 -en-1 -y 1 )methy l)p iperazin-1 -y 1)-2-((2-methy 1 IH-indoI-5-yI)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyI)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4A for EXAMPLE 1F and

EXAMPLE 3H for EXAMPLE 1 Gin EXAMPLE IH. ^!H NMR (300MHz, DMSO-d₆) δ 10.98 (m, 2H), 8.80 (dd, IH), 8.58 (d, IH), 7.82 (dd, IH), 7,50 (d, IH), 7.34 (d, 2H), 7,27 (d, IH), 7.05 (m, 4H), 6.75 (d, IH), 6.62 (d, lH),6.10(d, IH), 3.60 (m, 4H),3.45 (m, 2H), 3.01 (brs, 4H), 2.71 (brs, 3H), 2.38 (m, 8H), 2.14 (br s, 6H), 1.95 (m, 2H), 1.81 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

EXAMPLE 5

4-(4-((4'-chloro-l, 1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-chlorophenoxy)-N-((3-nitro-4((tetrahydro-2 H-pyran-4-y Imethy 1 )am i no)pheny l)su Ifony l)benzam ide ( EXAMPLE 5A methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-I -yI)-2-(2-chlorophenoxy)benzoate

This EXAMPLE was prepared by substituting 2-chlorophenol for EXAMPLE ID in EXAMPLE 1E.

EXAMPLE 5B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin- l-yl)-2-(2-chlorophenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 5A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 5C

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2-chlorophenoxy )-N-((3-nitro-4((tetrahydro-2H-pyran-4-yImethyl)amino)phenyl)su Ifony l)benzam ide

202

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE IF in EXAMPLE IH. The crude product was purified by preparative HPLC using a 250 x 50 mm Cl8 column and eluting with 20-100% CH₃CN vs, 0,1% trifluoroacetic acid in water, giving the product as a trifluoroacetate salt, ^]H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, IH), 9,58 (v br s, 5 IH), 8.63 (t, IH), 8.46 (d, IH), 7,79 (dd, IH), 7,71 (br s, IH), 7.52 (m, 5H), 7,35 (m, 4H), 7.15 (d, IH), 7.13 (m, IH), 6.99 (m, IH), 6.78 (dd,IH), 6.65 (d, IH), 6.40 (s, lH),4.35(v brs, IH), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, IH), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 6

4-(4-((4'-chloro-l, 1 '-biphenyl-2-yl)methyl)piperazin-l -y!)-2-(3-chlorophenoxy)-N-((3-mtro-4((tetrahydro-2 H-pyran-4-y Imethy l)am ino)phenyl)su Ifony 1 )benzamide

EXAMPLE 6A 15 methyl 4-(4-((4'-chlorobiphenyl-2-yl)Tnethyl)piperazin-l-yl)-2-(3-chlorophenoxy)benzoate This EXAMPLE was prepared by substituting 3-chlorophenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 6B

4-(4-((4'-ch lorobiphenyl-2-yl)methyl)piperazin-1-y 1)-2-(3-chlorophenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 6A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 6C

4-(4-((4'-chloro-l,r-biphenyl-2-y[)methyl)piperazin-l-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE 5B in EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) δ 11.85 (br s, IH), 9.60 (v br s, IH), 8.63 (t, IH), 8,43 (d, IH), 7.72 (dd, IH), 7.70 (brs, IH), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, IH), 7.19 (dd, IH), 7.14 (d, lH),6.95(m, IH), 6.80 (dd, lH),6.72(m, lH),6.70(m, IH), 6,56 (d, 1H),4.35 (v br s, IH), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, IH), 1.63 (m,2H), 1.28 (m, 2H).

EXAMPLE 7

4-(4-((4'-ch loro-1,1 '-biphenyl-2-yl )methyl)piperazin-l -yl)-2-(4-chlorophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

203

EXAMPLE 7A methyl 4-( 4-((4¹-ch lorobipheny l-2-yl)methyl)piperazin-1-y 1)-2-(4-chlorophenoxy) benzoate This EXAMPLE was prepared by substituting 4-chlorophenol for EXAMPLE ID in

EXAMPLE IE.

EXAMPLE 7B

4-(4-((4'-chlorobipheny 1-2-yl)methyl)piperazin-1 -yl)-2-(4-chlorophenoxy)benzoic acid This EXAMPLE was prepared by substituting EXAMPLE 7A for EXAMPLE IE in

EXAMPLE IF.

EXAMPLE 7C

4-(4-((4'-chloro-1,1 ^r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-chlorophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 5B in

EXAMPLE 5C. ’H NMR (300 MHz, DMSO-d_t) 5 11.81 (brs, lH),9.58(v brs, 1H), 8,63 (t, 1H), 8,46 (d, 1H), 7,73 (dd, 1H)_: 7.71 (br s, 1H), 7.50 (m, 5H), 7.38 (d, 2H),7.33(m, 1H), 7.25 (m, 2H), 7.15 (d, 1H), 6.79 (m,3H), 6.50 (d, 1H), 4.35 (v brs, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H),

EXAMPLE 8

4-(4-((4'-chloro-1, r-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(3-nitrophenoxy )-N-((3-nitro-4((tetrahydro-2H-pyran-4-yImethyl)amino)phenyl)sulfonyl)benzamide ( EXAMPLE 8A methyl 4-(4-((4'-ch lorobipheny l-2-y I (methy I )piperazin-1-y 1)-2-(3-nitrophenoxy (benzoate This EXAMPLE was prepared by substituting 3-nitrophenol for EXAMPLE 1D in EXAMPLE IE.

EXAMPLE 8B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l -y 1)-2-(3-nitrophenoxy )benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 8A for EXAMPLE 1E in EXAMPLE IF.

EXAMPLE 8C

4-(4-((4'-chloro-l ,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-nitrophenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)sulfonyl)benzamide

204

This EXAMPLE was prepared by substituting EXAMPLE 8B for EXAMPLE 5B in EXAMPLE 5C, ^lH NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, IH), 9,59 (v br s, 1H), 8.60 (t, 1H), 8.39 (d, 1H), 7.70 (m, 3H), 7,50 (m, 6H), 7,38 (m,4H), 7.23 (m, 1H), 7.10 (d, IH), 6,85 (dd, IH), 6.63 (d,lH), 4,35 (v br s, IH), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3,36 (m, 4H), 3.27 (m, 5 2H), 1.90 (m, IH), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 9

4-(4-((4'-chloro-l,l'-bipheny 1-2-yl)methyl)piperazin-l-yl)-2-(3-(hydroxymethyl)phenoxy)-N-((4((3-morphol in-4 -y Ipropy l)amino)-3 -n itropheny l)su Ifony i )benzamide

EXAMPLE 9A methy 1 4-(4-( (4’-chlorobipheny 1-2-yl )methyl Jpiperazin-1 -y I )-2-(3 (hydroxymethyl )phenoxy)benzoate

This EXAMPLE was prepared by substituting 3-(hydroxymethyl)phenoI for EXAMPLE 15 ID in EXAMPLE IE.

EXAMPLE 9B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-y 1)-2-(3-(hydrDxymethyl)phenoxy)benzoic acid This EXAMPLE was prepared by substituting EXAMPLE 9A for EXAMPLE IE in

EXAMPLE IF.

EXAMPLE 9C

4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(3-(hydroxymethyl)phenoxy)-N-((4((3-morphol tn-4 -ylpropyl)amino)-3 -nitropheny l)su Ifony l)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 9B for EXAMPLE 1F and

EXAMPLE 4A for EXAMPLE 1G in EXAMPLE IH, except that the purification was performed by HPLC according to EXAMPLE 5C. ^lH NMR (300 MHz, DMSO-d₅) δ 11.63 (br s, 1H),9.6O (v br s, 2H), 8.70 (t, IH), 8.50 (d, IH), 7,80 (dd, IH), 7.67 (br s, IH), 7.50 (m, 5H), 7,40 (m,2H), 7.35 (br s, IH), 7,20 (m, 2H), 6.95 (d, IH), 6.75 (m, 3H), 6,40 (s, IH), 4,40 (s, 2H), 4.35-2.80 (m, 30 22 H), 1.98 (m,2H).

EXAMPLE 10

4-(4-((4'-ch loro-1,1 '-b ipheny 1 -2-y I )methy 1 )piperazin-1 -y 1)-2-(2-ch lorophenoxy )-N-((4-((3 morpholin-4-ylpropyl)amino)-3-nitropheny l)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE IF and

EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purification was performed

205 by HPLC according to EXAMPLE 5C, 'H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 9.62 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.71 (brs, 1H), 7.52 (m,5H), 7.40 (m, 3H), 7.33 (br s, 1H), 7,16 (m, 2H), 7.02 (m, 1H), 6.79(dd,lH), 6.70 (d, 1H), 6.40 (s, 1H), 4.35-2.80 (m, 22 H), 1.98 (m,2H).

EXAMPLE 11

4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(2-chlorophenoxy)-N-((4-((3(d imethy lam ino)propy l)am ino)-3 -nitropheny l)sulfony l)benzamide

EXAMPLE 11A

4-(3-(dimethylamino)propylamino)-3-nitrobenzenesulfonamide This EXAMPLE was prepared by substituting 3-(dimethylamino)-l-propylamine for 3(N-morpholinyl)-l-propylamine in EXAMPLE 4A.

EXAMPLE! IB

4-(4-((4 '-chloro-1,1 '-biphenyl-2-y l)methyl)piperazin-1 -y I )-2-(2-chIorophenoxy)-N-((4-((3(dimethylamino)propyl)amino)-3-n itropheny l)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H, except that the purification was performed by HPLC according to EXAMPLE 5C. ' H NMR (300 MHz, DMSO-d₆) 6 11.77 (br s, 1H), 9,38 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, !H),7.82(dd, 1H), 7.65 (brs, lH),7.52(m, 5H), 7.40 (m,3H), 7.33 (br s, 1H), 7.16(m, 2H), 7.02 (m, 1H), 6.79 (dd,lH),6.70 (d, 1H),6.4O (s, 1H), 4.35-2.80 (m, 12 H), 2.80 (s, 3H), 2.78 (s, 3H), ! .98 (m, 2H).

EXAMPLE 12

4-( 4-((4'-chloro-1, Γ-bipheny 1-2-y l)methyl)piperazin-l-yl )-2-(3 -chlorophenoxy )-N -((4-((3morphol in-4-y Ipropy l)amino)-3 -nitropheny l)sulfony l)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE IF and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purification was performed 30 by HPLC according to EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) 6 11,85 (br s, IH), 9.63 (vbrs, 2H), 8.66 (t, 1H), 8.43 (d, 1H), 7.78 (dd, 1H), 7.67 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.20 (dd, 1H), 7.14 (d, 1H), 6.95 (m, 1H), 6,80 (dd, 1H), 6.72 (m, IH), 6.70 (m, 1H), 6.53 (s, 1H), 4.35-2.80 (m, 22 Η), 1.98 (m, 2H).

206

EXAMPLE 13

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(4-chIorophenoxy)-N-((4-((3morpholin-4-yIpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE IF and

EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purification was performed by HPLC according to EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, IH), 9,63 (v br s, 2H), 8,70 (t, 1H), 8.50 (d, 1H), 7.80 (dd, IH), 7.69 (br s, JH), 7.50 (m, 5H), 7.38 (d, 2H), 7,33 (m, IH), 7.25 (m, 2H), 7.15 (d, IH), 6.79 (m, 3H), 6.50 (d, 1H), 4.35-2.80 (m, 22 H), 1.98 (m, 2H).

EXAMPLE 14 ( 4-(4-((4'-chloro-l,l'-biphenyl-2-yl)methyl)piperazin-l-y!)-2-(3-chloroplienoxy)-N-( (4-((3(d imethy lamino)propy 1 )am ino)-3 -n itropheny l)sulfony l)benzam ide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE IF and

EXAMPLE 1 IA for EXAMPLE 1G in EXAMPLE 1H, except that the purification was performed by HPLC according to EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) δ 11.85 (br s, 1H), 9.63 (v br s, 2H), 8.70 (t, 1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7,20 (dd, IH), 7.14 (d, 1H), 6.95 (m, 1H), 6,80 (dd, IH), 6.72 (m, 1H), 6.70 (m, 1H), 6.56 (s, 1H), 4.35-2.80 (m, 12 H), 2.52 (s, 3H), 2.50 (s, 3H), 2.00 (m, 2H).

EXAMPLE 15

4-(4-((4'-chl oro-1,1 '-biphenyl-2-yI)methyl)piperazin-l-yl)-2-(4-chlorophenoxy)-N-((4-((3(dimethy lam ino)propyl)amino)-3-n itropheny l)sulfonyl)benzam ide ( This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 1F and

EXAMPLE 1 IA for EXAMPLE 1G in EXAMPLE 1H. except that the purification was performed by HPLC according to EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.38 (v br s, 1H), 8.68 (t, IH), 8.50 (d, IH), 7.80 (dd, IH), 7.69 (br s, IH), 7.50 (m, 5H), 7.40 (d, 2H), 7.33 (m, IH), 7.25 (m, 2H), 7.15 (d, IH), 6.80 (m, 3H), 6.46 (s, IH), 4.35-2,80 (m, 12 H), 2.81 (s, 3H), 2,79 (s,3H), 1.98 (m, 2H).

EXAMPLE 16

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3(dimethy lam ino)propyl)amino)-3-n itropheny l)sulfony 1)-2-((1-methy 1-1H-indo 1-4yl)oxy)benzamide

207

EXAMPLE 16A

-(tri isopropyl silyl)- lH-indol-4-ol

4-Benzyloxy indole (1 g) was treated with 60% oily NaH (135 mg) and tri isopropylsilyl chloride (1 g) in THF, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman’s catalyst (0,19 g) and a hydrogen balloon.

EXAMPLE 16B methyl 2-(] H-indol-4-yloxy)-4-(4-((4'-chlorobipheny 1-2-ylJmethyIJpiperazin-l-yi)benzoate This EXAMPLE was prepared by substituting EXAMPLE 16A for EXAMPLE ID in

EXAMPLE 1E. The crude material from the ether formation was desilylated using tetrabutyl ammonium fluoride in THF/water 95/5 for 1 hour prior to purification,

EXAMPLE 16C methyl 4-(4-((4'-chlorobiphenyI-2-yI)methyl)piperazin-l-ylJ-2-(l-methy LlH-indol-415 yloxyjbenzoate

EXAMPLE 16B (148 mgj, 60% oily NaH (9 mgj and methy] iodide (57 mgj in THF (I mLJ were stirred at room temperature overnight. The mixture was chromatographed on silica gel with 20% ethyl acetate in hexanes.

EXAMPLE 16D

4-(4-((4'-chlorobipheny 1-2-y IjmethyIJpiperazin-l-y 1)-2-( I-methy I-lH-indol-4-yloxy)benzoic acid This EXAMPLE was prepared by substituting EXAMPLE 16C for EXAMPLE IE in

EXAMPLE IF.

(

EXAMPLE 16E

4-(4-((4 '-ch loro-1,1 '-bipheny 1-2-yl Jmethy 1 Jpiperazin-1 -ylJ-N-((4-((3(dimethylamino)propylJamino)-3-nitrophenylJsulfonylJ-2-((l-methyl-lH-indol-4y I Joxy Jbenzam ide

This EXAMPLE was prepared by substituting EXAMPLE 11A for EXAMPLE 1G and 30 EXAMPLE 16D for EXAMPLE IF in EXAMPLE 1H, except that the purification was performed by HPLC according to EXAMPLE 5C. 'H NMR (300 MHz, DMSO-d₆) δ 11.58 (br s, 1HJ, 9.42 (br s, 2HJ, 8.64 (t, 1HJ, 8.44 (d, 1HJ, 7.77 (dd, 1HJ, 7.66 (brs, IH), 7,50 (m, 5H), 7,37 (d, 2HJ, 7.30 (m, 1H), 7,25 (d, 1H), 7.19 (d, 1HJ, 7.06 (d, 1H), 7.00 (dd, 1HJ, 6.75 (dd, 1HJ, 6.40 (d, 1H), 6.38 (s, 1HJ, 6.23 (d, 1HJ, 4.35-2.80 (m, 12 HJ, 3.80 (s,3H),2.79 (s, 3HJ, 2.77 (s, 3H), 1.96 (m, 35 2HJ.

208

EXAMPLE 17

2-(3 -(acety lam ino)phenoxy)-4-(4-((4'-ch loro-1,1 '-bipheny l-2-yl)methy l)pi perazin-1 -yl)-N-((3 nitro-4-(( tetr ahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzam ide

EXAMPLE 17A methyl 2-(3-acetamidophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl)benzoate This EXAMPLE was prepared by substituting 3-acetamidophenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE I7B

2-(3 -acetam idophenoxy)-4-(4-((4'-ch lorobipheny 1-2 -y l)methy l)pi perazin-1 -y! Jbenzoic acid This EXAMPLE was prepared by substituting EXAMPLE 17A for EXAMPLE I E in EXAMPLE IF,

EXAMPLE 17C

2-(3-(acetylaminD)phenoxy)-4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3nitro-4-((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 17B for EXAMPLE IF in

EXAMPLE IH, ’H NMR (300 MHz, DMSO-d₆) δ 11.48 (s, 1 H), 9.89 (s, IH), 8.59 (m, IH),

8.50 (d, IH), 7.71 (dd, IH), 7.47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd,

IH), 6.50 (dd, IH), 6.39 (d, IH), 3.86 (dd, 2H), 3,37 (m, 2H), 3.30 (m, 6H), 3.16 (m, 4H), 2.35 (s, 4H), 2.00 (s, 3H), 1.89 (m, IH), 1.63 (dd, 2H), L27(m, 2H).

Λ EXAMPLE 18

2-(4-aminophenoxy )-4-(4-((4-chloro-1,1'-bi pheny 1-2-yl)methyl)piperazin-l-yl)-N-((3-n itro-4((tetrahydro-2H-pyran-4-yl methyl )am in o)pheny 1 )su Ifony l)benzamide

EXAMPLE 18A methyl 2-(4-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4'-ch lorobipheny 1-23 0 yl)methyl)piperazin-1 -yl)benzoate

This EXAMPLE was prepared by substituting N-tert-butoxycarbonyl-4-ammophenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 18B

2-(4-(tert-butoxy carbony lam ino)phenoxy )-4-(4-( (4'-ch lorobipheny 1-2-yl)methyl )piperazin-lyl)benzoic acid

209

This EXAMPLE was prepared by substituting EXAMPLE 18A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 18C tert-butyl 4-(5-(4-((4'-chlorobipheny 1-2-y I jmethyl Jpiperazin- 1-y 1)-2-(3-nitro-4-((tetrahydro-2Hpyran-4-yl)methylamino)phenylsu1fonylcarbanioyl)phenoxyjphenyIcarbamate

This EXAMPLE was prepared by substituting EXAMPLE 18B for EXAMPLE IF in

EXAMPLE IH.

EXAMPLE 18D

2-(4-aniinophenoxy)-4-(4-((4'-ch)oro-Ι,Γ-bipheny 1-2-yl)methyl)piperazin-]-yl)-N-((3-nitro-4((tetrahydro-2H-pyran-4-y Imethy Ijaminojphenyljsu Ifony Ijbenzamide

This EXAMPLE was prepared by substituting EXAMPLE 18C for EXAMPLE 1A in EXAMPLE IB. ^!H NMR (300 MHz, DMSO-d₆j δ ppm 11.41 (s, IH), 9.54 (s, 1H), 8.66 (t. IH), 15 8.59 (d, IH), 7.86 (dd, IH), 7.67 (m, IH), 7,51 (dd, 5Hj, 7.38 (d, 2H), 7.31 (m, IH), 7.25 (d, IH),

6.82 (m, 4H), 6.69 (dd, ]H), 6.24 (m, IH), 4.26 (s, 2H), 3.85 (dd, 2H), 3.35 (m, 4H), 3.26 (td, 4H), 3.04 (m, 4H), 2.81 (m, 2H), 1.91 (m, IH), 1.62 (dd, 2H), 1.26 (m, 2H).

EXAMPLE 19

0 2-(3 -aminophenoxy )-4-(4-((4'-chloro-1,1 '-bipheny 1 -2-y I jmethyl jpiperazin -1 -y l)-N-((3 -nitro-4((tetrahydro-2H-pyran-4-y Imethy l)am inojpheny I jsu Ifony] jbenzam ide

EXAMPLE 19A methyl 2-(3 -(tert- butoxy carbonylamino jphenoxy)-4-(4-((4'-chlorobipheny 1-225 yljmethy I jpiperazin-] -yljbenzoate

This EXAMPLE was prepared by substituting N-tert-butoxycarbonyl-3-aminophenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 19B

2-(3-(tert-butoxycarbonylaminojphenoxy )-4-(4-((4'-chlorobipheny 1-2-yljmethyl jpiperazin-1yljbenzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 19A for EXAMPLE 1E in EXAMPLE IF.

210

EXAMPLE 19C tert-butyl 3-(5-(4-((4'-chlorobipheny 1-2-yl)methyl)piperazin-1 -yl)-2-(3-nitro-4-((tetrahydro-2Hpyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)phenylcarbamate

This EXAMPLE was prepared by substituting EXAMPLE 19B for EXAMPLE IF tn 5 EXAMPLE 1H.

EXAMPLE 19D

2-(3 -aminophenoxy )-4-(4-( (4'-ch loro-1,1 '-bipheny 1-2-y l)methy I)piperazin-1 -y l)-N-((3 -n itro-4((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 19C for EXAMPLE 1A in

EXAMPLE IB. 'H NMR (300 MHz, DMSO-d₆) δ ppm 11.39 (s, 1H), 9.50 (s, 1H), 8.64 (ΐ, 1H), 8.54 (d, 1H), 7.75 (dd,2H),7.51 (d, 5H), 7.38 (m, 2H), 7.31 (m, lH),7.16(d, JH),6.92 (t, 1H), 6.73 (dd, 1H), 6.38 (d, lH),6.28(m, 1H), 6.09 (m, 1H),6.O2 (d, 1H), 5.24 (m, lH),4.36(m, 1H), 3.86 (dd,2H), 3.72 (m, 1H), 3.28 (m, 8H), 3.20 (m, 1H),3.O4 (m, 3H), 2.85 (m, 1H), L90 (m,

1 Η), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 20

4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -yl)-2-(3-methoxyphenoxy)-N-((3-nitro-4((tetrahydro-2H-pyran-4-ylmethyi)amino)phenyl)sulfonyl)benzamide

EXAMPLE 20A methyl 4-(4-((4'-chlorobiphenyL2-yl)methyl)piperazin- 1-y 1)-2-(3-methoxyphenoxy)benzoate This EXAMPLE was prepared by substituting 3-methoxyphenol for EXAMPLE 1D in EXAMPLE IE.

EXAMPLE 20B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl )-2-(3-methoxyphenoxy)benzoic acid This EXAMPLE was prepared by substituting EXAMPLE 20A for EXAMPLE 1E in EXAMPLE IF.

EXAMPLE 20C

4-(4-((4'-ch 1 oro-1,1 '-bi pheny 1 -2-y 1 )methy 1 )piperazin-1 -y 1 )-2-(3 -methoxy phenoxy )-N-((3 -n itro-4((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 20B for EXAMPLE IF in 35 EXAMPLE 1H. ^]H NMR (300 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 7,47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H),7.U (m, 2H), 6,76 (dd, 1H), 6.53 (ddd,

211

1H), 6.35 (m, 3H), 3.86 (m, 2H), 3.66 (s, 3H), 3.32 (m, 6H), 3.17 (m, 4H), 2.36 (m, 4H), 1.92 (m, 1H), 1.64 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 21

4-(4-(( 4'-chloro-1,1 ’-biphenyl-2-yl)methyl)piperazin-1 -yl)-2-(3-(dimethylamino)phenoxy)-N-((3nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyI)suIfonyl)benzamide

EXAMPLE 21A methyl 4-(4-( (4'-chloro bi phenyl-2 -y 1 )methy l)piperazin-1 -y I )-2-(3 10 (dimethylamino)phenoxy)benzoate

This EXAMPLE was prepared by substituting 3-(dimethylamino)phenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 21B

4-(4-((4'-chIorobiphenyl-2-yl)methyI)piperazin- 1-y 1)-2-(3 -(d imethyIamino)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 21A for EXAMPLE 1E in EXAMPLE IF.

EXAMPLE 21C

4-(4-((4’-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-l -yl)-2-(3-(dimethylamino)phenoxy)-N-((3nitro-4-((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony 1 )benzam ide

This EXAMPLE was prepared by substituting EXAMPLE 21B for EXAMPLE IF in EXAMPLE 1H. 'H NMR (300 MHz, DMSO-d₆) 8 ppm 11.36 (s, 1H), 8.63 (t, 1H), 8.51 (d, 1H), 7.79 (dd, 1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H), 7.15 (d, 1H), 7.04(1, 1H),6.72 (dd, 1H), 25 6.39 (dd, 1H), 6.33 (d, 1H), 6.24 (t, 1H), 6.10 (dd, 1H), 3.86 (dd, 2H), 3.32 (m, 6H), 3.13 (m, 4H),

2.83 (s, 6H), 2.34 (m, 4H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 22

4-(4-((4 '-chloro-1,1 '-bipheny 1-2-y l)methy l)piperazin-1 -y 1)-2-(3 -cyanophenoxy )-N-((3-n itro-430 ((tetrahydro-2H-pyran-4-y Imethy l)amino)phenyl)su Ifony l)benzamide

EXAMPLE 22A methyl 4-(4-((4’-ch lorob i phenyl-2-yl)methy 1 )pi perazin-1 -y 1)-2-(3 -cyanophenoxy)benzoate This EXAMPLE was prepared by substituting 3-cyanophenol for EXAMPLE 1D in

EXAMPLE IE.

212

EXAMPLE 22B

4-(4-( (4'-ch lorobipheny 1-2-yl)methyl)pi perazin-1-y 1)-2-(3-cyanophenoxy )benzoic acid

A mixture of EXAMPLE 22A (0.081 g) in pyridine (2 mL) in a 10 mL microwave vial equipped with a magnetic stir bar was treated with Lil (0.402 g), flushed with nitrogen and heated 5 in a CEM microwave reactor at 120°C for 30 minutes. The mixture was concentrated, acidified with IN HC1, extracted with ethyl acetate and dried (MgSO₄), filtered and concentrated. The concentrate was purified by column chromatography on silica gel, eluting with a gradient of 010% methanol in dichloromethane.

EXAMPLE 22C

4-(4-((4'-chloro-l,T-biphenyl-2-y I )methy I )p iperazin-1-y 1)-2-(3-cyanophenoxy)-N-((3-nitro-4((tetrahydro-2 H-pyran-4-y Imethy l)amino)phenyl)sulfonyl)benzam ide

This EXAMPLE was prepared by substituting EXAMPLE 22B for EXAMPLE IF in EXAMPLE IH. Ή NMR (300 MHz, DMSO-d₆) δ ppm 11.78 (s, IH), 8.62 (t, IH), 8.41 (d, IH), 15 7.72 (dd, IH), 7.48 (m, 6H), 7.34 (m, 4H), 7.25 (m, IH), 7.08 (m, 3H). 6.82 (dd, IH), 6.54 (d,

IH), 3.87 (dd, 2H), 3.33 (m, 6H), 3.22 (m, 4H), 2.38 (m, 4H), 1.93 (m. IH), 1.65 (dd, 2H), 1.29 (m, 2H).

EXAMPLE 23

4-(4-((4'-chloro-l ,r-bipheny]-2-yl)methyl)piperazin- l-yl)-2-((2-methyl-1,3-benzothiazol-6yI)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

EXAMPLE 23A methyl 4-(4-((4'-chlorobipheny 1-2-yl)methyl)piperazin-1-y 1)-2-(2-methylbenzo[d ]thiazo 1-625 yloxy)benzoate

This EXAMPLE was prepared by substituting 2-methylbenzothiazol-6-ol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 23 B

4-(4-( (4'-chlorobipheny 1-2-yl )methyl)piperazin-1-y 1)-2-(2-methy lbenzo[d]thiazo 1-6yloxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 23A for EXAMPLE IE in EXAMPLE IF.

213

EXAMPLE 23 C 4-(4-((4'-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-1 -yl)-2-((2-methyl-1,3-benzothiazol-6yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 23B for EXAMPLE JF in 5 EXAMPLE 1H. Ή NMR (300MHz, DMSO-d_t) δ 11.78 (s, 1H), 8.56 (t, 1H), 8.40 (d, 1H), 7,71 (d, 2H), 7.64 (dd, 1H),7.51 (m, 5H), 7.37 (d, 2H), 7.32 (m, 1H),7.28 (d, 1H), 6.98 (dd, 1H),6.79 (dd, 1H), 6.51 (m, ]H), 4.33 (br s, 1H), 3.87 (dd, 2H), 3.69 (br s, 2H), 3.28 (m, 4H), 3,04 (br s, 2H), 2.84 (br s, 1H), 2,74 (s, 3H), 2.49 (m, 4H), ] .90 (br s, 1H), 1,63 (dd, 2H), 1.28 (m, 3H).

EXAMPLE 24

4-(4-((4'-ch loro-1,1 '-biphenyl-2 -y I)methy 1 )piperazin-1 -yl)-2-((2-methy 1- ] ,3 -benzothiazol-5yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

EXAMPLE 24A methyl 4-(4-((4^,-chlorobipheny!-2-yl)methyl)piperazin-l-y 1)-2-(2-methylbenzo[d]thiazol-5yloxy)benzoate

This EXAMPLE was prepared by substituting 2-methylbenzothiazoI-5-ol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 24B

4-(4-((4'-chlorobiph eny l-2-yl)methyI)piperazin-]-y ))-2-(2-methy lbenzo[d]thiazol-5yloxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 24A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 24C

4-(4-((4'-chloro-Ι,Γ-bipheny 1-2-yl )methyl)pi perazin-l-yl)-2-((2-methy 1-1,3-benzothiazol-5y l)oxy)-N -((4-((3 -morpho 1 in-4-y lpropyl)amino)-3 -nitropheny l)su lfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 24B and EXAMPLE 4A for 30 EXAMPLE IF and EXAMPLE 1G respectively, in EXAMPLE 1 Η. 'H NMR (300MHz, DMSOd₆) δ 11.83 (s, 1H), 9.48 (br s, 1H), 8.64 (t, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.76 (dd, 1H), 7.50 (m, 5H), 7.37 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.04 (d, 1H), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s, iH), 4.35 (br s, 1H), 3.98 (m, 3H), 3.77 (br s, 2H), 3.60 (t, 4H), 3.49 (m, 2H), 3.15 (m, 4H), 3.04 (m, 4H), 2.75 (s, 3H), 2.56 (m, 2H), 1.94 (m, 2H).

214

EXAMPLE 25

4-(4-((4¹-chloro-1,1 '-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((4-((3(d imethy lamino)propyl)amino)-3-n itropheny I)sulfony 1)-2-((2-m ethyl-1,3-benzothiazol-5yl)oxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 24B and EXAMPLE 11A for

EXAMPLE IF and EXAMPLE IG respectively, in EXAMPLE IH. ^lH NMR (300MHz, DMSOd₆) δ 11,86(s, IH), 9.23 (brs, IH), 8.63 (t, IH), 8.46 (d, IH), 7.88 (d, IH), 7.77 (dd, 2H), 7.51 (m, 6H), 7.39 (m, 3H), 7.32 (br s, lH),7.19(m, IH), 7.04 (d, IH), 6.98 (dd, lH),6.79(dd, IH), 6.49 (br s, IH), 4.37 (br s, IH), 3.76 (br s, 2H), 3.49 (m, 4H), 3.11 (m, 4H), 2.79 (s, 3H), 2.77 (s, 10 3H), 2.76 (s, 3H), 1.94 (m, 2H).

EXAMPLE 26

4-(4-((4'-ch loro-l,l'-biphenyl-2-y I )methyl)piperazin-1-y 1)-2-(2-(3-(dimethy lam ino)-3oxopropyl )phenoxy)-N-((3 -n itro-4-((tetrahydro-2H-pyran-4- y Imethy 1 )am ino)pheny l)sul fony l)benzamide

EXAMPLE 26A

3-(2-hydroxypheny l)-N,N -d i methylpropanam ide

A solution of chroman-2-one (444 mg) in THF (1 mL) was treated with dimethyl amine 20 (7.5 mL) and stirred at room temperature for 5 hours. The solution was concentrated. The concentrate was filtered through a small pad of silica gel.

EXAMPLE 26B methyl 4-(4-((4'-chlorobipheny 1-2-yl)methyl)piperazin-l-yl )-2-(2-(3-(dimethy lamino)-325 oxopropyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 26A for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 26C

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1 -y I )-2-(2-(3-(dimethy lam &gt;no)-3oxopropyl)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 26B for EXAMPLE IE in

EXAMPLE IF.

215

EXAMPLE 26D 4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyl)piperazin-1-y 1)-2-(2-(3-(dimethy lamino)-3oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethy 1 )am ino)pheny l)sulfony 1 )benzam ide

This EXAMPLE was prepared by substituting EXAMPLE 26C for EXAMPLE IF in

EXAMPLE 1H. ^lH NMR (500 MHz, DMSO-d_fi) δ 11.74 (s, 1H), 8.65 (t, 1H), 8.44 (d, 1H), 7.73 (dd, 2H), 7.52 (m, 5H), 7.35 (d, 3H), 7.13 (dd, 2H), 6.96 (t, 1H), 6.87 (t, 1H), 6.75 (dd, 1H), 6.44 (d, 1H), 6.39 (d, 1H), 3.87 (dd, 2H), 3.67 (br, 8H), 3.34 (t, 2H), 3.28 (t, 2H), 3.00 (br, 2H), 2.9] (s, 3H), 2.79 (s, 3H), 2.74 (t, 2H), 2.55 (t, 2H), 1.91 (m, 1H), 1.64 (d, 2H), 1.29 (m, 2H).

EXAMPLE 27

4-(4-( (4'-ch loro-Ι.Γ-biphenyl-2-yl)methyl )piperazin-1-y 1)-2-(2-(2-(dimethy lam ino)-2oxoethy()phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide

EXAMPLE 27A

2-(2-hydroxypheny I )-N ,N-d imethy (acetamide

This EXAMPLE was prepared by substituting benzofuran-2(3H)-one for chroman-2-one in EXAMPLE 26A.

EXAMPLE 27B methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yI)-2-(2-(2-(dimethylamino)-2oxoethyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 27A for EXAMPLE ID in 25 EXAMPLE IE.

EXAMPLE 27C

4-(4-((4'-chlorobipheny l-2-y l)methy l)piperazin-1 -yl )-2-(2-(2-(d i methy lam i no)-2oxoethyl)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 27B for EXAMPLE IE tn

EXAMPLE IF.

EXAMPLE 27D

4-(4-((4'-chloro-1,1 '-bipheny 1-2-y l)methy l)piperazin-1 -y 1)-2-(2 -(2-(d imethy lamino)-235 oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethy()amino)phenyl)sulfonyl)benzamide

216

This EXAMPLE was prepared by substituting EXAMPLE 27C for EXAMPLE IF in EXAMPLE IH. 'H NMR (400 MHz, DMSO-d_sj δ 8.64 (ζ IH), 8.52 (d, IH), 7.82 (dd, IH), 7.70 (s, IH), 7.52 (dd, 5H), 7.37 (d,2H), 7.33 (s, lH),7.19(m, 2H), 7.14 (t, IH), 7.03 (t, IH), 6.70 (m, 2H), 6.23 (s, IH), 3.86 (dd, 2H), 3.64 (s, 2H), 3.40 (br, 12H), 3.25 (t, 2H), 2.92 (s, 3H), 2.72 (s, 5 3H), 1.91 (s, IH), 1.63 (d,2H), 1.28 (m,2H).

EXAMPLE 28

4-(4-((4'-chloro-1,1'-bipheny 1-2-yl jmethy ljpiperazin-1-y 1)-2-(2-(3(dimethylaminojpropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4- y Imethy Ijaminojpheny I jsulfony [jbenzamide

EXAMPLE 28A methyl 4-(4-((4'-chlorobiphenyI-2-yljmethyl)piperazin-l-ylj-2-(2-(3(dimethylaminojpropyljphenoxyjbenzoate

A solution of EXAMPLE 26B (211 mgj in THF (1.7 mL j at room temperature was treated with borane (689 μι) and stirred for 24 hours. The mixture was quenched with IN HC1 and heated at 50°C overnight. The solution was concentrated. The concentrate was purified by flash chromatography (0-5¾ 7N NH₃ in 10% methanol/dichloromethane j.

EXAMPLE 28B

4-(4-((4'-ch lorobi phenyl-2 -yl jmethy Ijpi perazin -1 -y 1)-2-(2-(3 (dimethy lammojpropy 1 jphenoxyjbenzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 28A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 28C

4-(4-((4'-ch loro-Ι,Γ-bipheny l-2-yl)methyl)piperazin-1-y 1)-2-(2-(3(dimethylamino)propyljphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y Imethy Ijaminojphenyl jsulfony I jbenzamide

This EXAMPLE was prepared by substituting EXAMPLE 28B for EXAMPLE IF in

EXAMPLE IH. Ή NMR (500 MHz, DMSO-d₆j 6 8.65 (t, 1 Hj, 8.44 (d, IH), 7.75 (dd, IH), 7.51 (m, 6H), 7.39 (d, 2H), 7.32 (s, IH), 7.16 (m, 2Hj, 6.98 (m, IHj, 6.90 (t, 1 Hj, 6.76 (d, 1 Hj, 6.48 (d, IHj, 6.37 (s, IH), 3.87 (d, 2Hj, 3.35 (m, 2Hj, 3.29 (m, 2H), 3.07 (s, 2H), 2.79 (s, 6H), 2.61 (t, 2H), 1.94 (s. 2H), 1.64 (d, 2H), 1.30 (m, 2H).

217

EXAMPLE 29

4-(4-((4L_chloro-l, i '-biphenyI-2-yl)methyl)piperazin-l-yl)-2-(2-(2(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide

EXAMPLE 29A methyl 4-(4-((4'-chlorobiphenyl-2-yl )methy I )pi perazin-1 -yI )-2 -(2 -(2(dimethylamino)ethyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 27B for EXAMPLE 26B in 10 EXAMPLE 28A.

EXAMPLE 29 B ⁴-0-((⁴'-^chlorobipheny 1-2-yl)methyl)piperazin-1-y 1)-2-(2-(2(dimethylamino)ethyl)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 29A for EXAMPLE IE in 15 EXAMPLE IF.

EXAMPLE 29C

4-(4-(( 4'-ch loro-Ι,Γ-bipheny l-2-yl)methy I )piperazin-1-y 1)-2-(2-(2(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 29B for EXAMPLE 1F in

EXAMPLE 1H. 'H NMR (400 MHz, DMSO-de) δ 8.64 (ζ 1H), 8.44 (d, 1H), 7.72 (m, 2H), 7.53 (m, 5H), 7.38 (d, 2H), 7.32 (m, lH),7.19(dd, 1H), 7.15 (d, 1H), 7.01 (td, 1H), 6.90 (t, 1H), 6.79 (dd, 1H), 6.49 (d, 1H), 6.42 (d, 1H), 3.88 (m, 2H), 3.60 (br, 10H), 3.35 (t, 2H), 3.29 (t, 4H), 2.97 (m, 2H), 2.81 (m, 6H), 1.92 (s, 1H), 1.65 (m, 2H), L30(m,2H).

EXAMPLE 30

2-(5-( 4-((4'-ch lorobipheny]-2-yl)methyI)piperazin-1-y 1)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)rnethylamino)phenylsu]fonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide

EXAMPLE 30A methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-y 1)-2-(2(d imethy Icarbamoy 1 )phenoxy )benzoate

This EXAMPLE was prepared by substituting 2-hydroxy-N,N-dimethyIbenzamide for

EXAMPLE ID in EXAMPLE IE.

218

EXAMPLE 30B

4-(4-((4'-chlorobiphenyI-2-yl)methyl)piperazin-l-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 30A for EXAMPLE 1E in

EXAMPLE IF,

EXAMPLE 30C

2-(5-( 4-((4'-chlorobipheny 1-2-yl)methyl)piperazin-1-y 1)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methy land no)phenylsu Ifony lcarbamoyl)phenoxy)-N,N-dimethylbenzamide i 0 This EXAMPLE was prepared by substituting EXAMPLE 3OB for EXAMPLE IF in

EXAMPLE IH. 'HNMR (400 MHz, DMSO-d₆) 8 8.63 (t, IH), 8.52 (d, IH), 7.83 (dd, IH), 7.71 (s, IH), 7.51 (m, 5H), 7.30 (m, 5H), 7.20 (d, IH), 7.13 (t, IH), 6.82 (d, IH), 6.74 (m, IH), 6.24 (d, IH), 4.30 (s, IH), 3.80 (br, 1 IH), 3.34 (t, 2H), 3.27 (t, 2H), 2.79 (s, 3H), 2.66 (s, 3H), 1.90(s, IH), 1.62 (d,2H), 1.27 (ddd, 2H).

EXAMPLE 31

4-(4-((4^,-chloro-LT-biphenyl-2-yl)methyl)piperazm-l-yl)-2-(2((dimethylandno)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4y lmethyl)am ino)pheny 1 )su Ifony 1 )benzami de

EXAMPLE 31A methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-l-yl)-2-(2((d imethy lam ino)methyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 30A for EXAMPLE 26B in 25 EXAMPLE 28A.

EXAMPLE 3IB 4-(4-((4'-chlorobiphenyl-2-yl)niethyl)piperazin-l-y 1)-2-(2((dimethylamino)methyl)phenoxy)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 31A for EXAMPLE 1E in

EXAMPLE IF.

219

EXAMPLE 31C

4-(4-((4-chloro-]₃r-biphenyl-2-yl)methyl)piperazin-l-yl)-2-(2((dimethylaminojmethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4ylmethyljaminojphenyljsulfonyl jbenzamide

This EXAMPLE was prepared by substituting EXAMPLE 3 IB for EXAMPLE IF in

EXAMPLE IH. 'H NMR (400 MHz, DMSO-d₆) δ 8.62 (m, IH), 8.38 (d. lH),7,70(dd, IH), 7.61 (d, IH), 7.51 (d, 4H), 7.39 (m, 4H), 7.33 (s, IH), 7.15 (m, 2H), 6.97 (ζ IH), 6.84 (d, IH), 6.61 (s, IH), 6,43 (d, IH), 4.33 (s, 2H), 3.88 (d, 2H), 3.55 (br, 10H), 3.35 (m₃ 2H), 3.29 (m, 2H), 2.78 (s, 6H), 1.92 (s, 1 Η), 1.64 (d, 2H), 1.31 (m, 2H).

EXAMPLE 32

4-(4-((4'-chloro-l,r-biphenyl-2-yl)methyI)piperazin-l-yl)-N-((4-((3(dimethy lam ino)propyl)amino)-3-nitropheny Ijsulfony 1)-2-(3-morpholin-4-ylphenoxy jbenzam ide

EXAMPLE 32A methyl 4-(4-( (4'-ch lorobipheny 1-2-yljmethy I jpiperazin-1-y 1)-2-(3-morpholinophenoxy jbenzoate This EXAMPLE was prepared by substituting 3-morpholinophenol for EXAMPLE ID in EXAMPLE IE.

EXAMPLE 32B

4-(4-((4'-ch lorobipheny 1-2-yl)methyl)piperazin-l-yIj-2-(3-morpholinophenoxy jbenzoic acid This EXAMPLE was prepared by substituting EXAMPLE 32A for EXAMPLE IE in EXAMPLE IF.

EXAMPLE 32C

4-(4-( (4'-chloro-l, l'-biphenyI-2-yl)methyl)piperazin-l -yl)-N-((4-((3(dimethy lamino jpropy 1 jam inoj-3 -n itropheny 1 jsu Ifony 1)-2 -(3 -morphoIin-4-yl phenoxy jbenzam ide This EXAMPLE was prepared by substituting EXAMPLE 32B for EXAMPLE IF and

EXAMPLE 11A for EXAMPLE 1G in EXAMPLE IH. 'H NMR (400MHz, DMSO-d₆j δ 11.61 30 (brs, IH), 9.50 (br s, IH), 8.69 (t, IH), 8.51 (d, IH), 7.83 (dd, lH),7.68(m, IH), 7.50 (m, 5H), 7.39 (m, 2Hj, 7.31 (m, IH), 7.15 (d, IH). 7.08 (m, IH), 6.75 (dd, IH), 6.59 (dd, IH), 6.40 (m, 2H), 6.23 (m, IH), 3.71 (m, 4H), 3.52 (m, 4Hj, 3.40 (m, 4H). 3.13 (m, 4H), 3.00 (m, 6H), 2,78 (s, 6H), 1.96 (m, 2H).

220

EXAMPLE 33

4.(4-((4'-chloro-l,Γ-biρhenyl-2-yl)methyl)pipeΓazin-l-yl)-2-(3-(2,4-dimethyl-L3-thiazol·5y l)phenoxy)-N-((4-((3 - morphoiin-4-y Ipropy 1 Jam ino)-3 -nitropheny 1 Jsu Ifony IJbenzam ide

EXAMPLE 33A methyl 2-(3-(benzyloxyJphenoxy)-4-(4-((4'-chlorobiphenyl-2-ylJmethylJpiperazin-l-yl)benzoate