This application claims priority to United States Provisional Application Serial No. 61/145611, filed January 19, 2009, which is incorporated by reference in its entirety.

HELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of Bcl-2 anti-apoptotic proteins, compositions containing the compounds, and methods of treating diseases during which anti-apoptotic Bcl-2 proteins are expressed.

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 therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula I

(I), wherein

A ¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene or A ^1A ; A ^1A is cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene; wherein A ¹ is unsubstituted or substituted with one or two or three or four or five independently selected R ¹ , OR ¹ , SR ¹ , S(O)R ¹ , SO ₂ R ¹ , C(O)R ¹ , C(O)OR ¹ , OC(O)R ¹ , NHR ¹ , N(R ¹ K C(N)C(O)R ¹ , C(O)NHR ¹ , C(O)N(R ¹ K C(O)NHOH, C(O)NHOR ¹ , C(O)NHSO ₂ R ¹ , NHC(O)R ¹ , NR ¹ C(O)R ¹ , NHC(O)OR ¹ , NR ¹ C(O)OR ¹ , NR ¹ C(O)NHR ¹ , NR ¹ C(O)N(R ¹ K NHC(O)NH ₂ , NHC(O)NHR ¹ , NHC(O)N(R ¹ K SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N(R ¹ K NHS(O)R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHSO ₂ NHR ¹ , N(CH ₃ )SO ₂ N(CH ₃ )R ¹ , (O), NH ₂ , NO ₂ , N ₃ , OH, F, Cl, Br, I, CN, CF ₃ , OCF ₃ , CF ₂ CF ₃ , OCF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹ , C(N)N(R ¹ )!, CNOH, CNOCH ₃ , C(O)NH ₂ or C(0)0R ^1A ; R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R ^1A is cycloalkyl, cycloalkenyl or cycloalkynyl;

R ² is phenyl, which is unfused or fused with benzene, heteroarene or R ^2A ; R ^2A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴ 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 ⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶ , NC(R ^6A )(R ^6B ), R ⁷ , OR ⁷ , SR ⁷ , S(O)R ⁷ , SO ₂ R ⁷ ,

- ? - NHR ⁷ , N(R ⁷ ) ₂ , C(O)R ⁷ , C(O)NH ₂ , C(O)NHR ⁷ , C(O)N(R ⁷ ) ₂ , NHC(O)R ⁷ , NR ⁷ C(O)R ⁷ , NHSO ₂ R ⁷ , NHC(O)OR ⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁷ , SO ₂ N(R ⁷ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ⁷ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NHR ¹ , OH, (0), C(O)OH, (0), N ₃ , CN, NH ₂ , CF ₃ , CF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁶ is C ₂ -C ₅ -spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N ₃ ,

CN, CF ₃ , CF ₂ CF ₃ , F, Cl, Br, I, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ ;

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-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH ₂ moiety unreplaced or replaced with O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ or NH;

R ⁷ is R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ ;

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

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

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

R ¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ¹² , OR ¹² , SR ¹² , S(O)R ¹² , SO ₂ R ¹² , C(O)R ¹² ,

C(O)OR ¹² , OC(O)R ¹² , OC(O)OR ¹² , NH ₂ , NHR ¹² , N(R ¹² ) ₂ , NHC(O)R ¹² , NR ¹² C(O)R ¹² , NHS(O) ₂ R ¹² , NR ¹² S(O) ₂ R ¹² , NHC(O)OR ¹² , NR ¹² C(O)OR ¹² , NHC(O)NH ₂ , NHC(O)NHR ¹² , NHC(O)N(R ¹² ) ₂ , NR ¹² C(O)NHR ¹² , NR ¹² C(O)N(R ¹² ) ₂ , C(O)NH ₂ , C(O)NHR ¹² , C(O)N(R ¹² ) ₂ , C(O)NHOH, C(O)NHOR ¹² , C(O)NHSO ₂ R ¹² , C(O)NR ¹² SO ₂ R ¹² , SO ₂ NH ₂ , SO ₂ NHR ¹² , SO ₂ N(R ¹² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹² , C(N)N(R ¹² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ¹² is R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ ;

R ¹³ is phenyl, which is unfused or fused with benzene, heteroarene or R ^13A ; R ^13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^14A ; R ^14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R ^15A ; R ^15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ¹⁶ is alkyl, alkenyl or alkynyl;

Z ¹ Is R ²⁶ Or R ²⁷ ;

Z ² is R ²⁸ , R ²⁹ or R ³⁰ ;

Z ^1A and Z ^2A are both absent or are taken together to form CH ₂ , CH ₂ CH ₂ or Z ^12A ; Z ^12A is C ₂ -C ₆ -alkylene having one or two CH ₂ moieties replaced by NH, N(CH ₃ ), S,

S(O) or SO ₂ ;

L ¹ is a R ³⁷ , OR ³⁷ , SR ³⁷ , S(O)R ³⁷ , SO ₂ R ³⁷ , C(O)R ³⁷ , C(O)OR ³⁷ , OC(O)R ³⁷ , OC(O)OR ³⁷ , NHR ³⁷ , C(O)NH, C(O)NR ³⁷ , C(O)NHOR ³⁷ , C(O)NHSO ₂ R ³⁷ , SO ₂ NH, SO ₂ NHR ³⁷ , C(N)NH, C(N)NHR ³⁷ ; R ² is phenylene which is unfused or fused with benzene or heteroarene or R ^{2 A} ; R ^{2 A} is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

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

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

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

R ³⁰ is cycloalkylene, 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; R ³⁷ 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 SO ₂ R ^37B , C(O)R ^37B , C(O)OR ^37B , OC(O)R ^37B , OC(O)OR ^37B , NH ₂ , NHR ^37B , N(R ^37B ) ₂ , NHC(O)R ^37B , NR ^37B C(O)R ^37B , NHS(O) ₂ R ^37B , NR ^37B S(O) ₂ R ^37B , NHC(O)OR ^37B ,

NR ^37B C(O)OR ^37B , NHC(O)NH ₂ , NHC(O)NHR ^37B , NHC(O)N(R ^37B ) ₂ , NR ^37B C(O)NHR ^37B , NR ^37B C(O)N(R ^37B ) ₂ , C(O)NH ₂ , C(O)NHR ^37B , C(O)N(R ^37B ) ₂ , C(O)NHOH, C(O)NHOR ^37B , C(O)NHSO ₂ R ^37B , C(O)NR ^37B SO ₂ R ^37B , SO ₂ NH ₂ , SO ₂ NHR ^37B , SO ₂ N(R ^37B ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ^37B , C(N)N(R ^37B ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

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

Z ³ is R ³⁸ , R ³⁹ or R ⁴⁰ ; R ³⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R ^38A ; R ^38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^39A ; R ^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁰ 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 R ² and R ²⁷ are unsubstituted or substituted, (i.e., if Z ^1A and Z ^2A are absent) or further unsubstituted or further substituted (i.e., if Z ^1A and Z ^2A are present) with one or more R ⁴¹ , OR ⁴¹ , SR ⁴¹ , S(O)R ⁴¹ , SO ₂ R ⁴¹ , C(O)R ⁴¹ , C(O)OR ⁴¹ ,

OC(O)R ⁴¹ , OC(O)OR ⁴¹ , NH ₂ , NHR ⁴¹ , N(R ⁴¹ ) ₂ , NHC(O)R ⁴¹ , NR ⁴¹ C(O)R ⁴¹ , NHS(O) ₂ R ⁴¹ , NR ⁴¹ S(O) ₂ R ⁴¹ , NHC(O)OR ⁴¹ , NR ⁴¹ C(O)OR ⁴¹ , NHC(O)NH ₂ , NHC(O)NHR ⁴¹ , NHC(O)N(R ⁴¹ ) ₂ , NR ⁴¹ C(O)NHR ⁴¹ , NR ⁴¹ C(O)N(R ⁴¹ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴¹ , C(O)N(R ⁴¹ ) ₂ , C(O)NHOH, C(O)NHOR ⁴¹ , C(O)NHSO ₂ R ⁴¹ , C(O)NR ⁴¹ SO ₂ R ⁴¹ , SO ₂ NH ₂ , SO ₂ NHR ⁴¹ , SO ₂ N(R ⁴¹ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴¹ , C(N)N(R ⁴¹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴¹ is R ⁴² , R ⁴³ , R ⁴⁴ or R ⁴⁵ ;

R ⁴² is phenyl, which is unfused or fused with benzene, heteroarene or R ^42A ; R ^42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^43A ; R ^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴⁴ 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; R ⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R ⁴⁶ , OR ⁴⁶ , SR ⁴⁶ , S(O)R ⁴⁶ , SO ₂ R ⁴⁶ , C(O)R ⁴⁶ , C(O)OR ⁴⁶ , OC(O)R ⁴⁶ , OC(O)OR ⁴⁶ , NH ₂ , NHR ⁴⁶ , N(R ⁴⁶ ) ₂ , NHC(O)R ⁴⁶ , NR ⁴⁶ C(O)R ⁴⁶ , NHS(O) ₂ R ⁴⁶ , NR ⁴⁶ S(O) ₂ R ⁴⁶ , NHC(O)OR ⁴⁶ , NR ⁴⁶ C(O)OR ⁴⁶ , NHC(O)NH ₂ , NHC(O)NHR ⁴⁶ , NHC(O)N(R ⁴⁶ ) ₂ , NR ⁴⁶ C(O)NHR ⁴⁶ , NR ⁴⁶ C(O)N(R ⁴⁶ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴⁶ , C(O)N(R ⁴⁶ ) ₂ , C(O)NHOH, C(O)NHOR ⁴⁶ , C(O)NHSO ₂ R ⁴⁶ , C(O)NR ⁴⁶ SO ₂ R ⁴⁶ , SO ₂ NH ₂ , SO ₂ NHR ⁴⁶ ,

SO ₂ N(R ⁴⁶ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴⁶ , C(N)N(R ⁴⁶ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴⁶ is alkyl, alkenyl, alkynyl, R ⁴⁷ , R ⁴⁸ or R ⁴⁹ ; R ⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R ^47A ; R ^47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^48A ; R ^48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^49A ; R ^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the moieties represented by R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ , R ⁴⁸ , and R ⁴⁹ are independently unsubstituted or substituted with one or more independently selected R ⁵⁰ , OR ⁵⁰ , SR ⁵⁰ , S(O)R ⁵⁰ , SO ₂ R ⁵⁰ , C(O)R ⁵⁰ , C(O)OR ⁵⁰ , OC(O)R ⁵⁰ , OC(O)OR ⁵⁰ , NH ₂ , NHR ⁵⁰ , N(R ⁵⁰ ) ₂ , NHC(O)R ⁵⁰ , NR ⁵⁰ C(O)R ⁵⁰ , NHS(O) ₂ R ⁵⁰ , NR ⁵⁰ S(O) ₂ R ⁵⁰ , NHC(O)OR ⁵⁰ , NR ⁵⁰ C(O)OR ⁵⁰ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁰ , NHC(O)N(R ⁵⁰ ) ₂ , NR ⁵⁰ C(O)NHR ⁵⁰ , NR ⁵⁰ C(O)N(R ⁵⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁰ , C(O)N(R ⁵⁰ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁰ , C(O)NHSO ₂ R ⁵⁰ , C(O)NR ⁵⁰ SO ₂ R ⁵⁰ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁰ , SO ₂ N(R ⁵⁰ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁰ , C(N)N(R ⁵ V CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁰ is R ⁵¹ , R ⁵² , R ⁵³ or R ⁵⁴ ;

R ⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene or R ^51A ; R ^51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁵² is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^52A ; R ^52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁵³ 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; R ⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁵⁵ , OR ⁵⁵ , SR ⁵⁵ , S(O)R ⁵⁵ , SO ₂ R ⁵⁵ , C(O)R ⁵⁵ , C(O)OR ⁵⁵ , OC(O)R ⁵⁵ , OC(O)OR ⁵⁵ , NH ₂ , NHR ⁵⁵ , N(R ⁵⁵ ) ₂ , NHC(O)R ⁵⁵ , NR ⁵⁵ C(O)R ⁵⁵ , NHS(O) ₂ R ⁵⁵ , NR ⁵⁵ S(O) ₂ R ⁵⁵ , NHC(O)OR ⁵⁵ , NR ⁵⁵ C(O)OR ⁵⁵ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁵ , NHC(O)N(R ⁵⁵ ) ₂ , NR ⁵⁵ C(O)NHR ⁵⁵ , NR ⁵⁵ C(O)N(R ⁵⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁵ , C(O)N(R ⁵⁵ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁵ , C(O)NHSO ₂ R ⁵⁵ , C(O)NR ⁵⁵ SO ₂ R ⁵⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁵ ,

SO ₂ N(R ⁵⁵ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁵ , C(N)N(R ⁵⁵ ) ₂ , CNOH, CNOCH ₃ , OH,

(O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

RR ⁵⁵⁵⁵ iiss aallkkyyll,, aallkkeennyyll,, aallkkyynnyyll,, pphheenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or more independently selected R ⁵⁷ , OR ⁵⁷ , SR ⁵⁷ , S(O)R ⁵⁷ , SO ₂ R ⁵⁷ , C(O)R ⁵⁷ , C(O)OR ⁵⁷ , OC(O)R ⁵⁷ , OC(O)OR ⁵⁷ , NH ₂ , NHR ⁵⁷ , N(R ⁵⁷ ) ₂ , NHC(O)R ⁵⁷ , NR ⁵⁷ C(O)R ⁵⁷ , NHS(O) ₂ R ⁵⁷ , NR ⁵⁷ S(O) ₂ R ⁵⁷ , NHC(O)OR ⁵⁷ , NR ⁵⁷ C(O)OR ⁵⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁷ , NHC(O)N(R ⁵⁷ ) ₂ , NR ⁵⁷ C(O)NHR ⁵⁷ , NR ⁵⁷ C(O)N(R ⁵⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁷ , C(O)N(R ⁵⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁷ , C(O)NHSO ₂ R ⁵⁷ , C(O)NR ⁵⁷ SO ₂ R ⁵⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁷ , SO ₂ N(R ⁵⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁷ , C(N)N(R ⁵⁷ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁵⁷ is R ⁵⁸ , R ⁵⁹ , R ⁶⁰ or R ⁶¹ ;

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

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

R ⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶² , OR ⁶² , SR ⁶² , S(O)R ⁶² , SO ₂ R ⁶² , C(O)R ⁶² , C(O)OR ⁶² , OC(O)R ⁶² , OC(O)OR ⁶² , NH ₂ , NHR ⁶² , N(R ⁶² ) ₂ , NHC(O)R ⁶² , NR ⁶² C(O)R ⁶² ,

NHS(O) ₂ R ⁶² , NR ⁶² S(O) ₂ R ⁶² , NHC(O)OR ⁶² , NR ⁶² C(O)OR ⁶² , NHC(O)NH ₂ , NHC(O)NHR ⁶² , NHC(O)N(R ⁶² ) ₂ , NR ⁶² C(O)NHR ⁶² , NR ⁶² C(O)N(R ⁶² ) ₂ , C(O)NH ₂ , C(O)NHR ⁶² , C(O)N(R ⁶² ) ₂ , C(O)NHOH, C(O)NHOR ⁶² , C(O)NHSO ₂ R ⁶² , C(O)NR ⁶² SO ₂ R ⁶² , SO ₂ NH ₂ , SO ₂ NHR ⁶² , SO ₂ N(R ⁶² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶² , C(N)N(R ⁶² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶² is R ⁶³ , R ⁶⁴ , R ⁶⁵ or R ⁶⁶ ;

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

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

R ⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^A ; R ^A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁶⁶ is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶⁷ , OR ⁶⁷ , SR ⁶⁷ , S(O)R ⁶⁷ , SO ₂ R ⁶⁷ , C(O)R ⁶⁷ , C(O)OR ⁶⁷ , OC(O)R ⁶⁷ , OC(O)OR ⁶⁷ , NH ₂ , NHR ⁶⁷ , N(R ⁶⁷ ) ₂ , NHC(O)R ⁶⁷ , NR ⁶⁷ C(O)R ⁶⁷ , NHS(O) ₂ R ⁶⁷ , NR ⁶⁷ S(O) ₂ R ⁶⁷ , NHC(O)OR ⁶⁷ , NR ⁶⁷ C(O)OR ⁶⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁷ , NHC(O)N(R ⁶⁷ ) ₂ , NR ⁶⁷ C(O)NHR ⁶⁷ , NR ⁶⁷ C(O)N(R ⁶⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁷ , C(O)N(R ⁶⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁷ , C(O)NHSO ₂ R ⁶⁷ , C(O)NR ⁶⁷ SO ₂ R ⁶⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁷ , SO ₂ N(R ⁶⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁷ , C(N)N(R ⁶⁷ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein the moieties represented by R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶³ , R ⁶⁴ , R ⁶⁵ , and R ⁶⁷ are unsubstituted or substituted with one or more independently selected R ⁶⁸ , OR ⁶⁸ , SR ⁶⁸ , S(O)R ⁶⁸ , SO ₂ R ⁶⁸ , C(O)R ⁶⁸ , C(O)OR ⁶⁸ , OC(O)R ⁶⁸ , OC(O)OR ⁶⁸ , NH ₂ , NHR ⁶⁸ , N(R ⁶⁸ ) ₂ , NHC(O)R ⁶⁸ , NR ⁶⁸ C(O)R ⁶⁸ , NHS(O) ₂ R ⁶⁸ , NR ⁶⁸ S(O) ₂ R ⁶⁸ , NHC(O)OR ⁶⁸ , NR ⁶⁸ C(O)OR ⁶⁸ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁸ , NHC(O)N(R ⁶⁸ ) ₂ , NR ⁶⁸ C(O)NHR ⁶⁸ , NR ⁶⁸ C(O)N(R ⁶⁸ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁸ , C(O)N(R ⁶⁸ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁸ , C(O)NHSO ₂ R ⁶⁸ , C(O)NR ⁶⁸ SO ₂ R ⁶⁸ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁸ , SO ₂ N(R ⁶⁸ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁸ , C(N)N(R ⁶⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁶⁸ is R ⁶⁹ , R ⁷⁰ , R ⁷¹ or R ⁷² ;

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

R ⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^70A ; R ^70A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^71A ; R ^71A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁷³ , OR ⁷³ , SR ⁷³ , S(O)R ⁷³ , SO ₂ R ⁷³ , C(O)R ⁷³ , C(O)OR ⁷³ , OC(O)R ⁷³ , OC(O)OR ⁷³ , NH ₂ , NHR ⁷³ , N(R ⁷³ ) ₂ , NHC(O)R ⁷³ , NR ⁷³ C(O)R ⁷³ ,

NHS(O) ₂ R ⁷³ , NR ⁷³ S(O) ₂ R ⁷³ , NHC(O)OR ⁷³ , NR ⁷³ C(O)OR ⁷³ , NHC(O)NH ₂ , NHC(O)NHR ⁷³ , NHC(O)N(R ⁷³ ) ₂ , NR ⁷³ C(O)NHR ⁷³ , NR ⁷³ C(O)N(R ⁷³ ) ₂ , C(O)NH ₂ , C(O)NHR ⁷³ , C(O)N(R ⁷³ ) ₂ , C(O)NHOH, C(O)NHOR ⁷³ , C(O)NHSO ₂ R ⁷³ , C(O)NR ⁷³ SO ₂ R ⁷³ , SO ₂ NH ₂ , SO ₂ NHR ⁷³ , SO ₂ N(R ⁷³ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁷³ , C(N)N(R ⁷³ ) ₂ , CNOH, CNOCH ₃ , OH, (0), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and the moieties represented by R ⁶⁹ , R ⁷⁰ , and R ⁷¹ are unsubstituted or substituted with one or more independently selected NH ₂ , C(O)NH ₂ , C(O)NHOH, SO ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents.

In another embodiment of Formula (I), A ¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene or A ^1A ; A ^1A is heterocycloalkene; wherein A ¹ is unsubstituted or substituted with one or two or three or four or five independently selected R ¹ , OR ¹ , C(O)OR ¹ , NHR ¹ , N(R ^! ) ₂ , C(N)C(O)R ¹ , C(O)NHR ¹ , NHC(O)R ¹ , NR ¹ C(O)R ¹ , (O), NO ₂ , F, Cl, Br, I, CF ₃ ;

R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R is phenyl;

R ³ is heteroaryl;

R ⁴ is heterocycloalkyl; R ⁵ is alkyl, or alkenyl, each of which is unsubstituted or substituted R ⁷ , SR ⁷ , N(R ⁷ ) ₂ ,

NHC(O)R ⁷ , F, Cl, Br or I substituents;

R ⁷ is R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ ;

R ⁸ is phenyl;

R ⁹ is heteroaryl; R ¹⁰ is heterocycloalkyl;

R ¹¹ is alkyl;

Z ¹ Is R ²⁶ ;

Z ² is R ³⁰ ;

L ¹ is a R ³⁷ ; R ² is phenylene;

R ³⁰ is heterocycloalkylene;

R ³⁷ is R ^37A ;

R ^37A is alkylene, or alkenylene, each of which is unsubstituted or substituted with

R 37B R ^37B is phenyl;

Z ³ is R ³⁸ , or R ⁴⁰ ;

R ³⁸ is phenyl;

R ⁴⁰ is cycloalkyl, or cycloalkenyl; wherein the moieties represented by R ²⁶ and R ²⁷ are unsubstituted or substituted with

OR 41

R ⁴¹ is R ⁴² , or R ⁴³ ;

R ⁴² is phenyl, which is unfused or fused with heteroarene; R ⁴³ is heteroaryl, which is unfused or fused with heteroarene; wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or more independently selected R ⁵⁷ , OR ⁵⁷ , C(O)OR ⁵⁷ , F, Cl, Br or I substituents; R ⁵⁷ is R ⁵⁸ , or R ⁶¹ ; R ⁵⁸ is phenyl; R ⁶¹ is alkyl; and wherein the moieties represented by R ⁵⁸ , are unsubstituted or substituted with one or more independently selected F, Cl, Br or I substituents.

Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula II

(H) wherein

A ¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene or A ^1A ; A ^1A is cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene; wherein A ¹ is unsubstituted or substituted with one or two or three or four or five independently selected R ¹ , OR ¹ , SR ¹ , S(O)R ¹ , SO ₂ R ¹ , C(O)R ¹ , C(O)OR ¹ , OC(O)R ¹ , NHR ¹ , N(R ¹ K C(N)C(O)R ¹ , C(O)NHR ¹ , C(O)N(R ¹ K C(O)NHOH, C(O)NHOR ¹ , C(O)NHSO ₂ R ¹ , NHC(O)R ¹ , NR ¹ C(O)R ¹ , NHC(O)OR ¹ , NR ¹ C(O)OR ¹ , NR ¹ C(O)NHR ¹ , NR ¹ C(O)N(R ¹ K NHC(O)NH ₂ , NHC(O)NHR ¹ , NHC(O)N(R ¹ K SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N(R ¹ K NHS(O)R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHSO ₂ NHR ¹ , N(CH ₃ )SO ₂ N(CH ₃ )R ¹ , (O), NH ₂ , NO ₂ , N ₃ , OH, F, Cl, Br, I, CN, CF ₃ , OCF ₃ , CF ₂ CF ₃ , OCF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹ , C(N)N(R ¹ K CNOH, CNOCH ₃ , C(O)NH ₂ or C(0)0R ^1A ;

R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R ^1A is cycloalkyl, cycloalkenyl or cycloalkynyl;

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

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

R ⁴ 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 independently selected R ⁶ , NC(R ^6A )(R ^6B ), R ⁷ , OR ⁷ , SR ⁷ , S(O)R ⁷ , SO ₂ R ⁷ , NHR ⁷ , N(R ⁷ K C(O)R ⁷ , C(O)NH ₂ , C(O)NHR ⁷ , C(O)N(R ⁷ K NHC(O)R ⁷ , NR ⁷ C(O)R ⁷ , NHSO ₂ R ⁷ , NHC(O)OR ⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁷ , SO ₂ N(R ⁷ K NHC(O)NH ₂ , NHC(O)NHR ⁷ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NHR ¹ , OH, (O), C(O)OH, (O), N ₃ , CN, NH ₂ , CF ₃ , CF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶ is C ₂ -C ₅ -spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N ₃ , CN, CF ₃ , CF ₂ CF ₃ , F, Cl, Br, I, NH ₂ , NH(CH ₃ ) or N(CH ₃ K

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-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH ₂ moiety unreplaced or replaced with O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ or NH;

R ⁷ is R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ ; R ⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R ^8A ; R ^8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^9A ; R ^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R ^10A ; R ^10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ¹² , OR ¹² , SR ¹² , S(O)R ¹² , SO ₂ R ¹² , C(O)R ¹² , C(O)OR ¹² , OC(O)R ¹² , OC(O)OR ¹² , NH ₂ , NHR ¹² , N(R ¹² ) ₂ , NHC(O)R ¹² , NR ¹² C(O)R ¹² ,

NHS(O) ₂ R ¹² , NR ¹² S(O) ₂ R ¹² , NHC(O)OR ¹² , NR ¹² C(O)OR ¹² , NHC(O)NH ₂ , NHC(O)NHR ¹² , NHC(O)N(R ¹² ) ₂ , NR ¹² C(O)NHR ¹² , NR ¹² C(O)N(R ¹² ) ₂ , C(O)NH ₂ , C(O)NHR ¹² , C(O)N(R ¹² ) ₂ , C(O)NHOH, C(O)NHOR ¹² , C(O)NHSO ₂ R ¹² , C(O)NR ¹² SO ₂ R ¹² , SO ₂ NH ₂ , SO ₂ NHR ¹² , SO ₂ N(R ¹² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹² , C(N)N(R ¹² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ¹² is R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ ;

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

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

R ¹ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R ^15A ; R ^15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹⁶ is alkyl, alkenyl or alkynyl; wherein the moiety represented by R ¹⁰¹ is H, R ⁴¹ , OR ⁴¹ , SR ⁴¹ , S(O)R ⁴¹ , SO ₂ R ⁴¹ ,

C(O)R ⁴¹ , C(O)OR ⁴¹ , OC(O)R ⁴¹ , OC(O)OR ⁴¹ , NH ₂ , NHR ⁴¹ , N(R ⁴¹ ) ₂ , NHC(O)R ⁴¹ , NR ⁴¹ C(O)R ⁴¹ , NHS(O) ₂ R ⁴¹ , NR ⁴¹ S(O) ₂ R ⁴¹ , NHC(O)OR ⁴¹ , NR ⁴¹ C(O)OR ⁴¹ , NHC(O)NH ₂ , NHC(O)NHR ⁴¹ , NHC(O)N(R ⁴¹ ) ₂ , NR ⁴¹ C(O)NHR ⁴¹ , NR ⁴¹ C(O)N(R ⁴¹ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴¹ , C(O)N(R ⁴¹ ) ₂ , C(O)NHOH, C(O)NHOR ⁴¹ , C(O)NHSO ₂ R ⁴¹ , C(O)NR ⁴¹ SO ₂ R ⁴¹ , SO ₂ NH ₂ , SO ₂ NHR ⁴¹ , SO ₂ N(R ⁴¹ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴¹ , C(N)N(R ⁴¹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴¹ is R ⁴² , R ⁴³ , R ⁴⁴ or R ⁴⁵ ; R ⁴² is phenyl, which is unfused or fused with benzene, heteroarene or R ^42A ; R ^42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴³ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^43A ; R ^43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^UA ; R ^44A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R ⁴⁶ , OR ⁴⁶ , SR ⁴⁶ , S(O)R ⁴⁶ , SO ₂ R ⁴⁶ , C(O)R ⁴⁶ , C(O)OR ⁴⁶ , OC(O)R ⁴⁶ , OC(O)OR ⁴⁶ , NH ₂ , NHR ⁴⁶ , N(R ⁴⁶ ) ₂ , NHC(O)R ⁴⁶ , NR ⁴⁶ C(O)R ⁴⁶ , NHS(O) ₂ R ⁴⁶ , NR ⁴⁶ S(O) ₂ R ⁴⁶ , NHC(O)OR ⁴⁶ , NR ⁴⁶ C(O)OR ⁴⁶ , NHC(O)NH ₂ , NHC(O)NHR ⁴⁶ , NHC(O)N(R ⁴⁶ ) ₂ , NR ⁴⁶ C(O)NHR ⁴⁶ , NR ⁴⁶ C(O)N(R ⁴⁶ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴⁶ , C(O)N(R ⁴⁶ ) ₂ , C(O)NHOH, C(O)NHOR ⁴⁶ , C(O)NHSO ₂ R ⁴⁶ , C(O)NR ⁴⁶ SO ₂ R ⁴⁶ , SO ₂ NH ₂ , SO ₂ NHR ⁴⁶ , SO ₂ N(R ⁴⁶ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴⁶ , C(N)N(R ⁴⁶ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴⁶ is alkyl, alkenyl, alkynyl, R ⁴⁷ , R ⁴⁸ or R ⁴⁹ ;

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

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

R ⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^49A ; R ^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the moieties represented by R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ , R ⁴⁸ , and R ⁴⁹ are independently unsubstituted or substituted with one or more independently selected R ⁵⁰ , OR ⁵⁰ , SR ⁵⁰ , S(O)R ⁵⁰ , SO ₂ R ⁵⁰ , C(O)R ⁵⁰ , C(O)OR ⁵⁰ , OC(O)R ⁵⁰ , OC(O)OR ⁵⁰ , NH ₂ , NHR ⁵⁰ , N(R ⁵⁰ ) ₂ , NHC(O)R ⁵⁰ , NR ⁵⁰ C(O)R ⁵⁰ , NHS(O) ₂ R ⁵⁰ , NR ⁵⁰ S(O) ₂ R ⁵⁰ , NHC(O)OR ⁵⁰ , NR ⁵⁰ C(O)OR ⁵⁰ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁰ , NHC(O)N(R ⁵⁰ ) ₂ , NR ⁵⁰ C(O)NHR ⁵⁰ , NR ⁵⁰ C(O)N(R ⁵⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁰ , C(O)N(R ⁵⁰ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁰ , C(O)NHSO ₂ R ⁵⁰ , C(O)NR ⁵⁰ SO ₂ R ⁵⁰ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁰ , SO ₂ N(R ⁵⁰ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ ,

C(N)NHR ⁵⁰ , C(N)N(R ⁵⁰ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁰ is R ⁵¹ , R ⁵² , R ⁵³ or R ⁵⁴ ; R ⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene or R ^51A ; R ^51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁵² is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^52A ; R ^52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁵⁵ , OR ⁵⁵ , SR ⁵⁵ , S(O)R ⁵⁵ , SO ₂ R ⁵⁵ , C(O)R ⁵⁵ , C(O)OR ⁵⁵ , OC(O)R ⁵⁵ , OC(O)OR ⁵⁵ , NH ₂ , NHR ⁵⁵ , N(R ⁵⁵ ) ₂ , NHC(O)R ⁵⁵ , NR ⁵⁵ C(O)R ⁵⁵ ,

NHS(O) ₂ R ⁵⁵ , NR ⁵⁵ S(O) ₂ R ⁵⁵ , NHC(O)OR ⁵⁵ , NR ⁵⁵ C(O)OR ⁵⁵ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁵ , NHC(O)N(R ⁵⁵ ) ₂ , NR ⁵⁵ C(O)NHR ⁵⁵ , NR ⁵⁵ C(O)N(R ⁵⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁵ , C(O)N(R ⁵⁵ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁵ , C(O)NHSO ₂ R ⁵⁵ , C(O)NR ⁵⁵ SO ₂ R ⁵⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁵ , SO ₂ N(R ⁵⁵ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁵ , C(N)N(R ⁵⁵ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or more independently selected R ⁷ , OR ⁵⁷ , SR ⁵⁷ , S(O)R ⁵⁷ , SO ₂ R ⁵⁷ , C(O)R ⁵⁷ , C(O)OR ⁵⁷ , OC(O)R ⁵⁷ , OC(O)OR ⁵⁷ , NH ₂ , NHR ⁵⁷ , N(R ⁵⁷ ) ₂ , NHC(O)R ⁵⁷ , NR ⁵⁷ C(O)R ⁵⁷ , NHS(O) ₂ R ⁵⁷ , NR ⁵⁷ S(O) ₂ R ⁵⁷ , NHC(O)OR ⁵⁷ , NR ⁵⁷ C(O)OR ⁵⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁷ , NHC(O)N(R ⁵⁷ ) ₂ , NR ⁵⁷ C(O)NHR ⁵⁷ , NR ⁵⁷ C(O)N(R ⁵⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁷ , C(O)N(R ⁵⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁷ , C(O)NHSO ₂ R ⁵⁷ , C(O)NR ⁵⁷ SO ₂ R ⁵⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁷ , SO ₂ N(R ⁵⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁷ , C(N)N(R ⁵⁷ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁷ is R ⁵⁸ , R ⁵⁹ , R ⁶⁰ or R ⁶¹ ;

R ⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R ^58A ; R ^58A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^9A ; R ^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ° 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; R ⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶² , OR ⁶² , SR ⁶² , S(O)R ⁶² , SO ₂ R ⁶² , C(O)R ⁶² , C(O)OR ⁶² , OC(O)R ⁶² , OC(O)OR ⁶² , NH ₂ , NHR ⁶² , N(R ⁶² ) ₂ , NHC(O)R ⁶² , NR ⁶² C(O)R ⁶² , NHS(O) ₂ R ⁶² , NR ⁶² S(O) ₂ R ⁶² , NHC(O)OR ⁶² , NR ⁶² C(O)OR ⁶² , NHC(O)NH ₂ , NHC(O)NHR ⁶² , NHC(O)N(R ⁶² ) ₂ , NR ⁶² C(O)NHR ⁶² , NR ⁶² C(O)N(R ⁶² ) ₂ , C(O)NH ₂ , C(O)NHR ⁶² , C(O)N(R ⁶² ) ₂ , C(O)NHOH, C(O)NHOR ⁶² , C(O)NHSO ₂ R ⁶² , C(O)NR ⁶² SO ₂ R ⁶² , SO ₂ NH ₂ , SO ₂ NHR ⁶² , SO ₂ N(R ⁶² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶² , C(N)N(R ⁶² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶² is R ⁶³ , R ⁶⁴ , R ⁶⁵ or R ⁶⁶ ; R ³ is phenyl, which is unfused or fused with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

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

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

R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶⁷ , OR ⁶⁷ , SR ⁶⁷ , S(O)R ⁶⁷ , SO ₂ R ⁶⁷ , C(O)R ⁶⁷ , C(O)OR ⁶⁷ , OC(O)R ⁶⁷ , OC(O)OR ⁶⁷ , NH ₂ , NHR ⁶⁷ , N(R ⁶⁷ ) ₂ , NHC(O)R ⁶⁷ , NR ⁶⁷ C(O)R ⁶⁷ , NHS(O) ₂ R ⁶⁷ , NR ⁶⁷ S(O) ₂ R ⁶⁷ , NHC(O)OR ⁶⁷ , NR ⁶⁷ C(O)OR ⁶⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁷ , NHC(O)N(R ⁶⁷ ) ₂ , NR ⁶⁷ C(O)NHR ⁶⁷ , NR ⁶⁷ C(O)N(R ⁶⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁷ , C(O)N(R ⁶⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁷ , C(O)NHSO ₂ R ⁶⁷ , C(O)NR ⁶⁷ SO ₂ R ⁶⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁷ , SO ₂ N(R ⁶⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁷ , C(N)N(R ⁶⁷ ) ₂ , CNOH, CNOCH ₃ , OH,

(O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

RR ⁶⁶⁷⁷ iiss aallkkyyll,, aallkkeennyyll,, aallkkyynnyyll,, pphheenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein the moieties represented by R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶³ , R ⁶⁴ , R ⁶⁵ , and R ⁶⁷ are unsubstituted or substituted with one or more independently selected R ⁶⁸ , OR ⁶⁸ , SR ⁶⁸ , S(O)R ⁶⁸ , SO ₂ R ⁶⁸ , C(O)R ⁶⁸ , C(O)OR ⁶⁸ , OC(O)R ⁶⁸ , OC(O)OR ⁶⁸ , NH ₂ , NHR ⁶⁸ , N(R ⁶⁸ ) ₂ , NHC(O)R ⁶⁸ , NR ⁶⁸ C(O)R ⁶⁸ , NHS(O) ₂ R ⁶⁸ , NR ⁶⁸ S(O) ₂ R ⁶⁸ , NHC(O)OR ⁶⁸ , NR ⁶⁸ C(O)OR ⁶⁸ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁸ , NHC(O)N(R ⁶⁸ ) ₂ , NR ⁶⁸ C(O)NHR ⁶⁸ , NR ⁶⁸ C(O)N(R ⁶⁸ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁸ , C(O)N(R ⁶⁸ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁸ , C(O)NHSO ₂ R ⁶⁸ , C(O)NR ⁶⁸ SO ₂ R ⁶⁸ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁸ , SO ₂ N(R ⁶⁸ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁸ , C(N)N(R ⁶⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶⁸ is R ⁶⁹ , R ⁷⁰ , R ⁷¹ or R ⁷² ;

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

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

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

R ⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁷³ , OR ⁷³ , SR ⁷³ , S(O)R ⁷³ , SO ₂ R ⁷³ , C(O)R ⁷³ , C(O)OR ⁷³ , OC(O)R ⁷³ , OC(O)OR ⁷³ , NH ₂ , NHR ⁷³ , N(R ⁷³ ) ₂ , NHC(O)R ⁷³ , NR ⁷³ C(O)R ⁷³ , NHS(O) ₂ R ⁷³ , NR ⁷³ S(O) ₂ R ⁷³ , NHC(O)OR ⁷³ , NR ⁷³ C(O)OR ⁷³ , NHC(O)NH ₂ , NHC(O)NHR ⁷³ , NHC(O)N(R ⁷³ ) ₂ , NR ⁷³ C(O)NHR ⁷³ , NR ⁷³ C(O)N(R ⁷³ ) ₂ , C(O)NH ₂ , C(O)NHR ⁷³ , C(O)N(R ⁷³ ) ₂ , C(O)NHOH, C(O)NHOR ⁷³ , C(O)NHSO ₂ R ⁷³ , C(O)NR ⁷³ SO ₂ R ⁷³ , SO ₂ NH ₂ , SO ₂ NHR ⁷³ , SO ₂ N(R ⁷³ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁷³ , C(N)N(R ⁷³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and the moieties represented by R ⁹ , R ⁷⁰ , and R ⁷¹ are unsubstituted or substituted with one or more independently selected NH ₂ , C(O)NH ₂ , C(O)NHOH, SO ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents. Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula III

(III) wherein

A ¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene or A ^1A ; A ^1A is cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene; wherein A ¹ is unsubstituted or substituted with one or two or three or four or five independently selected R ¹ , OR ¹ , SR ¹ , S(O)R ¹ , SO ₂ R ¹ , C(O)R ¹ , C(O)OR ¹ , OC(O)R ¹ , NHR ¹ , N(R ¹ K C(N)C(O)R ¹ , C(O)NHR ¹ , C(O)N(R ¹ K C(O)NHOH, C(O)NHOR ¹ , C(O)NHSO ₂ R ¹ , NHC(O)R ¹ , NR ¹ C(O)R ¹ , NHC(O)OR ¹ , NR ¹ C(O)OR ¹ , NR ¹ C(O)NHR ¹ , NR ¹ C(O)N(R ¹ K NHC(O)NH ₂ , NHC(O)NHR ¹ , NHC(O)N(R ¹ K SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N(R ¹ K NHS(O)R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHSO ₂ NHR ¹ , N(CH ₃ )SO ₂ N(CH ₃ )R ¹ , (O), NH ₂ , NO ₂ , N ₃ , OH, F, Cl, Br, I, CN, CF ₃ , OCF ₃ , CF ₂ CF ₃ , OCF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹ , C(N)N(R ¹ )!, CNOH, CNOCH ₃ , C(O)NH ₂ or C(0)0R ^1A ; R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R ^1A is cycloalkyl, cycloalkenyl or cycloalkynyl;

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

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

R ⁴ 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 ⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶ , NC(R ^6A )(R ^6B ), R ⁷ , OR ⁷ , SR ⁷ , S(O)R ⁷ , SO ₂ R ⁷ , NHR ⁷ , N(R ⁷ ) ₂ , C(O)R ⁷ , C(O)NH ₂ , C(O)NHR ⁷ , C(O)N(R ⁷ ) ₂ , NHC(O)R ⁷ , NR ⁷ C(O)R ⁷ , NHSO ₂ R ⁷ , NHC(O)OR ⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁷ , SO ₂ N(R ⁷ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ⁷ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NHR ¹ , OH, (O), C(O)OH, (O), N ₃ , CN, NH ₂ , CF ₃ , CF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶ is C ₂ -C ₅ -spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N ₃ , CN, CF ₃ , CF ₂ CF ₃ , F, Cl, Br, I, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ ;

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-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH ₂ moiety unreplaced or replaced with O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ or NH;

R ⁷ is R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ ;

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

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

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

R ¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ¹² , OR ¹² , SR ¹² , S(O)R ¹² , SO ₂ R ¹² , C(O)R ¹² , C(O)OR ¹² , OC(O)R ¹² , OC(O)OR ¹² , NH ₂ , NHR ¹² , N(R ¹² ) ₂ , NHC(O)R ¹² , NR ¹² C(O)R ¹² , NHS(O) ₂ R ¹² , NR ¹² S(O) ₂ R ¹² , NHC(O)OR ¹² , NR ¹² C(O)OR ¹² , NHC(O)NH ₂ , NHC(O)NHR ¹² , NHC(O)N(R ¹² ) ₂ , NR ¹² C(O)NHR ¹² , NR ¹² C(O)N(R ¹² ) ₂ , C(O)NH ₂ , C(O)NHR ¹² , C(O)N(R ¹² ) ₂ , C(O)NHOH, C(O)NHOR ¹² , C(O)NHSO ₂ R ¹² , C(O)NR ¹² SO ₂ R ¹² , SO ₂ NH ₂ , SO ₂ NHR ¹² , SO ₂ N(R ¹² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹² , C(N)N(R ¹² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ¹² is R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ ; R ¹³ is phenyl, which is unfused or fused with benzene, heteroarene or R ^13A ; R ^13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

RR ¹¹⁴⁴ iiss hheetteerrooaarryyll,, wwhhiicchh iiss uunnffuusseedd oorr ffuusseedd wwiitthh bbeennzzeennee,, t heteroarene or R ^14A ; R ^14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R ^15A ; R ^15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹ is alkyl, alkenyl or alkynyl; wherein the moiety represented by R ¹⁰¹ is H, R ⁴¹ , OR ⁴¹ , SR ⁴¹ , S(O)R ⁴¹ , SO ₂ R ⁴¹ ,

C(O)R ⁴¹ , C(O)OR ⁴¹ , OC(O)R ⁴¹ , OC(O)OR ⁴¹ , NH ₂ , NHR ⁴¹ , N(R ⁴¹ ) ₂ , NHC(O)R ⁴¹ , NR ⁴¹ C(O)R ⁴¹ , NHS(O) ₂ R ⁴¹ , NR ⁴¹ S(O) ₂ R ⁴¹ , NHC(O)OR ⁴¹ , NR ⁴¹ C(O)OR ⁴¹ , NHC(O)NH ₂ , NHC(O)NHR ⁴¹ , NHC(O)N(R ⁴¹ ) ₂ , NR ⁴¹ C(O)NHR ⁴¹ , NR ⁴¹ C(O)N(R ⁴¹ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴¹ , C(O)N(R ⁴¹ ) ₂ , C(O)NHOH, C(O)NHOR ⁴¹ , C(O)NHSO ₂ R ⁴¹ , C(O)NR ⁴¹ SO ₂ R ⁴¹ , SO ₂ NH ₂ , SO ₂ NHR ⁴¹ , SO ₂ N(R ⁴¹ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴¹ , C(N)N(R ⁴¹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴¹ is R ⁴² , R ⁴³ , R ⁴⁴ or R ⁴⁵ ;

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

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

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

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R ⁴⁶ , OR ⁴⁶ , SR ⁴⁶ , S(O)R ⁴⁶ , SO ₂ R ⁴⁶ , C(O)R ⁴⁶ , C(O)OR ⁴⁶ , OC(O)R ⁴⁶ , OC(O)OR ⁴⁶ , NH ₂ , NHR ⁴⁶ , N(R ⁴⁶ ) ₂ , NHC(O)R ⁴⁶ , NR ⁴⁶ C(O)R ⁴⁶ , NHS(O) ₂ R ⁴⁶ , NR ⁴⁶ S(O) ₂ R ⁴⁶ , NHC(O)OR ⁴⁶ , NR ⁴⁶ C(O)OR ⁴⁶ , NHC(O)NH ₂ , NHC(O)NHR ⁴⁶ , NHC(O)N(R ⁴⁶ ) ₂ , NR ⁴⁶ C(O)NHR ⁴⁶ , NR ⁴⁶ C(O)N(R ⁴⁶ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴⁶ , C(O)N(R ⁴⁶ ) ₂ , C(O)NHOH, C(O)NHOR ⁴⁶ , C(O)NHSO ₂ R ⁴⁶ , C(O)NR ⁴⁶ SO ₂ R ⁴⁶ , SO ₂ NH ₂ , SO ₂ NHR ⁴⁶ , SO ₂ N(R ⁴⁶ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴⁶ , C(N)N(R ⁴⁶ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴⁶ is alkyl, alkenyl, alkynyl, R ⁴⁷ , R ⁴⁸ or R ⁴⁹ ; R ⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R ^47A ; R ^47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

RR ⁴⁸ iiss hheetteerrooaarryyll,, wwhhiicchh iiss uunnffuusseedd oorr ffuusseedd wwiitthh bbeennzzeennee,, t heteroarene or R ^48A ; R ^48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^49A ; R ^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the moieties represented by R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ , R ⁴⁸ , and R ⁴⁹ are independently unsubstituted or substituted with one or more independently selected R ⁵⁰ , OR ⁵⁰ , SR ⁵⁰ , S(O)R ⁵⁰ , SO ₂ R ⁵⁰ , C(O)R ⁵⁰ , C(O)OR ⁵⁰ , OC(O)R ⁵⁰ , OC(O)OR ⁵⁰ , NH ₂ , NHR ⁵⁰ , N(R ⁵⁰ ) ₂ , NHC(O)R ⁵⁰ , NR ⁵⁰ C(O)R ⁵⁰ , NHS(O) ₂ R ⁵⁰ , NR ⁵⁰ S(O) ₂ R ⁵⁰ , NHC(O)OR ⁵⁰ , NR ⁵⁰ C(O)OR ⁵⁰ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁰ , NHC(O)N(R ⁵⁰ ) ₂ , NR ⁵⁰ C(O)NHR ⁵⁰ , NR ⁵⁰ C(O)N(R ⁵⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁰ , C(O)N(R ⁵⁰ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁰ , C(O)NHSO ₂ R ⁵⁰ , C(O)NR ⁵⁰ SO ₂ R ⁵⁰ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁰ , SO ₂ N(R ⁵⁰ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ ,

C(N)NHR ⁵⁰ , C(N)N(R ⁵⁰ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁰ is R ⁵¹ , R ⁵² , R ⁵³ or R ⁵⁴ ;

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

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

R ⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁵⁵ , OR ⁵⁵ , SR ⁵⁵ , S(O)R ⁵⁵ , SO ₂ R ⁵⁵ , C(O)R ⁵⁵ , C(O)OR ⁵⁵ , OC(O)R ⁵⁵ , OC(O)OR ⁵⁵ , NH ₂ , NHR ⁵⁵ , N(R ⁵⁵ ) ₂ , NHC(O)R ⁵⁵ , NR ⁵⁵ C(O)R ⁵⁵ , NHS(O) ₂ R ⁵⁵ , NR ⁵⁵ S(O) ₂ R ⁵⁵ , NHC(O)OR ⁵⁵ , NR ⁵⁵ C(O)OR ⁵⁵ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁵ , NHC(O)N(R ⁵⁵ ) ₂ , NR ⁵⁵ C(O)NHR ⁵⁵ , NR ⁵⁵ C(O)N(R ⁵⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁵ , C(O)N(R ⁵⁵ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁵ , C(O)NHSO ₂ R ⁵⁵ , C(O)NR ⁵⁵ SO ₂ R ⁵⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁵ , SO ₂ N(R ⁵⁵ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁵ , C(N)N(R ⁵⁵ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or more independently selected R ⁷ , OR ⁵⁷ , SR ⁵⁷ , S(O)R ⁵⁷ , SO ₂ R ⁵⁷ , C(O)R ⁵⁷ , C(O)OR ⁵⁷ , OC(O)R ⁵⁷ , OC(O)OR ⁵⁷ , NH ₂ , NHR ⁵⁷ , N(R ⁵⁷ ) ₂ , NHC(O)R ⁵⁷ , NR ⁵⁷ C(O)R ⁵⁷ , NHS(O) ₂ R ⁵⁷ , NR ⁵⁷ S(O) ₂ R ⁵⁷ , NHC(O)OR ⁵⁷ , NR ⁵⁷ C(O)OR ⁵⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁷ , NHC(O)N(R ⁵⁷ ) ₂ , NR ⁵⁷ C(O)NHR ⁵⁷ , NR ⁵⁷ C(O)N(R ⁵⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁷ , C(O)N(R ⁵⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁷ , C(O)NHSO ₂ R ⁵⁷ , C(O)NR ⁵⁷ SO ₂ R ⁵⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁷ , SO ₂ N(R ⁵⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁷ , C(N)N(R ⁵⁷ ) ₂ , CNOH, CNOCH ₃ , OH, (0), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁷ is R ⁵⁸ , R ⁵⁹ , R ⁶⁰ or R ⁶¹ ;

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

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

R ⁶⁰ 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;

R ⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶² , OR ⁶² , SR ⁶² , S(O)R ⁶² , SO ₂ R ⁶² , C(O)R ⁶² ,

C(O)OR ⁶² , OC(O)R ⁶² , OC(O)OR ⁶² , NH ₂ , NHR ⁶² , N(R ⁶² ) ₂ , NHC(O)R ⁶² , NR ⁶² C(O)R ⁶² , NHS(O) ₂ R ⁶² , NR ⁶² S(O) ₂ R ⁶² , NHC(O)OR ⁶² , NR ⁶² C(O)OR ⁶² , NHC(O)NH ₂ , NHC(O)NHR ⁶² , NHC(O)N(R ⁶² ) ₂ , NR ⁶² C(O)NHR ⁶² , NR ⁶² C(O)N(R ⁶² ) ₂ , C(O)NH ₂ , C(O)NHR ⁶² , C(O)N(R ⁶² ) ₂ , C(O)NHOH, C(O)NHOR ⁶² , C(O)NHSO ₂ R ⁶² , C(O)NR ⁶² SO ₂ R ⁶² , SO ₂ NH ₂ , SO ₂ NHR ⁶² , SO ₂ N(R ⁶² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶² , C(N)N(R ⁶² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶² is R ⁶³ , R ⁶⁴ , R ⁶⁵ or R ⁶⁶ ;

R ⁶³ is phenyl, which is unfused or fused with benzene, heteroarene or R ^63A ; R ^63A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^64A ; R ^64A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^65A ; R ^65A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶⁷ , OR ⁶⁷ , SR ⁶⁷ , S(O)R ⁶⁷ , SO ₂ R ⁶⁷ , C(O)R ⁶⁷ , C(O)OR ⁶⁷ , OC(O)R ⁶⁷ , OC(O)OR ⁶⁷ , NH ₂ , NHR ⁶⁷ , N(R ⁶⁷ ) ₂ , NHC(O)R ⁶⁷ , NR ⁶⁷ C(O)R ⁶⁷ , NHS(O) ₂ R ⁶⁷ , NR ⁶⁷ S(O) ₂ R ⁶⁷ , NHC(O)OR ⁶⁷ , NR ⁶⁷ C(O)OR ⁶⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁷ , NHC(O)N(R ⁶⁷ ) ₂ , NR ⁶⁷ C(O)NHR ⁶⁷ , NR ⁶⁷ C(O)N(R ⁶⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁷ , C(O)N(R ⁶⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁷ , C(O)NHSO ₂ R ⁶⁷ , C(O)NR ⁶⁷ SO ₂ R ⁶⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁷ ,

SO ₂ N(R ⁶⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁷ , C(N)N(R ⁶⁷ ) ₂ , CNOH, CNOCH ₃ , OH,

(0), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

RR ⁷⁷ iiss aallkkyyll,, aallkkeennyyll,, aallkkyynnyyll,, pphhenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein the moieties represented by R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶³ , R ⁶⁴ , R ⁶⁵ , and R ⁶⁷ are unsubstituted or substituted with one or more independently selected R ⁶⁸ , OR ⁶⁸ , SR ⁶⁸ , S(O)R ⁶⁸ , SO ₂ R ⁶⁸ , C(O)R ⁶⁸ , C(O)OR ⁶⁸ , OC(O)R ⁶⁸ , OC(O)OR ⁶⁸ , NH ₂ , NHR ⁶⁸ , N(R ⁶⁸ ) ₂ , NHC(O)R ⁶⁸ , NR ⁶⁸ C(O)R ⁶⁸ , NHS(O) ₂ R ⁶⁸ , NR ⁶⁸ S(O) ₂ R ⁶⁸ , NHC(O)OR ⁶⁸ , NR ⁶⁸ C(O)OR ⁶⁸ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁸ , NHC(O)N(R ⁶⁸ ) ₂ , NR ⁶⁸ C(O)NHR ⁶⁸ , NR ⁶⁸ C(O)N(R ⁶⁸ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁸ , C(O)N(R ⁶⁸ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁸ , C(O)NHSO ₂ R ⁶⁸ , C(O)NR ⁶⁸ SO ₂ R ⁶⁸ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁸ , SO ₂ N(R ⁶⁸ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁸ , C(N)N(R ⁶⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁶⁸ is R ⁶⁹ , R ⁷⁰ , R ⁷¹ or R ⁷² ;

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

R ⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^70A ; R ^70A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^71A ; R ^71A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁷³ , OR ⁷³ , SR ⁷³ , S(O)R ⁷³ , SO ₂ R ⁷³ , C(O)R ⁷³ , C(O)OR ⁷³ , OC(O)R ⁷³ , OC(O)OR ⁷³ , NH ₂ , NHR ⁷³ , N(R ⁷³ ) ₂ , NHC(O)R ⁷³ , NR ⁷³ C(O)R ⁷³ ,

NHS(O) ₂ R ⁷³ , NR ⁷³ S(O) ₂ R ⁷³ , NHC(O)OR ⁷³ , NR ⁷³ C(O)OR ⁷³ , NHC(O)NH ₂ , NHC(O)NHR ⁷³ , NHC(O)N(R ⁷³ ) ₂ , NR ⁷³ C(O)NHR ⁷³ , NR ⁷³ C(O)N(R ⁷³ ) ₂ , C(O)NH ₂ , C(O)NHR ⁷³ , C(O)N(R ⁷³ ) ₂ , C(O)NHOH, C(O)NHOR ⁷³ , C(O)NHSO ₂ R ⁷³ , C(O)NR ⁷³ SO ₂ R ⁷³ , SO ₂ NH ₂ , SO ₂ NHR ⁷³ , SO ₂ N(R ⁷³ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁷³ , C(N)N(R ⁷³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

RR ⁷⁷³³ iiss aallkkyyll,, aallkkeennyyll,, aallkkeennyyll,, pphheennyyll,, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and tthhee mmooiieettiieess rreepprreesseenntteedd bbyy RR ⁶⁶⁹⁹ ,, RR ⁷⁷⁰⁰ ,, and R ⁷¹ are unsubstituted or substituted with one or more independently selected NH ₂ , C(O)NH ₂ , C(O)NHOH, SO ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents.

Still another embodiment pertains to compounds having Formula I, which are

4- [4-(cyclohexylmethyl)-4-methoxypiperidin- 1 -yl] -N- { [5 -( { ( 1 R)-3 -(dimethylamino)- 1 - [(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl }benzamide;

N-{ [5-({(lR)-3-(dimethylamino)-l-[(phenylthio)methyl]propyl}ami no)-4-nitrothien-2- yl] sulfonyl } -4- [4-methoxy-4-(3-methylbenzyl)piperidin- 1 -yljbenzamide ;

N-{ [5-({(lR)-3-(dimethylamino)-l-[(phenylthio)methyl]propyl}ami no)-4-nitrothien-2- yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazin-l-yl]be nzamide; 4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(4- { [2-

(phenylthio)ethyl] amino } piperidin- 1 -yl)sulfonyl]benzamide;

N- [(4- { acetyl[2-(phenylthio)ethyl] amino } piperidin- 1 -yl)sulfonyl] -4- { 4- [(4'-chloro- 1,1'- biphenyl-2-yl)methyl]piperazin-l-yl}benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(4- { methyl[2- (phenylthio)ethyl] amino } piperidin- 1 -yl)sulfonyl]benzamide;

4-{4-[(4' _-c hloro-l,l'-biphenyl-2-yl)methyl]piperazin-l-yl}-N-{ [5-({(lR)-3-

[isopropyl(methyl) amino] - 1 - [(phenylthio)methyl]propyl } amino)-4-nitrothien-2- yl] sulfonyl } benzamide ;

4-(4- { [2-(4-chlorophenyl)cyclohex- 1 -en- 1 -yljmethyl } piperazin- 1 -yl)-N- { [5 -( { ( 1 R)-3 - [isopropyl(methyl) amino] - 1 - [(phenylthio)methyl]propyl } amino)-4-nitrothien-2- yl] sulfonyl } benzamide ;

4-(4-{ [2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-N-{ [5-

({(lR)-3- [isopropyl(methyl)amino] - 1 - [(phenylthio)methyl]propyl } amino)-4-nitrothien-2- yl] sulfonyl } benzamide ; N-{ [(5Z)-5-(acetylimino)-4-methyl-4,5-dihydro-l,3,4-thiadiazol- 2-yl]sulfonyl}-4-{4-[(4'- chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } benzamide;

N- { [2-(acetylamino)-4-methyl- 1 ,3 -thiazol-5 -yl] sulfonyl } -4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2- yl)methyl]piperazin- 1 -yl }benzamide;

N-( { 5 - [(benzoylamino)methyl] thien-2-yl } sulfonyl)-4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2- yl)methyl]piperazin- 1 -yl }benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(6-chloroimidazo [2,1- b][l,3]thiazol-5-yl)sulfonyl]benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N-(morpholin-4- ylsulf onyl)benzamide ; 4- { 4- [(4'-chloro- 1 , l'-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(2,4-dimethyl- 1 ,3 -thiazol-5 - yl)sulfonyl]benzamide;

4- { 4-[(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- { [4-phenyl-5-

(trifluoromethyl)thien-3 -yl] sulf onyl } benzamide ; 4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(5-fluoro-3 -methyl- 1 - benzothien-2-yl)sulfonyl]benzamide;

N-(1 ,3 -benzothiazol-2-ylsulfonyl)-4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 - yl} benzamide;

4- { 4-[(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N-(thien-2-ylsulfonyl)benzamide; 4- { 4- [(4'-chloro- 1 , l'-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(5 ,7- dimethyl[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)sulfonyl]benzam ide; ethyl 4- { [(4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 - yl}benzoyl)amino]sulfonyl}-5-methyl-l,2-diphenyl-lH-pyrrole- 3-carboxylate; methyl 5- { [(4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 - yl}benzoyl)amino]sulfonyl}-l-methyl-lH-pyrrole-2-carboxylate ;

4-{4-[(4'-chloro-l,l'-biphenyl-2-yl)methyl]piperazin-l-yl }-N-{ [5-(l,3-dimethyl-lH-pyrazol-

5-yl)isoxazol-4-yl]sulfonyl}benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(4-chloro-3 -methylisothiazol- 5-yl)sulfonyl]benzamide; N-[(5-bromo-3-methyl- 1 -benzothien-2-yl)sulfonyl]-4- {4-[(4'-chloro- 1 , l'-biphenyl-2- yl)methyl]piperazin- 1 -yl }benzamide;

4-{4-[(4'-chloro-l,l'-biphenyl-2-yl)methyl]piperazin-l-yl }-N-({5-[(E)-2-(l,2,4-oxadiazol-3- yl)vinyl]thien-2-yl } sulfonyl)benzamide;

4-{4-[(4'-chloro-l,l'-biphenyl-2-yl)methyl]piperazin-l-yl }-N-{ [l-(2-chloroethyl)-3,5- dimethyl- lH-pyrazol-4-yl]sulfonyl}benzamide;

5- { [(4- { 4-[(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl }benzoyl)amino]sulfonyl } -N- (1 -ethylpropyl)- 1 ,3,4-thiadiazole-2-carboxamide;

4- { 4- [(4'-chloro- 1 , l'-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(5-chloro- 1 ,3 -dimethyl- 1 H- pyrazol-4-yl)sulfonyl]benzamide; 4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(4-nitro-5 -piperidin- 1 -ylthien- 2-yl)sulfonyl]benzamide;

4- { 4-[(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N-[(5-isoxazol-5-yl-2- furyl)sulfonyl]benzamide; 4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(3 ,5 -dimethylisoxazol-4- yl)sulfonyl]benzamide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-2-(lH- indol-5-yloxy)-N-({4-m ^' tro-5-[(3-pyrrolidin-l-ylpropyl)amino]thien-2- yl}sulfonyl)benzamide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-N-[(5-

{ [3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]- 2-(lH-indol-5- yloxy)benzamide ;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-2-(lH- indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitro thien-2- yl } sulfony l)benzamide ;

N-{ [5-({(lR)-3-(dimethylamino)-l-[(phenylthio)methyl]propyl}ami no)-4-nitrothien-2- yljsulfonyl } -4- { 4- [2-(trifluoromethyl)benzylidene]piperidin- 1 -yl }benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methylene]piperidin- 1 -yl } -N- [( 1 , 1 - dioxidotetrahydrothien-3-yl)sulfonyl]benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methylene]piperidin- 1 -yl } -N- [(5 -chloro-3 -methyl- 1 - benzothien-2-yl)sulfonyl]benzamide;

4- { 4- [(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl } -N- [(5 -chloro-3 -methyl- 1 - benzothien-2-yl)sulfonyl]-2-phenoxybenzamide; 2-(3-chlorophenoxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl}piperazin-l-yl)-Ν-[(5,7-dimethyl[l,2,4]triazolo[l ,5-a]pyrimidin-2- yl)sulfonyl]benzamide;

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl }piperazin- 1 -yl)-N- [(5 ,7- dimethyl[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6 -fluoro-lH-indol-5- yl)oxy]benzamide;

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-2-[(6,7- difluoro-lH-indol-5-yl)oxy]-N-[(5,7-dimethyl[l,2,4]triazolo[ l,5-a]pyrimidin-2- yl)sulfonyl]benzamide; tert-butyl (2S)-2-{ [(5-{ [4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl}piperazin-l-yl)-2-(lH-pyrrolo[2,3-b]pyridin-5-ylox y)benzoyl]sulfamoyl}-4- methyl-l,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate; tert-butyl (2S)-2-{ [(5-{ [2-(lH-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4- dimethylcyclohex- 1 -en- 1 -yljmethyl }piperazin- 1 -yl)benzoyl]sulfamoyl } -4-methyl- 1,3- thiazol-2-yl)oxy]methyl } morpholine-4-carboxylate; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-N-({2- [(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-l,3-thi azol-5-yl}sulfonyl)-2-(lH- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;

2-(lH-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yljmethyl }piperazin- l-yl)-N-({ 2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl- 1 ,3- thiazol-5-yl } sulfonyl)benzamide; tert-butyl (2S)-2-{ [(5-{ [4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl}piperazin-l-yl)-2-(lH-indazol-4-yloxy)benzoyl]sulf amoyl}-4-methyl-l,3-thiazol- 2-yl)oxy]methyl}morpholine-4-carboxylate; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}pi perazin-l-yl)-N-({2- [(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-l,3-thi azol-5-yl}sulfonyl)-2-(lH- indazol-4-yloxy)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, 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, 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, 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 (I) 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 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 term "C _x -C _y alkyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond containing x to y carbon atoms. The term "C ₂ -C ₄ 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- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-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 "C _x -C _y 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 -CH ₂ CH=CH-.

The term "alkyl" as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term "Cχ-C _y alkyl" means a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms. For example "C ₂ -C ₁₀ alkyl" means a straight or branched chain, saturated hydrocarbon containing 2 to 10 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-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 term "Cχ-C _y alkylene" means a divalent group derived from a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms. For example "C ₂ -C ₆ alkylene" means a straight or branched chain, saturated hydrocarbon containing 2 to 6 carbon atoms. Examples of alkylene include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and -CH ₂ CH(CH ₃ )CH ₂ -. 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 "C _x -C _y 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, 1-propynyl, 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 monocyclic 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 non- 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[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.0 ³ ' ⁷ ]nonane (octahydro-2,5-methanopentalene 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 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, lH-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl (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 O, 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 contained within the rings. The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quarternized. Representative examples of heterocycloalkane 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, dithianyl, isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, and trithianyl. The term "heterocycloalkene," or "heterocycloalkenyl," or "heterocycloalkenylene," 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 O, 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 the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quarternized. Representative examples of heterocycloalkene groups include, but are not limited to, tetrahydrooxocinyl, 1,4,5,6-tetrahydropyridazinyl, 1,2,3,6- tetrahydropyridinyl, dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl, dihydro- 1,3,4- thiadiazol-2-yl, and thiopyranyl.

The term "phenylene," as used herein, means a divalent radical formed by removal of a 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 C ₂ -spiroalkyl, C ₃ -spiroalkyl, C ₄ -spiroalkyl, Cs-spiroalkyl, C _ό -spiroalkyl, C ₇ -spiroalkyl, Cg-spiroalkyl, Cg-spiroalkyl and the like.

The term "spiroheteroalkyl," as used herein, means spiroalkyl having one or two CH ₂ moieties replaced with independently selected O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ 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 CH ₂ moieties replaced with independently selected O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ or NH and one or two CH moieties unreplaced or replaced with N and also means spiroalkenyl having one or two CH ₂ moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ 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 "C ₂ -C ₅ -spiroalkyl," as used herein, means C ₂ -spiroalkyl, C ₃ -spiroalkyl, C ₄ -spiroalkyl, and Cs-spiroalkyl. The term "C ₂ -spiroalkyl," as used herein, means eth-1 ,2-ylene, both ends of which replace hydrogen atoms of the same CH ₂ moiety.

The term "C ₃ -spiroalkyl," as used herein, means prop-l,3-ylene, both ends of which replace hydrogen atoms of the same CH ₂ moiety.

The term "C ₄ -spiroalkyl," as used herein, means but- 1 ,4-ylene, both ends of which replace hydrogen atoms of the same CH ₂ moiety.

The term "Cs-spiroalkyl," as used herein, means pent-l,5-ylene, both ends of which replace hydrogen atoms of the same CH ₂ moiety.

The term "C _ό -spiroalkyl," as used herein, means hex-l,6-ylene, both ends of which replace hydrogen atoms of the same CH ₂ moiety. The term "NH protecting group," as used herein, means trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl, 1,1- dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1- adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2- nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthyl- methylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene,

2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, S^-dimethyl-S-oxycyclo-hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term "C(O)OH protecting group," as used herein, means methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para- methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloro- ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, l,l-dimethyl-2-propenyl, 3-methyl- 3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

The term "OH or SH protecting group," as used herein, means benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1 , 1 -dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2- (triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1 -adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl,

2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1 , 1 -dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1 -ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 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 of Z 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 & 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, 13-10. 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 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, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I. 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 ( ² H), tritium ( ³ H) or ¹⁴ C 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 D ₂ SO ₄ /D ₂ O. 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 Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications

WO 1997010223, WO2005099353, WO 1995007271, 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 nonisotope-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., Can. 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 Bcl-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, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. 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. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). 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 & 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 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 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, phosphates, phosphate esters, and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide, and ether functional groups, c) use of aminals, hemi-aminals, polymers, salts, complexes, phosphoramides, acetals, hemiacetals, and ketal forms of the drug. For example, see Andrejus Korolkovas's, "Essentials of Medicinal Chemistry", John Wiley- Interscience 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

+ ^C1

Acyl Chloride Alkoxide Ester

Amides can be prepared from substrates of formula (I) 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

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

Scheme 3

O heat O

R^OH ⁺ HN(R) 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 , L , Z , Z , Z , Z , 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 A ¹ , L ¹ , Z ^1A , Z ^2A , Z ¹ , Z ² , and Z ³ can be combined with embodiments defined for any other of A ¹ , L ¹ , Z ^1A , Z ^2A , Z ¹ , Z ² , and Z ³ . One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (I)

(I), wherein

A ¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene or A ^1A ; A ^1A is cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene; wherein A ¹ is unsubstituted or substituted with one or two or three or four or five independently selected R ¹ , OR ¹ , SR ¹ , S(O)R ¹ , SO ₂ R ¹ , C(O)R ¹ , C(O)OR ¹ , OC(O)R ¹ , NHR ¹ , N(R ¹ K C(N)C(O)R ¹ , C(O)NHR ¹ , C(O)N(R ¹ K C(O)NHOH, C(O)NHOR ¹ , C(O)NHSO ₂ R ¹ , NHC(O)R ¹ , NR ¹ C(O)R ¹ , NHC(O)OR ¹ , NR ¹ C(O)OR ¹ , NR ¹ C(O)NHR ¹ , NR ¹ C(O)N(R ¹ K NHC(O)NH ₂ , NHC(O)NHR ¹ , NHC(O)N(R ¹ K SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N(R ¹ K NHS(O)R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHSO ₂ NHR ¹ , N(CH ₃ )SO ₂ N(CH ₃ )R ¹ , (O), NH ₂ , NO ₂ , N ₃ , OH, F, Cl, Br, I, CN, CF ₃ , OCF ₃ , CF ₂ CF ₃ , OCF ₂ CF ₃ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹ , C(N)N(R ¹ )!, CNOH, CNOCH ₃ , C(O)NH ₂ or C(0)0R ^1A ; R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R ^1A is cycloalkyl, cycloalkenyl or cycloalkynyl;

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

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

R ⁴ 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 independently selected R ⁶ , NC(R ^6A )(R ^6B ), R ⁷ , OR ⁷ , SR ⁷ , S(O)R ⁷ , SO ₂ R ⁷ , NHR ⁷ , N(R ⁷ K C(O)R ⁷ , C(O)NH ₂ , C(O)NHR ⁷ , C(O)N(R ⁷ K NHC(O)R ⁷ , NR ⁷ C(O)R ⁷ , NHSO ₂ R ⁷ , NHC(O)OR ⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁷ , SO ₂ N(R ⁷ K NHC(O)NH ₂ , NHC(O)NHR ⁷ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NHR ¹ , OH, (O), C(O)OH, (O), N ₃ , CN, NH ₂ , CF ₃ , CF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁶ is C ₂ -C ₅ -spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N ₃ , CN, CF ₃ , CF ₂ CF ₃ , F, Cl, Br, I, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ ;

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- 1 -yl, azetidin- 1 -yl, pyrrolidin- 1 -yl or piperidin- 1 -yl, each having one

CH ₂ moiety unreplaced or replaced with O, C(O), CNOH, CNOCH ₃ , S, S(O), SO ₂ or NH;

R ⁷ is R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ ;

R ⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R ^8A ; R ^8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^9A ; R ^9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R ^10A ; R ^10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ¹² , OR ¹² , SR ¹² , S(O)R ¹² , SO ₂ R ¹² , C(O)R ¹² , C(O)OR ¹² , OC(O)R ¹² , OC(O)OR ¹² , NH ₂ , NHR ¹² , N(R ¹² ) ₂ , NHC(O)R ¹² , NR ¹² C(O)R ¹² , NHS(O) ₂ R ¹² , NR ¹² S(O) ₂ R ¹² , NHC(O)OR ¹² , NR ¹² C(O)OR ¹² , NHC(O)NH ₂ , NHC(O)NHR ¹² , NHC(O)N(R ¹² ) ₂ , NR ¹² C(O)NHR ¹² , NR ¹² C(O)N(R ¹² ) ₂ , C(O)NH ₂ , C(O)NHR ¹² , C(O)N(R ¹² ) ₂ , C(O)NHOH, C(O)NHOR ¹² , C(O)NHSO ₂ R ¹² , C(O)NR ¹² SO ₂ R ¹² , SO ₂ NH ₂ , SO ₂ NHR ¹² ,

SO ₂ N(R ¹² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ¹² , C(N)N(R ¹² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ¹² is R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ ;

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

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

R ¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R ^15A ; R ^15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ¹⁶ is alkyl, alkenyl or alkynyl;

ZSs R ²⁶ Or R ²⁷ ;

Z ² is R ²⁸ , R ²⁹ or R ³⁰ ;

Z ^1A and Z ^2A are both absent or are taken together to form CH ₂ , CH ₂ CH ₂ or Z ^12A ; Z ^12A is C ₂ -C ₆ -alkylene having one or two CH ₂ moieties replaced by NH, N(CH ₃ ), S, S(O) or SO ₂ ;

L ¹ is a R ³⁷ , OR ³⁷ , SR ³⁷ , S(O)R ³⁷ , SO ₂ R ³⁷ , C(O)R ³⁷ , C(O)OR ³⁷ , OC(O)R ³⁷ , OC(O)OR ³⁷ , NHR ³⁷ , C(O)NH, C(O)NR ³⁷ , C(O)NHOR ³⁷ , C(O)NHSO ₂ R ³⁷ , SO ₂ NH, SO ₂ NHR ³⁷ , C(N)NH, C(N)NHR ³⁷ ;

R ² is phenylene which is unfused or fused with benzene or heteroarene or R ^{2 A} ; R ^{2 A} is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ²⁷ is heteroarylene, which is unfused or fused with benzene or heteroarene or R ^27A ; R ^27A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ²⁸ is phenylene, which is unfused or fused with benzene, heteroarene or R ^28A ; R ^28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ²⁹ is heteroarylene, which is unfused or fused with benzene or het< R ^29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;

R ³⁰ is cycloalkylene, 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;

R ³⁷ 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 , SO ₂ R ^37B , C(O)R ^37B , C(O)OR ^37B , OC(O)R ^37B , OC(O)OR ^37B , NH ₂ , NHR ^37B , N(R ^37B ) ₂ , NHC(O)R ^37B , NR ^37B C(O)R ^37B , NHS(O) ₂ R ^37B , NR ^37B S(O) ₂ R ^37B , NHC(O)OR ^37B , NR ^37B C(O)OR ^37B , NHC(O)NH ₂ , NHC(O)NHR ^37B , NHC(O)N(R ^37B ) ₂ , NR ^37B C(O)NHR ^37B , NR ^37B C(O)N(R ^37B ) ₂ , C(O)NH ₂ , C(O)NHR ^37B , C(O)N(R ^37B ) ₂ , C(O)NHOH, C(O)NHOR ^37B , C(O)NHSO ₂ R ^37B , C(O)NR ^37B SO ₂ R ^37B , SO ₂ NH ₂ , SO ₂ NHR ^37B , SO ₂ N(R ^37B ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ^37B , C(N)N(R ^37B ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

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

Z ³ is R ³⁸ , R ³⁹ or R ⁴⁰ ; R ³⁸ is phenyl, which is unfused or fused with benzene, heteroarene or R ^38A ; R ^38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ³⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^39A ; R ^39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁰ 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 R ² and R ²⁷ are unsubstituted or substituted, (i.e., if Z ^1A and Z ^2A are absent) or further unsubstituted or further substituted (i.e., if Z ^1A and Z ^2A are present) with one or more R ⁴¹ , OR ⁴¹ , SR ⁴¹ , S(O)R ⁴¹ , SO ₂ R ⁴¹ , C(O)R ⁴¹ , C(O)OR ⁴¹ , OC(O)R ⁴¹ , OC(O)OR ⁴¹ , NH ₂ , NHR ⁴¹ , N(R ⁴¹ ) ₂ , NHC(O)R ⁴¹ , NR ⁴¹ C(O)R ⁴¹ , NHS(O) ₂ R ⁴¹ , NR ⁴¹ S(O) ₂ R ⁴¹ , NHC(O)OR ⁴¹ , NR ⁴¹ C(O)OR ⁴¹ , NHC(O)NH ₂ , NHC(O)NHR ⁴¹ , NHC(O)N(R ⁴¹ ) ₂ , NR ⁴¹ C(O)NHR ⁴¹ , NR ⁴¹ C(O)N(R ⁴¹ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴¹ , C(O)N(R ⁴¹ ) ₂ , C(O)NHOH, C(O)NHOR ⁴¹ , C(O)NHSO ₂ R ⁴¹ , C(O)NR ⁴¹ SO ₂ R ⁴¹ , SO ₂ NH ₂ , SO ₂ NHR ⁴¹ ,

SO ₂ N(R ⁴¹ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴¹ , C(N)N(R ⁴¹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴¹ is R ⁴² , R ⁴³ , R ⁴⁴ or R ⁴⁵ ;

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

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

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

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R ⁴⁶ , OR ⁴⁶ , SR ⁴⁶ , S(O)R ⁴⁶ , SO ₂ R ⁴⁶ , C(O)R ⁴⁶ , C(O)OR ⁴⁶ , OC(O)R ⁴⁶ , OC(O)OR ⁴⁶ , NH ₂ , NHR ⁴⁶ , N(R ⁴⁶ ) ₂ , NHC(O)R ⁴⁶ , NR ⁴⁶ C(O)R ⁴⁶ , NHS(O) ₂ R ⁴⁶ , NR ⁴⁶ S(O) ₂ R ⁴⁶ , NHC(O)OR ⁴⁶ , NR ⁴⁶ C(O)OR ⁴⁶ , NHC(O)NH ₂ , NHC(O)NHR ⁴⁶ , NHC(O)N(R ⁴⁶ ) ₂ , NR ⁴⁶ C(O)NHR ⁴⁶ , NR ⁴⁶ C(O)N(R ⁴⁶ ) ₂ , C(O)NH ₂ , C(O)NHR ⁴⁶ , C(O)N(R ⁴⁶ ) ₂ , C(O)NHOH, C(O)NHOR ⁴⁶ , C(O)NHSO ₂ R ⁴⁶ , C(O)NR ⁴⁶ SO ₂ R ⁴⁶ , SO ₂ NH ₂ , SO ₂ NHR ⁴⁶ , SO ₂ N(R ⁴⁶ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁴⁶ , C(N)N(R ⁴⁶ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁴⁶ is alkyl, alkenyl, alkynyl, R ⁴⁷ , R ⁴⁸ or R ⁴⁹ ; R ⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene or R ^47A ; R ^47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

RR ⁴⁸ iiss hheetteerrooaarryyll,, wwhhiicchh iiss uunnffuusseedd oorr ffuusseedd wwiitthh bbeennzzeennee,, t heteroarene or R ^48A ; R ^48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^49A ; R ^49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the moieties represented by R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ , R ⁴⁸ , and R ⁴⁹ are independently unsubstituted or substituted with one or more independently selected R ⁵⁰ , OR ⁵⁰ , SR ⁵⁰ , S(O)R ⁵⁰ , SO ₂ R ⁵⁰ , C(O)R ⁵⁰ , C(O)OR ⁵⁰ , OC(O)R ⁵⁰ , OC(O)OR ⁵⁰ , NH ₂ , NHR ⁵⁰ , N(R ⁵⁰ ) ₂ , NHC(O)R ⁵⁰ , NR ⁵⁰ C(O)R ⁵⁰ , NHS(O) ₂ R ⁵⁰ , NR ⁵⁰ S(O) ₂ R ⁵⁰ , NHC(O)OR ⁵⁰ , NR ⁵⁰ C(O)OR ⁵⁰ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁰ , NHC(O)N(R ⁵⁰ ) ₂ , NR ⁵⁰ C(O)NHR ⁵⁰ , NR ⁵⁰ C(O)N(R ⁵⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁰ , C(O)N(R ⁵⁰ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁰ , C(O)NHSO ₂ R ⁵⁰ , C(O)NR ⁵⁰ SO ₂ R ⁵⁰ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁰ , SO ₂ N(R ⁵⁰ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ ,

C(N)NHR ⁵⁰ , C(N)N(R ⁵⁰ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁰ is R ⁵¹ , R ⁵² , R ⁵³ or R ⁵⁴ ;

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

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

R ⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁵⁵ , OR ⁵⁵ , SR ⁵⁵ , S(O)R ⁵⁵ , SO ₂ R ⁵⁵ , C(O)R ⁵⁵ , C(O)OR ⁵⁵ , OC(O)R ⁵⁵ , OC(O)OR ⁵⁵ , NH ₂ , NHR ⁵⁵ , N(R ⁵⁵ ) ₂ , NHC(O)R ⁵⁵ , NR ⁵⁵ C(O)R ⁵⁵ , NHS(O) ₂ R ⁵⁵ , NR ⁵⁵ S(O) ₂ R ⁵⁵ , NHC(O)OR ⁵⁵ , NR ⁵⁵ C(O)OR ⁵⁵ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁵ , NHC(O)N(R ⁵⁵ ) ₂ , NR ⁵⁵ C(O)NHR ⁵⁵ , NR ⁵⁵ C(O)N(R ⁵⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁵ , C(O)N(R ⁵⁵ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁵ , C(O)NHSO ₂ R ⁵⁵ , C(O)NR ⁵⁵ SO ₂ R ⁵⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁵ , SO ₂ N(R ⁵⁵ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁵ , C(N)N(R ⁵⁵ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or more independently selected R ⁷ , OR ⁵⁷ , SR ⁵⁷ , S(O)R ⁵⁷ , SO ₂ R ⁵⁷ , C(O)R ⁵⁷ , C(O)OR ⁵⁷ , OC(O)R ⁵⁷ , OC(O)OR ⁵⁷ , NH ₂ , NHR ⁵⁷ , N(R ⁵⁷ ) ₂ , NHC(O)R ⁵⁷ , NR ⁵⁷ C(O)R ⁵⁷ , NHS(O) ₂ R ⁵⁷ , NR ⁵⁷ S(O) ₂ R ⁵⁷ , NHC(O)OR ⁵⁷ , NR ⁵⁷ C(O)OR ⁵⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁵⁷ , NHC(O)N(R ⁵⁷ ) ₂ , NR ⁵⁷ C(O)NHR ⁵⁷ , NR ⁵⁷ C(O)N(R ⁵⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁵⁷ , C(O)N(R ⁵⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁵⁷ , C(O)NHSO ₂ R ⁵⁷ , C(O)NR ⁵⁷ SO ₂ R ⁵⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁵⁷ , SO ₂ N(R ⁵⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁵⁷ , C(N)N(R ⁵⁷ ) ₂ , CNOH, CNOCH ₃ , OH, (0), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁵⁷ is R ⁵⁸ , R ⁵⁹ , R ⁶⁰ or R ⁶¹ ;

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

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

R ⁶⁰ 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;

R ⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶² , OR ⁶² , SR ⁶² , S(O)R ⁶² , SO ₂ R ⁶² , C(O)R ⁶² ,

C(O)OR ⁶² , OC(O)R ⁶² , OC(O)OR ⁶² , NH ₂ , NHR ⁶² , N(R ⁶² ) ₂ , NHC(O)R ⁶² , NR ⁶² C(O)R ⁶² , NHS(O) ₂ R ⁶² , NR ⁶² S(O) ₂ R ⁶² , NHC(O)OR ⁶² , NR ⁶² C(O)OR ⁶² , NHC(O)NH ₂ , NHC(O)NHR ⁶² , NHC(O)N(R ⁶² ) ₂ , NR ⁶² C(O)NHR ⁶² , NR ⁶² C(O)N(R ⁶² ) ₂ , C(O)NH ₂ , C(O)NHR ⁶² , C(O)N(R ⁶² ) ₂ , C(O)NHOH, C(O)NHOR ⁶² , C(O)NHSO ₂ R ⁶² , C(O)NR ⁶² SO ₂ R ⁶² , SO ₂ NH ₂ , SO ₂ NHR ⁶² , SO ₂ N(R ⁶² ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶² , C(N)N(R ⁶² ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

R ⁶² is R ⁶³ , R ⁶⁴ , R ⁶⁵ or R ⁶⁶ ;

R ⁶³ is phenyl, which is unfused or fused with benzene, heteroarene or R ^63A ; R ^63A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R ⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroarene or R ^64A ; R ^64A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^65A ; R ^65A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three independently selected R ⁶⁷ , OR ⁶⁷ , SR ⁶⁷ , S(O)R ⁶⁷ , SO ₂ R ⁶⁷ , C(O)R ⁶⁷ , C(O)OR ⁶⁷ , OC(O)R ⁶⁷ , OC(O)OR ⁶⁷ , NH ₂ , NHR ⁶⁷ , N(R ⁶⁷ ) ₂ , NHC(O)R ⁶⁷ , NR ⁶⁷ C(O)R ⁶⁷ , NHS(O) ₂ R ⁶⁷ , NR ⁶⁷ S(O) ₂ R ⁶⁷ , NHC(O)OR ⁶⁷ , NR ⁶⁷ C(O)OR ⁶⁷ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁷ , NHC(O)N(R ⁶⁷ ) ₂ , NR ⁶⁷ C(O)NHR ⁶⁷ , NR ⁶⁷ C(O)N(R ⁶⁷ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁷ , C(O)N(R ⁶⁷ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁷ , C(O)NHSO ₂ R ⁶⁷ , C(O)NR ⁶⁷ SO ₂ R ⁶⁷ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁷ ,

SO ₂ N(R ⁶⁷ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁷ , C(N)N(R ⁶⁷ ) ₂ , CNOH, CNOCH ₃ , OH,

(0), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents;

RR ⁷⁷ iiss aallkkyyll,, aallkkeennyyll,, aallkkyynnyyll,, pphhenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein the moieties represented by R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶³ , R ⁶⁴ , R ⁶⁵ , and R ⁶⁷ are unsubstituted or substituted with one or more independently selected R ⁶⁸ , OR ⁶⁸ , SR ⁶⁸ , S(O)R ⁶⁸ , SO ₂ R ⁶⁸ , C(O)R ⁶⁸ , C(O)OR ⁶⁸ , OC(O)R ⁶⁸ , OC(O)OR ⁶⁸ , NH ₂ , NHR ⁶⁸ , N(R ⁶⁸ ) ₂ , NHC(O)R ⁶⁸ , NR ⁶⁸ C(O)R ⁶⁸ , NHS(O) ₂ R ⁶⁸ , NR ⁶⁸ S(O) ₂ R ⁶⁸ , NHC(O)OR ⁶⁸ , NR ⁶⁸ C(O)OR ⁶⁸ , NHC(O)NH ₂ , NHC(O)NHR ⁶⁸ , NHC(O)N(R ⁶⁸ ) ₂ , NR ⁶⁸ C(O)NHR ⁶⁸ , NR ⁶⁸ C(O)N(R ⁶⁸ ) ₂ , C(O)NH ₂ , C(O)NHR ⁶⁸ , C(O)N(R ⁶⁸ ) ₂ , C(O)NHOH, C(O)NHOR ⁶⁸ , C(O)NHSO ₂ R ⁶⁸ , C(O)NR ⁶⁸ SO ₂ R ⁶⁸ , SO ₂ NH ₂ , SO ₂ NHR ⁶⁸ , SO ₂ N(R ⁶⁸ ) ₂ , C(O)H, C(O)OH, C(N)NH ₂ , C(N)NHR ⁶⁸ , C(N)N(R ⁶⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I substituents; R ⁶⁸ is R ⁶⁹ , R ⁷⁰ , R ⁷¹ or R ⁷² ;