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

The present invention relates to compounds that inhibit the activity of Bcl-2 antiapoptotic proteins, compositions containing such compounds, and such compounds for use in methods of treating diseases in which anti-apoptotic Bcl-2 proteins are expressed.

BACKGROUND OF THE INVENTION [0002] Anti-apoptotic Bcl-2 proteins are associated with a number of diseases. In the field of therapy, there is therefore a need for compounds that inhibit the activity of anti-apoptotic Bcl-2 proteins.

[0003] Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or their combination in various cancers and immune system diseases.

[0004] 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 carcinoma, lymphoblastic leukemia, lymphoma lymphoma. or B-cells, melanoma, myeloid 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 PCT application US 2004/36770, published as WO 2005/049593, and PCT application US 2004/37911, published as WO 2005/024636.

[0005] The involvement of Bcl-2 proteins in immunological 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), 14091418. The involvement of Bcl-2 proteins in arthritis is disclosed in Application PCT / US2008 / 083478, published as WO 2009/064938. The involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in US Patent Application Serial No. 12 / 464,685, published as US 2010/0087436 A1.

SUMMARY OF THE INVENTION [0006] One embodiment of the present invention therefore relates to compounds or therapeutically acceptable salts thereof that are useful as inhibitors of anti-apoptotic Bcl-2 proteins, wherein the compound is selected from the following:

N - ({3-chloro-4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] phenyl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4dimetylocykloheks- 1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide;

N - ({3-chloro-4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] phenyl} sulfonyl) -4- (4 - {[4- (4-chlorophenyl) -6,6dimetylo- 5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide;

N - ({5-chloro-6 - [(trans-4-hydroxycyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) 4,4-dimethyl-1 en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indazol-4-yl) oxy] benzamide;

N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indazol-4-yl) oxy] benzamide;

5 - [(4- {4 - [({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) carbamoyl] -3- [(6- fluoro-1H-indol-5-yl) oxy] phenyl} piperazin-1-yl) methyl] -4- (4-chlorophenyl) -3,6-dihydropyridine (2H) tert-butyl carboxylate;

EP-2507211B1PL

N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[4- (4-chlorophenyl) -1- (1,3-difluoropropan-2-yl) -1,2,5,6-tetrahydropyridin-3-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy ] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-4-1Hindazol yl) oxy] -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

N - ({5-chloro-6 - [(trans-4-hydroxycyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) 4,4-dimethyl-1 en-1-yl] methyl} piperazin-1-yl) -2 - [(7-fluoro-1H-indazol-4-yl) oxy] benzamide;

N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(7-fluoro-1H-indazol-4-yl) oxy] benzamide,

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[3-nitro-4 - ({[4- (oxetan-3-yl) morpholin-2-yl] methyl} amino) phenyl] sulfonyl} benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5 yl) oxy] -N - {[3-nitro-4 - ({[4- (oxetan-3-yl) morpholin-2-yl] methyl} amino) phenyl] sulfonyl} benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(7-fluoro-4-1Hindazol yl) oxy] -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

N - ({5-chloro-6 - [(trans-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4- dimethyl-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indazol-4-yl) oxy] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimetylooycloheks-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-chloro-6- (tetrahydro -2H-pyran-4-ylmethoxy) -pyridin-3-yl] sulfonyl} -2 - [(3-methyl-2-oxo-2,3-dihydro-1Hbenzimidazol-4-yl) oxy] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(2H-4fluorotetrahydro pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(3-methyl-2-oxo-2,3-dihydro-1Hbenzimidazol-4-yl) oxy] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[(trans 4-methoxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] -2 - [(3-methyl-2-oxo-2,3-dihydro-1Hbenzimidazol-4-yl) oxy] benzamide;

2 - [((3-amino-1H-indazol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

2 - [((3-amino-1H-indazol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -benzamide;

2 - [((3-amino-1H-indazol-4-yloxy] -N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -benzamide;

2 - [((3-amino-1H-indazol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -benzamide;

EP-2507211B1PL

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(4 - {[4-fluoro-1- (oxetan-3-yl) piperidin-4-yl] methoxy} -3-nitrophenyl) sulfonyl] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-4-1Hindazol yl) oxy] -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(4 - {[(trans-4-hydroxy-4-methylcyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

2 - [((3-amino-1H-indazol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - [(4 - {[(trans-4-methoxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - ({4 - [(cis-4-hydroxy-4-methylcyclohexyl) methoxy] -3-nitrophenyl} sulfonyl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(4 - {[(cis-4-hydroxy-4-metylocyklohoksylo) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

4- {4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[3-chloro-4- (tetrahydro- 2H-pyran-4-ylmethoxy) phenyl] sulfonyl} -2 - [(3-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-4-yl) oxy] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimetylooycloheks-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[(4cyklopropylomorfolin- 2-yl) methyl] amino} -3-nitrophenyl) sulfonyl] -2 - [(3-methyl-2-oxo-2,3-dihydro-1Hbenzimidazol-4-yl) oxy] benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[3-nitro-4- (2-oxaspiro [3.5] non-7-ylmethoxy ) phenyl] sulfonyl} benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - ({4 - [(trans-4-hydroxy-4-methylcyclohexyl) methoxy] -3-nitrophenyl} sulfonyl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[4 - ([(2S) -4-cyklopropylomorfolin-2-yl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -N - ({5-chloro-6 - [(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin- 3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -N - ({5-chloro-6 - [(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin- 3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -benzamide;

2 - [((3-amino-1H-indazol-4-yl) oxy] -N - ({5-chloro-6 - [(trans-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) benzamide;

EP-2507211B1PL

N - ({5-chloro-6 - [(trans-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -2 - [(3-chloro-1Hindazol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(4 - {[(cis-4-ethyl-4-hydroxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[3-nitro-4 - ({[(2S) -4- (oxetan-3-yl) morpholin-2-yl] methyl} amino) phenyl] sulfonyl} benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - ({5-nitro-6 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] pyridin-3-yl} sulfonyl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - ({3-nitro-4 - [(2-Oxa-spiro [3.5] non-7-ylmethyl) amino] phenyl} sulfonyl) -benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[4 - ({[trans-4- (morpholin-4-yl) cyclohexyl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(4 - {[cis-4- (morpholin-4-yl) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] benzamide;

4 - ((4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({5-cyano-6- [( trans-4-hydroxy-4-methylcyclohexyl) methoxy] pyridin-3-yl} sulfonyl) -2 - [(6-fluoro-1H-indazol-4-yl) oxy] benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - {[4 - ({[4 - ({[4- (methoxymethyl) cyclohexyl] methyl} amino) -3-nitrophenyl] sulfonyl} amino) -3-nitrophenyl] sulfonyl} benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(3-nitro-4 - {[(3R) -1- (oxetan-3-yl) pyrrolidin-3-yl] amino} phenyl) sulfonyl] benzamide;

2 - [((6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazine -1-yl) -N - [(3-nitro-4 - {[(3S) -1- (oxetan-3-yl) pyrrolidin-3-yl] amino} phenyl) sulfonyl] benzamide;

N- [4 - ({2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-ene -1ylo] methyl} piperazin-1-yl) benzoyl} sulfamoyl) -2-nitrophenyl] morpholine-4-carboxamide; and

N- [4 - ({2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-ene -1ylo] methyl} piperazin-1-yl) benzoyl} sulfamoyl) -2-nitrophenyl] -4-cyanopiperidine-1-carboxamide.

[0007] Yet another embodiment relates to 2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en- 1-yl] methyl} piperazin-1-yl) -N - [(3-nitro-4 - {[(3R) -1- (oxetan-3-yl) pyrrolidin-3-yl] amino} phenyl) sulfonyl] benzamide; and its therapeutically acceptable salts.

[0008] Another embodiment relates to compositions for the treatment of bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, cancer

EP-2507211B1EN esophagus, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphoma, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, chronic myeloma , small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of a compound of the invention.

[0009] The compounds of the invention are useful in a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid 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 a compound of the invention.

[0010] The compounds of the invention are useful in a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid 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 a compound of the invention and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION [0011] The variable moieties used herein are represented by identifiers (in upper case letters with upper numerical and / or alphabetical indices) and can be implemented in detail.

[0012] It should be understood that for all moieties and their combinations their correct valences are preserved, that monovalent moieties having more than one atom are drawn from left to right and are attached by their left ends, and that divalent moieties are also drawn from left to the right.

[0013] It should also be understood that the specific implementation of the variable moiety may be the same or different from another specific implementation having the same identifier.

[0014] The term "NH protecting group," as used herein, means trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, methylthenyl, trifluoro para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, benzylmethyl, benzylmethyl, benzylmethyl para-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pirydylometylenową.

Cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl-2-oxo-2-oxo-2-oxo , 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, parametoxybenzyl, bis (para-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, paranitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydrate 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, methyloxymethyl, methyloxyhexyl methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[0016] The term "OH or SH protecting group," as used herein, means a benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, oxycarbonyloxy 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, 8-benzyloxycarbonyl, yloxycarbonyl) , 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), parametoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylhydryl , tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds [0017] Geometric isomers may exist in the present compounds. The compounds of the present invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where the term "E" means higher priority substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z "means the higher priority substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as defined by Cahn-Ingold-Prelog precedence rules. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. Substituents at the cycloalkyl group

EP 2 2507211B1EN or heterocycloalkyl are designated as being in cis or trans configuration. Furthermore, the invention contemplates various isomers and mixtures thereof obtained by placing substituents on the adamantane ring system. Two substituents on a single ring in the adamantane ring system are designated as being in the relative configuration Z or E. For examples, see CD Jones, M. Kaselj, RN Salvatore, WJ le Noble, J. Org. Chem. 1998, 63, 2758-2760 and EL Eliel, and SH Wilen. (1994) Stereochemistry of Organic Compounds. New York, NY: John Wiley & Sons, Inc.

[0018] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, where the terms "R" and "S" have the meanings defined by 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 these carbon atoms. Atoms with an excess of one configuration over the other are assigned a higher amount configuration, preferably with an excess of about 85% -90%, more preferably with an excess of about 95% -99%, and even more preferably with an excess of more than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds that are enriched or isotope-labeled [0019] Compounds of the invention may exist in isotope-labeled or isotopically-enriched form, containing one or more atoms having an atomic weight or mass number different from the atomic weight or mass number most commonly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to,²H ³H ¹³C ¹⁴C ¹⁵N ¹⁸ABOUT, ³²P ³⁵S ¹⁸F ³⁶Cl, and ¹²⁵I. Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention.

[0020] In another embodiment, the isotope-labeled compounds comprise deuterium (²H), tritium (³H) or ¹⁴C. Isotope-labeled compounds of the present invention can be prepared by general methods known to those skilled in the art. Such isotope-labeled compounds may conveniently be prepared by performing the procedures disclosed in the Examples disclosed herein and Schemes by replacing with an readily available isotope-labeled reagent. In some cases, the compounds may be treated with isotope-labeled reagents to exchange a normal atom for its isotope, for example, a hydrogen atom may be exchanged for deuterium by the action of deuterium acid such as D₂SO₄/ D₂ABOUT. In addition to the above, relevant procedures and intermediates are disclosed, for example, in: Lizondo, J et al., Drugs Fut, 21 (11), 1116 (1996); Brickner, SJ et al., J Med Chem, 39 (3), 673 (1996); Mallesham, B et al., Org Lett, 5 (7), 963 (2003); PCT publications No. WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Patent Nos. 7,538,189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and U.S. Patent Application Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471.

[0021] Isotope-labeled compounds of the invention can be used as standards for determining the effectiveness of Bcl-2 inhibitors in binding assays. Compounds containing isotope have been used in pharmaceutical research to investigate the metabolic fate of compounds in vivo by assessing the mechanism of action and the metabolic pathway of an isotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in design

EP-2507211B1PL safe and effective therapeutic drugs, because either the active compound administered in vivo to the patient or metabolites produced from this parent compound turn out to be toxic or carcinogenic (Foster et al., Advances in Drug Research vol. 14, pp. 2-36, Academic Press, London, 1985;

Kato et al., J. Labeled Comp. Radiopharmaceut., 36 (10): 927-932 (1995); Kushner et al., Can. J. Physiol.

Pharmacol., 77, 79-88 (1999).

[0022] Furthermore, drugs containing a non-radioactive isotope, such as deuterated drugs called "heavy drugs" can be used to treat diseases and conditions dependent on Bcl-2 activity. Increasing the amount of isotope present in a compound above its natural abundance is called enrichment. Examples of enrichment amounts include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, up to about 100 mole% Replacement with a heavy isotope of up to about 15% of the normal atom was carried out for days to weeks in mammals, including rodents and dogs, with minimal adverse effects observed (Czajka DM and Finkel AJ, Ann. NY Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Chakja DM et al., Am. J. Physiol. 1961 201: 357). It has been found that acute substitution in human body fluids with deuterium as much as 15% -23% does not cause toxicity (Blagojevic N et al. In "Dosimetry & Treatment Planning for Neutron Capture Therapy", edited by Zamenhof R, Solares G and Harling O, 1994 Advanced Medical Publishing, Madison Wis. Pp. 125-134; Diabetes Metab. 23: 251 (1997)).

[0023] The importance of a stable isotope drug may change its physicochemical properties such as pKa and lipid solubility. These effects and changes may affect the pharmacodynamic response to the drug molecule if the isotopic substitution affects the area involved in the ligand-receptor interaction. While some physical properties of a stable isotope molecule are different from those of a non-labeled molecule, the chemical and biological properties are the same, with one important exception: due to the increased mass of the heavy isotope, any bond including the heavy isotope and another atom will be stronger than such just the bond between the light isotope and that atom. Accordingly, the inclusion of an isotope at the site of metabolism or enzymatic conversion will slow down these reactions, potentially altering the pharmacokinetic profile or efficacy with respect to the non-isotope compound.

Pharmaceutical compositions, combination therapies, methods of treatment, and administration [0024] Another embodiment includes pharmaceutical compositions comprising a compound of the invention and an excipient.

[0025] The compounds of the invention are useful in methods of treating cancer in a mammal, said methods comprising administering to them a therapeutically acceptable amount of a compound of the invention.

[0026] The compounds of the invention are useful in methods of treating an autoimmune disease in a mammal, said methods comprising administering to them a therapeutically acceptable amount of a compound of the invention.

[0027] Still another embodiment relates to compositions for the treatment of diseases in which anti-apoptotic Bcl-2 proteins are expressed, said compositions comprising an excipient and a therapeutically effective amount of a compound of the invention.

[0028] The compounds of the invention are useful in methods of treating a disease in a patient in which anti-apoptotic Bcl-2 proteins are expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound of the invention.

[0029] Still another embodiment relates to compositions for the treatment of bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of a compound of the invention.

[0030] The compounds of the invention are useful in methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound of the invention.

[0031] Still another embodiment relates to compositions for the treatment of diseases in which anti-apoptotic Bcl-2 proteins are expressed, said compositions comprising an excipient and a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

[0032] Compounds of the invention are useful in methods of treating a disease in a patient in which anti-apoptotic Bcl-2 proteins are expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of one or more additional therapeutic agents than one additional therapeutic agent.

[0033] Still another embodiment relates to compositions for the treatment of bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid 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 compositions comprising an excipient and a therapeutically effective amount of a compound having formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

[0034] The compounds of the invention are useful in methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, malignant T-cell or B-cell lymphomas, melanoma, myeloid 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 methods comprising administering to the patient a therapeutically effective amount of a compound of

Of the present invention and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

[0035] The compounds of the invention may exist as acid addition salts, base addition salts or zwitterions. Salts of compounds are prepared during isolation or after purification of compounds. Acid addition salts of compounds mean salts derived from the reaction of compounds with an acid. For example, acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, hydrochloride, heptophosphate, heptophosphate, hydrochlorate, lactobionate, lactate, maleate, mesitylene sulphonate, methanesulphonate, naphthylene sulphonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetate, trifluoroacetate, para-toluenesulfonate, and undecanoate compounds and their prodrugs are contemplated by the present invention. Base addition salts of compounds mean salts derived from the reaction of compounds with hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium and magnesium.

[0036] The compounds of the invention may be administered, for example, buccal, ophthalmic, orally, osmotic, parenteral (intramuscular, intraperitoneal, intestinal, intravenous, subcutaneous), rectal, topical, transdermal or vaginal.

[0037] Therapeutically effective amounts of the compounds of the invention depend on the recipient of the treatment, the disorder being treated and its severity, composition containing the compound, time of administration, route of administration, duration of treatment, strength of the compound, its rate of removal, and whether it is administered together another drug or not. The amount of the compound of the present invention used in the preparation of compositions for daily administration to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg / kg body weight. Single-dose compositions contain these amounts or combinations of their aliquots.

[0038] The compounds of the invention may be administered with or without excipient. Excipients include, for example, encapsulation materials or additives, such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrants, emulsifiers, fillers, fillers, flavors, humectants, lubricants , flavors, preservatives, propellants, non-stick agents, sterilizing agents, sweeteners, solubilizing agents, wetting agents and mixtures thereof.

[0039] Excipients for the preparation of compositions containing a compound of the invention for oral administration in a solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose , cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, starch, potato starch propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphates, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid,

EP 1 2507211B1EN stearyl fumarate, sucrose, surfactants, talc, gum tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof. Excipients for the preparation of compositions containing a compound of the present invention for ocular or oral administration in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, sorbitan fatty acid esters, oil from germs, peanut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for the preparation of compositions containing a compound of the present invention for osmotic administration include, for example, chlorofluorocarbons, ethanol, water and mixtures thereof. Excipients for the preparation of compositions containing a compound of the present invention for parenteral administration include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dectrose, germ oil, peanut oil, liposomes, oleic acid, olive oil olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, USP soybean oil or isotonic chloride solution, water and mixtures thereof. Excipients for the preparation of compositions containing a compound of the present invention for rectal or vaginal administration include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

[0040] The compounds of the invention are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, anti-metabolites, anti-mitotic agents, anti-proliferative agents, anti-viral agents, aurora kinase inhibitors, other apoptosis promoters (e.g., Bcl-xL inhibitors, Bcl-w and Bfl-1), death receptor pathway activators, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase 2 inhibitors, DVDs, inhibitors of viral oncogen receptor leukemia (ErbB2) receptors, growth factor inhibitors, heat shock protein (HSP) -90 inhibitors, histone deacetylase inhibitors ( HDAC), hormone therapies, immunological agents, inhibitors of protein inhibitors of apoptosis (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, inhibitors of the mammalian target of rapamycin, microRNA, inhibitors of mitogen-acted kinases regulated by extracellular signal, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), polysiphase enzyme-inhibitors, (PARP), platinum-containing chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide 3 (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, ethinoid / deltoid plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, and ligase inhibitors, including ubiquitous inhibitors with one or more of these measures.

[0041] BiTE antibodies are dual specificity antibodies that direct T cells to attack cancer cells by binding two cells simultaneously. Then the T cell attacks the target cancer cell. Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being bound by theory, one of the mechanisms by which T cells induce apoptosis of the target cancer cell is exocytosis of cytolytic granular components that include perforin and B granzyme. In this context, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance T cell-induced cytotoxic effects when they are

EP-2507211B1PL directed against cancer cells (VR Sutton, DL Vaux and JA Trapani, J. of Immunology

1997, 158 (12), 5783).

[0042] SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impose increased stability and / or increased cellular activity. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH-containing ribonucleotides₃, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like. SiRNAs can have varying lengths (e.g., 10,200 bp) and structures (e.g., hairpins, single / double-stranded, bulges, notches / gaps, mismatches) and are processed in cells, causing active gene silencing. Double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetrical ends (overhangs). A 1-2 nucleotide overhang can be present on the sense and / or antisense strand as well as on the 5 'and / or 3' ends of the given strand. For example, siRNAs directed at Mcl-1 have been shown to increase ABT-263 activity (i.e., N- (4- (4 - ((2- (4-chlorophenyl) -5,5-dimethyl-1-cyclohex-1 -en-1-yl) methyl) piperazin-1-yl) benzoyl) -4 - (((1R) -3- (morpholin-4-yl) -1 - ((phenylsulfanyl) methyl) propyl) amino) -3- ( (trifluoromethyl) sulfonyl) benzenesulfonamide) or ABT-737 (i.e., N- (4- (4 - ((4'chloro (1,1'-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4 - (((1R) -3- (dimethylamino) -1 - ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) in many tumor cell lines (Tse et al., Cancer Research 2008, 68 (9), 3421, and references therein).

[0043] Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are designed to have three or more antigen binding sites, and are generally not naturally occurring antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Double variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins containing two DVD heavy polypeptide chains and two DVD light polypeptide chains are referred to as DVD immunoglobulins. Each of the DVD immunoglobulin halves comprises a DVD heavy polypeptide chain, a DVD light polypeptide chain, and two antigen binding sites. Each binding site includes a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per one antigen binding site. Multispecific DVDs include DVD binding proteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

[0044] Alkylating agents include altretamine, AMD-473, AP-5280, apazinone, bendamustine, brostalicin, busulfan, carbocarbone, carmustine (BCNU), chlorambucil, CLORETAZINE^® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, photemustine, glufosfamide, ifosfamide, KW2170, lomustine (CCNU), mafosphamide, melphalan, mitobronitol, mitolactol, nimustine, N-thiazepium^® (bendamustine), treosulfan, rophosphamide and the like.

[0045] Angiogenesis inhibitors include endothelial specific tyrosine kinase (Tie-2) inhibitors, epidermal growth factor (EGFR) inhibitors, insulin growth factor 2 (IGFR-2) receptor inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, inhibitors matrix metalloproteinase 9 (MMP-9), platelet-derived growth factor receptor (PDGFR) inhibitors, analogs

Thrombospondin, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors and the like.

[0046] Antimetabolites include ALIMTA^® (pemetrexed disodium, LY231514, MTA), 5-azacytidine,

XELODA^® (capecitabine), karmofur, LEUSTAT^® (cladribine), clofarabine, cytarabine, cytarabine phosphate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethinyl-1-eD-ribofuranosylimidazole-4-carboxamide), etylquinabine, encinabine , GEMZAR^® (gemcitabine), hydroxyurea, ALKERAN^® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocphosphate, pelitrexol, pentostatin, raltitrexed, ribavirin, triapine, trimethrexate, S-1, tegafurur the like.

[0047] Antiviral agents include ritonavir, hydroxychloroquine and the like.

[0048] Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, specific Aurora A kinase inhibitors, specific Aurora B kinase inhibitors, and pan-Aurora kinase inhibitors and the like.

[0049] Bcl-2 protein inhibitors include AT-101 ((-) gossypol), GENASENSE^® (G3139 or oblimersen (antisense oligonucleotide directed against Bcl-2)), IPI-194, IPI-565, N- (4- (4 - ((4'-chloro (1,1'-biphenyl) -2-yl) methyl ) piperazin-1-yl) benzoyl) -4 - (((1R) -3- (dimethylamino) -1 - ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4 - ((2- (4-chlorophenyl) -5,5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4 - ((( 1R) -3- (morpholin-4-yl) -1 ((phenylsulfanyl) methyl) propyl) amino) -3 - ((trifluoromethyl) sulfonyl) benzenesulfonamide (ABT-263), GX070 (obatoclax) and the like.

[0050] Bcr-Abl kinase inhibitors include DASATINIB^® (BMS-354825), GLEEVEC^® (imatinib) and the like.

[0051] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R- rosovitin), ZK-304709 and the like.

[0052] COX-2 inhibitors include ABT-963, ARCOXIA^® (etoricoxib), BEXTRA^® (valdecoxib), BMS347070, CELEBREX^® (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX^® (deracoxib), JTE-522, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067 , SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX^® (rofecoxib) and the like.

[0053] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF vaccine, EMD7200, ERBITUX^® (cetuximab), HR3, IgA antibodies, IRESSA^® (gefitinib), TARCEVA^® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB^® (lapatinib) and the like.

[0054] ErbB2 receptor inhibitors include CP-724-714, CI-1033 (cherretinib), HERCEPTIN^®(trastuzumab), TYKERB^® (lapatinib), OMNITARG^® (2C4, petuzumab), TAK-165, GW-5720 1 6 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER2 vaccine), dual specificity antibody HER / 2neu, B7.her2IgG3, dual specificity anti-AS HER2 trifunctional antibodies, ARAB-209 mAB, mAB 2B-1 and the like.

[0055] Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, hydroxamic acid suberoilanilide (SAHA), TSA, valproic acid and the like.

[0056] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB^® (human recombinant anti-HSP90 antibody), NCS-683664, PU24FCl, PU-3, radycycol, SNX-2112, STA-9090 VER49009 and the like.

[0057] Inhibitors of apoptosis protein inhibitors include HGS1029, GDC-0145, GDC-0152, LCL-161,

LBW-242 and the like.

[0058] Drug and antibody conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35 , SGN-75 and the like.

[0059] Activators of the death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, konatumumab, ETR2ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

[0060] Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.

[0061] JAK-2 inhibitors include CEP-701 (lezaurtinib), XL019 and INCB018424 and the like.

[0062] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.

[0063] mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP competing TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.

[0064] Nonsteroidal anti-inflammatory drugs include AMIGESIC^® (salsalate), DOLOBID^® (diflunisal), MOTRIN^® (ibuprofen), ORUDIS^® (ketoprofen), RELAFEN^® (nabumeton), FELDENE^® (piroxicam), ibuprofen cream, ALEVE^® (naproxen) and NAPROSYN^® (naproxen), VOLTAREN^® (diclofenac), INDOCIN^®(indomethacin), CLINORIL^® (sulindak), TOLECTIN^® (tolometin), LODINE^® (etodolac), TORADOL^®(ketorolac), DAYPRO^® (oxaprosine) and the like.

[0065] PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

[0066] Platinum-containing chemotherapeutics include cisplatin, ELOXATIN^® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN^® (carboplatin), satraplatin, picoplatin and the like.

[0067] Polo-like kinase inhibitors include BI-2536 and the like.

[0068] Phosphoinositide 3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like. [0069] Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.

[0070] VEGFR inhibitors include AVASTIN^® (bevacizumab), ABT-869, AEE-788, ANGIOZYME ™ (ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR^®(sorafenib, BAY43-9006), pazopanib (GW-786034), watalanib (PTK-787, ZK-222584), SUTENT^®(sunitinib, SU-11248), VEGF trap, ZACTIMA ™ (vandetanib, ZD-6474), and the like.

[0071] Antibiotics include aclarubicin intercalating antibiotics, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE^® (bleomycin), daunorubicin, CAELYX^® or MYOCET^®(liposomal doxorubicin), elzamitrucin, epirbucin, glarbuicin, ZAVEDOS^® [0072] (idarubicin), mitomycin C, nemorubicin, neocarcinostatin, peplomycin, pirarubicin, rebecamycin, stimalamer, streptozocin, VALSTAR^® (valrubicin), zynostatin and the like.

[0073] Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR^® (irinotecan hydrochloride), camptothecin,

Cardioxane^® (dexrazoxine), diflomotecan, edotecarin, ELLENCE^® or PHARMORUBICINE^® (epirubicin), etoposide, exatecane, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, oratecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.

[0074] Antibodies include AVASTIN^® (bevacizumab), CD40 specific antibodies, chTNT1 / B, denosumab, ERBTTUX^® (cetuximab), HUMAX-CD4^® (zanolimumab), IGF1R specific antibodies, lintuzumab, PANOREX^® (edrekolomab), RENCAREX^® (WX G250), RTTUXAN^® (rituximab), tycylimumab, trastuzimab, type I and II antibodies to CD20, GA101, ofatumumab, ABT-806 (mAb806), ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specific antibodies and C-met specific antibodies, and the like.

[0075] Hormone therapies include ARIMIDEX^® (anastrozole), AROMASIN^® (exemestane), Arzoxifene, CASODEX^® (bicalutamide), CETROTIDE^® (cetrorelix), degarelix, deslorelin, DESOPAN^® (trilostane), dexamethasone, DROGENIL^® (flutamide), EVISTA^® (raloxifene), AFEMA ™ (fadrozole), FARESTON^®(toremifene), FASLODEX^® (fulvestrant), FEMARA^® (letrozole), formestane, glucocorticoids, HECTOROL^®(doxercalciferol), RENAGEL^® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE^®(megesterol), MIFEPREX^® (mifepristone), NILANDRON ™ (nilutamide), NOLVADEX^® (tamoxifen citrate), PLENAXIS ™ (abarelix), prednisone, PROPECIA^® (finasteride), rilostane, SUPREFACT^®(buserelin), TRELSTAR^® (luteotropic hormone (LHRH)), VANTAS^® (histrelin implant), VETORYL^®(trilostane or modrastan), ZOLADEX^® (phosphine, goserelin) and the like.

[0076] Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH1060), fenretinide, PANRETIN^® (allirethinoin), ATRAGEN^® (liposomal tretinoin), TARGRETIN^® (bexarotene), LGD-1550 and the like.

[0077] PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

[0078] Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.

[0079] Proteasome inhibitors include VELCADE^® (bortezomib), MG132, NPI-0052, PR-171 and the like.

[0080] Examples of immune drugs include interferons and other agents that enhance the immune response. Interferons include interferon alfa, interferon alfa-2a, interferon alfa-2b, interferon beta, interferon gamma-1a, ACTIMMUNE^® (interferon gamma-1b) or interferon gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE®, (IFN-α), BAM-002 (oxidized glutathione), BEROMUN^® (tasonermin), BEXXAR^® (tositumomab), CAMPATH^® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE^®(lenograstim), lentinan, leukocyte interferon alpha, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG ™ (gemtuzumab ozogamycin), NEUPOGEN^®(filgrastim), OncoVAC-CL, OVAREX^® (oregowomab), pemtumomab (Y-muHMFG1), PROVENGE^®(sipuleucel-T), sargaramostim, sisophylan, teceleukin, THERACYS^® (Bacillus Calomette-Guerin), ubenimex, VIRULIZIN^® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Maruyama specific substance (SSM)), WF-10 (tetrachlorodeecoxide (TCDO)), PROLEUKIN^® (aldesleukin), ZADAXIN^®(thymalfasin), ZENAPAX^® (daclizumab), ZEVALIN^® (90Y-Ibrytumomab tiuxetan) and the like.

[0081] Biological response modifiers are agents that modify the mechanisms of defense of living organisms or biological responses, such as the survival, growth or differentiation of tissue cells to direct them to have antitumor activity, and include crestin, lentinan, sisophiran, picybanil PF-3512676 (CpG-8954), ubenimex and the like.

[0082] Analogs of pyrimidines include cytarabine (ara C or arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA^® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR^® (gemcitabine), TOMUDEX^® (raltitrexed), TROKSATYL ™ (triacetyluridine, troxacitabine) and the like.

[0083] Purine analogues include LANVIS^® (thioguanine) and PURI-NETHOL^® (Mercaptopurine).

[0084] Anti-mitotic agents include batabulin, epothilone D (KOS-862), N- (2 - ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE^® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.

[0085] Ubiquitin ligase inhibitors include MDM2 inhibitors such as nutlins, NEDD8 inhibitors such as MLN4924, and the like.

[0086] The compounds of the present invention can also be used as radiosensitizers that enhance the effectiveness of radiation therapy. Examples of radiation therapy include external beam radiotherapy, teletherapy, brachytherapy and closed source, non-closed source radiotherapy, and the like.

[0087] In addition, compounds of the invention may be combined with other chemotherapeutic agents such as ABRAXANE ™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN^® (Ad5CMV-p53 vaccine), ALTOCOR^® or MEVACOR^® (lovastatin), AMPLIGEN^® (poly I: poly C12U, synthetic RNA), APTOSYN^® (egzysulind), AREDIA^® (pamidronic acid), arglabin, Lasparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE^® (tazarotene), AVE-8062 (combretastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxine (vaccine), CEAVAC^® (cancer vaccine), CELEUK^® (celmoleukin), CEPLENE^® (histamine dihydrochloride), CERVARIX^® (human papillomavirus vaccine), CHOP^® (C: CYTOXSAN^® (Cyclophosphamide); H: ADRIAMYCIN^® (Hydroxydoxorubicin); A: vincristine (ONCOVIN^®); P: prednisone), CYPAT ™ (cyproterone acetate), combrestatin A4P, DAB (389) EGF (catalytic and translocation domain of diphtheria toxin linked by His-Ala linker to human epidermal growth factor) or TransMID-107R ™ (diphtheria toxin), dacarbazine , dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON ™ (squalamine lactate), DIMERICINE^® (liposomal fluid T4N5), discodermolide, DX-8951f (exatecane mesylate), enzastaurine, EPO906 (epothilone B), GARDASIL^® (four-valent recombinant vaccine against human papillomavirus (types 6, 11, 16, 18)), GASTRIMMUNE^®, GENASENSE^®, GMK (ganglioside conjugate vaccine), GVAX^® (prostate cancer vaccine), halofuginone, hysterelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (besudotoks cyntredekiny), IL-13-exotoxin Pseudomonas, interferon-α, interferon-γ, JUNOVAN ™ or MEPACT ™ (mifamurtide), lonafarnib, 5,10-methylene tetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT^®(AE-941), NEUTREXIN® (trimetrexate glucuronide), NIPENT^® (pentostatin), ONCONASE^® (ribonuclease enzyme), ONCOPHAGE^® (melanoma vaccine therapy), ONCOVAX^® (IL-2 vaccine), ORATHECIN ™ (rubitecan), OSIDEM^® (cell based drug based antibody), OVAREX^® MAb (mouse monoclonal antibody), paclitaxel, PANDIMEX ™ (ginseng saponins containing

EP-2507211B1PL

20 (S) protopanaxadiol (aPPD) and 20 (S) protopanaxatriol (aPPT)), panitumumab, PANVAC^®-VF (experimental cancer vaccine), pegaspargase, PEG-Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB^® (catumaxomab), REVLIMID^® (lenalidomide), RSR13 (efaproxyral), SOMATULINE^® LA (lanreotide), SORIATANE^® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN^® (bexarotene), TAXOPREXIN^® (DHA-paclitaxel), TELCITE^®(canphosphamide, TLK286), temilifen, TEMODAR^® (temozolomide), tesmilifene, thalidomide, THERATOPE^® (STnKLH), thyme (2-amino-3,4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TNFERADE ™ (adenovector: DNA carrier containing the tumor necrosis factor α gene), Tracleer^® or ZAVESCA^® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX^® (arsenic trioxide), VIRULIZIN^®, ukrain (derivative of celandine alkaloids), vitaxin (anti-alfavbeta3 antibody), XCYTRIN^® (gadolinium motexafins), XINLAY ™ (atrasentan), XYOTAX ™ (paclitaxel polyglumex), YONDELIS^® (trabectedin), ZD-6126, ZINECARD^® (dexrazoxane), ZOMETA^® (zolendronic acid), zorubicin, and the like.

Data [0088] Determining the usefulness of compounds as binding agents, and inhibitors, of Bcl-2 antiapoptotic proteins was performed using the Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) assay. Tb-anti-GST antibody was purchased from Invitrogen (catalog number PV4216).

Probe Synthesis [0089] All reagents were used as received from the supplier, unless otherwise stated. Reagents for peptide synthesis including diisopropylethylamine (DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HBTU) hexafluorophosphate (HBTU), N-hydroxybenzotriazole ( HOBt) and piperidine were obtained from Applied Biosystems, Inc. (ABI), Foster City, CA or American Bioanalytical, Natick, MA. Refilled cartridges with 9-fluorenylmethyloxycarbonyl (Fmoc) amino acids (Fmoc-Ala-OH, Fmoc-Cys (Trt) OH, Fmoc-Asp (tBu) -OH, Fmoc-Glu (tBu) -OH, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His (Trt) -OH, Fmoc-IleOH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Met-OH, Fmoc-Asn (Trt) -OH, Fmoc -Pro-OH, FmorGln (Trt) -OH, Fmoc-Arg (Pbf) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH, Fmoc-Val-OH, Fmoc-Trp (Boc ) OH, Fmoc-Tyr (tBu) -OH) were obtained from ABI or Anaspec, San Jose, CA. Peptide synthesis resin (Fmoc-Rinka MBHA amide resin) and Fmoc-Lys (Mtt) -OH were obtained from Novabiochem, San Diego, CA. The single isomer of 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS) was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood Products, West Columbia, SC. Thioanisole, phenol, triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and isopropanol were obtained from Aldrich Chemical Co., Milwaukee, WI. Mass spectra with desorption and laser-assisted ionization (MALDI-MS) were recorded on the Applied Biosystems Voyager DE-PRO MS instrument). Electrospray mass spectra (ESI-MS) were recorded on a Finnigan SSQ7000 instrument (Finnigan Corp., San Jose, CA) in both positive and negative ion modes.

General procedure for solid phase peptide synthesis (SPPS) [0090] Peptides were synthesized using vessels filled with a maximum of 250 μmol Wang resin on an ABI 433A peptide synthesizer, using 250 μmol Fastmoc ™ coupling cycles. Filled cartridges containing 1 mmol of standard Fmoc-amino acids, except for the fluorophore attachment position, where 1 mmol of Fmoc-Lys (Mtt) -OH was placed in the cartridge, used with monitoring

EP-2507211B1PL conductivity. N-terminal acetylation was accomplished by using 1 mmol acetic acid in the cartridge under normal coupling conditions.

Removal of the 4-methyltrityl group (Mtt) from lysine [0091] The resin from the synthesizer was washed three times with dichloromethane and stored wet. 150 ml of a 95: 4: 1 mixture of dichloromethane: triisopropylsilane: trifluoroacetic acid was passed through the resin bed for 30 minutes. The mixture turned an intense yellow color and then faded to pale yellow. 100 ml N, N-dimethylformamide was passed through the bed for 15 minutes. The resin was then washed three times with N, N-dimethylformamide and filtered off. Ninhydrin tests showed a strong signal for the primary amine.

Importance of 6-carboxyfluorescein-NHS resin (6-FAM-NHS) [0092] The resin was treated with 2 equivalents of 6-FAM-NHS in 1% DIEA / N, N-dimethylformamide and stirred or shaken at ambient temperature overnight. After completion of the reaction, the resin was filtered off, washed three times with N, N-dimethylformamide, three times with (1 1 DCM and 1χχ methanol) and dried to give an orange gum which was negative in the ninihydrin test.

General procedure for cleaving and deprotecting the resin-bound peptide [0093] The peptides were cleaved from the resin by shaking for 3 hours at ambient temperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS , and 2.5% EDT (1 ml / 0.1 g resin). The resin was removed by filtration and washed twice with TFA. TFA was evaporated from the filtrates, and the product was precipitated with ether (10 mL / 0.1 g resin), recovered by centrifugation, washed twice with ether (10 mL / 0.1 g resin) and dried to give the crude peptide. General procedure for peptide purification [0094] Raw peptides were purified in a Gilson preparative HPLC system operating under the Unipoint® analytical program (Gilson, Inc., Middleton, WI) on a radial compression column containing two 25 χ 100 mm segments filled with Delta-Pak ™ C18 particles 15 μm with a pore size of 100 A and eluted using one of the gradient methods given below. One to two milliliters of the crude peptide solution (10 mg / mL in 90% DMSO / water) was purified per injection. Peaks from each run containing product (s) were combined and lyophilized. All preparative runs were performed at 20 ml / min using eluents as buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General analytical HPLC procedure [0095] Analytical HPLC was performed on a 1200 series Hewlett-Packard system with a diodearray detector and a Hewlett-Packard 1046A fluorescence detector operating under version A.03.04 of the HPLC 3D ChemStation software (Hewlett-Packard, Palo Alto, CA) on a YMC 4.6 x 250 mm column filled with 5 mm ODS-AQ particles with a pore size of 120 A and eluted using one of the gradient methods given below after initial equilibration under start conditions for 7 minutes. The eluents were buffer A: 0.1% TFA-water and buffer B: acetonitrile. The flow rate for all gradients was 1 ml / min.

F-Bak: Acetyl peptide probe (SEQ ID NO: 1) GQVGRQLAIIGDK (6-FAM) - (SEQ ID NO: 2) INR-NH₂ [0096] The Fmoc-Rink amide MBHA resin was extended using the general peptide synthesis procedure to obtain a resin bound protected peptide (1.020 g). The Mtt group was removed, 6-FAM18 labeled

EP-2507211B1PL

NHS and cleaved and deprotected as described above to give the crude product as an orange solid (0.37 g). This product was purified by RP-HPLC. Fractions in the main peak were tested by analytical RP-HPLC, and pure fractions were separated and lyophilized, the main peak giving the title compound (0.0802 g) as a yellow solid; MALDI-MS m / z = 2137.1 [(M + H)⁺].

Alternative F-Bak peptide probe synthesis: Acetyl- (SEQ ID NO: 1) GQVGRQLAIIGDK (6FAM) - (SEQ ID NO: 2) INR- NH₂ [0097] The protected peptide was stacked on 0.25 mmol Fmoc-Rink amide MBHA resin (Novabiochem) on an Applied Biosystems 433A automated peptide synthesizer performing Fastmoc ™ coupling cycles using prepared cartridges of 1 mmol amino acid, except fluorescein labeled lysine (6-FAM ), where 1 mmol Fmoc-Lys (4-methyltrityl) was weighed into the cartridge. The N-terminal acetyl group was incorporated by placing 1 mmol acetic acid in the cartridge and coupling as described above. Selective removal of the 4-methyltrityl group was achieved using a 95: 4: 1 DCM: TIS: TFA (v / v) solution flowing through the resin for 15 minutes, followed by stopping with dimethylformamide flow. The single 6-carboxyfluorescein-NHS isomer was reacted with the lysine side chain in 1% DIEA in N, N-dimethylformamide and the completeness of the reaction was confirmed by a ninhydrin test. The peptide was cleaved from the resin and the side chains were deprotected by treatment with a mixture of 80: 5: 5: 5: 2.5: 2.5 (v / v) TFA / water / phenol / thioanisole / triisopropylsilane / 3,6-dioxa-1,8-octanedithiol and crude peptide was recovered by precipitation with diethyl ether. The crude peptide was purified by reverse phase high performance liquid chromatography and its purity and identity was confirmed by analytical high performance liquid chromatography and mass spectrometry with desorption and ionization on a laser-assisted matrix (m / z = 2137.1 ((M + H)⁺)).

Assay by Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) [0098] Representative compounds were subsequently diluted in dimethyl sulfoxide (DMSO), starting from 50 μΜ (2 x initial concentration; 10% DMSO) and 10 μL were transferred to a 384 well plate . Then 10 μL protein / probe / antibody mix was added to each well at the final concentrations given in TABLE 1. The samples were then mixed on a shaker for 1 minute and incubated for an additional 3 hours at room temperature. For each assay, probe / antibody and protein / probe / antibody were included on each test plate as comparative negative and positive assays, respectively. Fluorescence was measured on an Envision instrument (Perkin Elmer) using an 340/35 nm excitation filter and 520/525 emission filter (F-Bak peptide) and 495/510 nm (Tb-labeled histidine antibody). Inhibition constants (Ki) are shown in TABLE 2 below and were determined using the Wang equation (Wang Z.-X. An Exact Mathematical Expression For Describing Competitive Binding Of Two Different Ligands To A Protein Molecule. FEBS Lett. 1995, 360: 111 -4).

TABLE 1. Protein, probe and antibody used for TR-FRET assays

<td>Protein</td><td>Probe</td><td>Protein (NM)</td><td>Probe (NM)</td><td>Antibody</td><td>Antibody (NM)</td>

<td>GSTBcl-2</td><td>Peptide probe F-Bak acetyl- (SEQ ID NO: 1-GQVGRQLAIIGDK (6-FAM) -NR SEQ ID NO: 2 INR-amide)</td><td> 1</td><td> 100</td><td>Tb-anti-GST</td><td> 1</td>

<td>6-FAM =</td><td colspan="3">6-carboxyfluorescein; Tb = terbium; GST = glutathione-S-transferase</td><td></td><td></td>

[0099] The samples were then mixed on a shaker for 1 minute and incubated for an additional 3 hours at room temperature. For each assay, probe / antibody and protein / probe / antibody were included on each test plate as comparative negative and positive assays, respectively. Fluorescence was measured on an Envision instrument (Perkin Elmer) using an 340/35 nm excitation filter and 520/525 emission filter (F-Bak peptide) and 495/510 nm (Tb-labeled histidine antibody).

[0100] Braking constants (K_and) for the compounds of the examples are shown in TABLE 2 below. Where K_l for a compound is represented by "&gt;" (greater than) a certain numerical value, it is meant that the binding affinity value is greater than the detection limits of the assay used. Where k_and for a compound is represented as "&lt;" (less than) a certain numerical value, it is meant that the binding affinity value is lower than the detection limit of the assay used.

[0101] Among the compounds in Table 2, the compounds of the invention are the compounds of Examples 412-458. TABLE 2. Ki binding of Bcl-2 by TR-FRET (μΜ)

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 1</td><td> 0,008354</td><td> 232</td><td> 0,001047</td>

<td> 2</td><td> 0,031467</td><td> 233</td><td> 0,000037</td>

<td> 3</td><td> 0,000827</td><td> 234</td><td> 0,000099</td>

<td> 4</td><td> 0,002474</td><td> 235</td><td> 0,000039</td>

<td> 5</td><td> 0,000746</td><td> 236</td><td> 0,000071</td>

<td> 6</td><td> 0,000787</td><td> 237</td><td> 0,000197</td>

<td> 7</td><td> 0,002592</td><td> 238</td><td> 0,000124</td>

<td> 8</td><td> 0,003451</td><td> 239</td><td> 0,000105</td>

<td> 9</td><td> 0,000754</td><td> 240</td><td> 0,000912</td>

<td> 10</td><td> 0,00072</td><td> 241</td><td> 0,000141</td>

<td> 11</td><td> 0,000171</td><td> 242</td><td> 0,000092</td>

<td> 12</td><td> 0,000331</td><td> 243</td><td> 0,000069</td>

<td> 13</td><td> 0,001621</td><td> 244</td><td> 0,001734</td>

<td> 14</td><td> 0,000079</td><td> 245</td><td> 0,00048</td>

<td> 15</td><td> 0,000586</td><td> 246</td><td> 0,000065</td>

<td> 16</td><td> 0,003039</td><td> 247</td><td> 0,000039</td>

<td> 17</td><td> 0,005578</td><td> 248</td><td> 0,000051</td>

<td> 18</td><td> 0,002487</td><td> 249</td><td> 0,000168</td>

<td> 19</td><td> 0,001679</td><td> 250</td><td> 0,000672</td>

<td> 20</td><td> 0,003965</td><td> 251</td><td> 0,000435</td>

<td> 21</td><td> 0,014054</td><td> 252</td><td> 0,001147</td>

<td> 22</td><td> 0,005455</td><td> 253</td><td> 0,00005</td>

<td> 23</td><td> 0,00827</td><td> 254</td><td> 0,000119</td>

<td> 24</td><td> 0,014984</td><td> 255</td><td> 0,007013</td>

<td> 25</td><td> 0,001501</td><td> 256</td><td> 0,000105</td>

<td> 26</td><td> 0,000511</td><td> 257</td><td> 0,000097</td>

<td> 27</td><td> 0,002212</td><td> 258</td><td> 0,000083</td>

<td> 28</td><td> 0,001326</td><td> 259</td><td> 0,000165</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 29</td><td> 0,000903</td><td> 260</td><td> 0,011834</td>

<td> 30</td><td> 0,000071</td><td> 261</td><td> 0,000186</td>

<td> 31</td><td> 0,002007</td><td> 262</td><td> 0,000276</td>

<td> 32</td><td> 0,001584</td><td> 263</td><td> 0,00011</td>

<td> 33</td><td> 0,007173</td><td> 264</td><td> 0,000068</td>

<td> 34</td><td> 0,000049</td><td> 265</td><td> 0,000363</td>

<td> 35</td><td> 0,000022</td><td> 266</td><td> 0,00081</td>

<td> 36</td><td> 0,00007</td><td> 267</td><td> 0,028426</td>

<td> 37</td><td> 0,000005</td><td> 268</td><td> 0,000042</td>

<td> 38</td><td> 0,000013</td><td> 269</td><td> 0,000469</td>

<td> 39</td><td> 0,000019</td><td> 270</td><td> &gt;1,195000</td>

<td> 40</td><td> 0,000019</td><td> 271</td><td> 0,001908</td>

<td> 41</td><td> 0,000027</td><td> 272</td><td> 0,00124</td>

<td> 42</td><td> 0,00003</td><td> 273</td><td> 0,000516</td>

<td> 43</td><td> 0,000034</td><td> 274</td><td> 0,000936</td>

<td> 44</td><td> 0,000036</td><td> 275</td><td> 0,000081</td>

<td> 45</td><td> 0,000047</td><td> 276</td><td> 0,000199</td>

<td> 46</td><td> 0,000047</td><td> 277</td><td> 0,000017</td>

<td> 47</td><td> 0,00005</td><td> 278</td><td> 0,039967</td>

<td> 48</td><td> 0,000053</td><td> 279</td><td> 0,001703</td>

<td> 49</td><td> 0,000062</td><td> 280</td><td> 0,00755</td>

<td> 50</td><td> 0,000062</td><td> 281</td><td> 0,000111</td>

<td> 51</td><td> 0,000066</td><td> 282</td><td> 0,001012</td>

<td> 52</td><td> 0,000072</td><td> 283</td><td> 0,01721</td>

<td> 53</td><td> 0,000077</td><td> 284</td><td> 0,079348</td>

<td> 54</td><td> 0,000082</td><td> 285</td><td> 0,000037</td>

<td> 55</td><td> 0,00009</td><td> 286</td><td> 0,003181</td>

<td> 56</td><td> 0,000106</td><td> 287</td><td> 0,000131</td>

<td> 57</td><td> 0,000147</td><td> 288</td><td> 0,000017</td>

<td> 58</td><td> 0,000155</td><td> 289</td><td> &lt;0,000010</td>

<td> 59</td><td> 0,000184</td><td> 290</td><td> 0,000251</td>

<td> 60</td><td> 0,000187</td><td> 291</td><td> 0,000273</td>

<td> 61</td><td> 0,00022</td><td> 292</td><td> 0,000191</td>

<td> 62</td><td> 0,000227</td><td> 293</td><td> 0,000233</td>

<td> 63</td><td> 0,000438</td><td> 294</td><td> 0,000127</td>

<td> 64</td><td> 0,000458</td><td> 295</td><td> 0,000077</td>

<td> 65</td><td> 0,00052</td><td> 296</td><td> &lt;0,000010</td>

<td> 66</td><td> 0,000592</td><td> 297</td><td> &lt;0,000010</td>

<td> 67</td><td> 0,000807</td><td> 298</td><td> 0,000054</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 68</td><td> 0,005934</td><td> 299</td><td> 0,051687</td>

<td> 69</td><td> 0,008246</td><td> 300</td><td> 0,013659</td>

<td> 70</td><td> 0,020421</td><td> 301</td><td> 0,000113</td>

<td> 71</td><td> 0,031597</td><td> 302</td><td> &lt;0,000010</td>

<td> 72</td><td> 0,031666</td><td> 303</td><td> 0,000092</td>

<td> 73</td><td> 0,03226</td><td> 304</td><td> 0,000822</td>

<td> 74</td><td> 0,18943</td><td> 305</td><td> 0,000146</td>

<td> 75</td><td> 0,076832</td><td> 306</td><td> 0,000671</td>

<td> 76</td><td> 0,2395</td><td> 307</td><td> 0,000524</td>

<td> 77</td><td> 0,45052</td><td> 308</td><td> 0,00004</td>

<td> 78</td><td> &gt;1,195000</td><td> 309</td><td> 0,00069</td>

<td> 79</td><td> 0,099826</td><td> 310</td><td> 0,000155</td>

<td> 80</td><td> 0,14872</td><td> 311</td><td> 0,000185</td>

<td> 81</td><td> 0,031048</td><td> 312</td><td> 0,000531</td>

<td> 82</td><td> 0,51156</td><td> 313</td><td> &lt;0,000010</td>

<td> 83</td><td> &gt;1,195000</td><td> 314</td><td> 0,003094</td>

<td> 84</td><td> 0,013654</td><td> 315</td><td> 0,004555</td>

<td> 85</td><td> 0,005626</td><td> 316</td><td> 0,000058</td>

<td> 86</td><td> 0,005263</td><td> 317</td><td> 0,000205</td>

<td> 87</td><td> 0,26427</td><td> 318</td><td> &lt;0,000010</td>

<td> 88</td><td> &gt;1,195000</td><td> 319</td><td> 0,000198</td>

<td> 89</td><td> 0,006111</td><td> 320</td><td> 0,000028</td>

<td> 90</td><td> 0,010626</td><td> 321</td><td> 0,000029</td>

<td> 91</td><td> &gt;1,195000</td><td> 322</td><td> 0,00453</td>

<td> 92</td><td> 0,002569</td><td> 323</td><td> 0,003484</td>

<td> 93</td><td> 0,01683</td><td> 324</td><td> &lt;0,000010</td>

<td> 94</td><td> 0,56121</td><td> 325</td><td> 0,000183</td>

<td> 95</td><td> 0,000428</td><td> 326</td><td> 0,000037</td>

<td> 96</td><td> &gt;1,195000</td><td> 327</td><td> 0,000212</td>

<td> 97</td><td> 0,14659</td><td> 328</td><td> 0,000068</td>

<td> 98</td><td> 0,000959</td><td> 329</td><td> 0,000108</td>

<td> 99</td><td> 0,071364</td><td> 330</td><td> &lt;0,000010</td>

<td> 100</td><td> 0,11299</td><td> 331</td><td> 0,000238</td>

<td> 101</td><td> 0,6695</td><td> 332</td><td> 0,000034</td>

<td> 102</td><td> 0,043518</td><td> 333</td><td> 0,000107</td>

<td> 103</td><td> 0,006755</td><td> 334</td><td> 0,000197</td>

<td> 104</td><td> 0,002321</td><td> 335</td><td> &lt;0,000010</td>

<td> 105</td><td> 0,003567</td><td> 336</td><td> &lt;0,000010</td>

<td> 106</td><td> 0,21452</td><td> 337</td><td> 0,000049</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 107</td><td> 0,000331</td><td> 338</td><td> &lt;0,000010</td>

<td> 108</td><td>bd</td><td> 339</td><td> 0,000057</td>

<td> 109</td><td> 0,000237</td><td> 340</td><td> 0,000385</td>

<td> 110</td><td> 0,000039</td><td> 341</td><td> 0,000017</td>

<td> 111</td><td> 0,01744</td><td> 342</td><td> 0,003340</td>

<td> 112</td><td> 0,000042</td><td> 343</td><td> 0,000009</td>

<td> 113</td><td> 0,000032</td><td> 344</td><td> 0,000042</td>

<td> 114</td><td> 0,000036</td><td> 345</td><td> 0,000005</td>

<td> 115</td><td> 0,000042</td><td> 346</td><td> &lt; 0,000010</td>

<td> 116</td><td> 0,000123</td><td> 347</td><td> 0,000377</td>

<td> 117</td><td> 0,000072</td><td> 348</td><td> 0,003779</td>

<td> 118</td><td> 0,000151</td><td> 349</td><td> 0,000019</td>

<td> 119</td><td> 0,000156</td><td> 350</td><td> &lt; 0,000010</td>

<td> 120</td><td> 0,000214</td><td> 351</td><td> 0,002843</td>

<td> 121</td><td> 0,000081</td><td> 352</td><td> 0,000079</td>

<td> 122</td><td> &lt;0,000001</td><td> 353</td><td> 0,000016</td>

<td> 123</td><td> 0,00011</td><td> 354</td><td> 0,000114</td>

<td> 124</td><td> 0,000033</td><td> 355</td><td> 0,009567</td>

<td> 125</td><td> 0,000075</td><td> 356</td><td> 0,002822</td>

<td> 126</td><td> 0,000068</td><td> 357</td><td> 0,000177</td>

<td> 127</td><td> 0,00003</td><td> 358</td><td> 0,000062</td>

<td> 128</td><td> 0,000064</td><td> 359</td><td> 0,000110</td>

<td> 129</td><td> 0,000107</td><td> 360</td><td> 0,000050</td>

<td> 130</td><td> 0,000067</td><td> 361</td><td> 0,000015</td>

<td> 131</td><td> 0,000066</td><td> 362</td><td> 0,000033</td>

<td> 132</td><td> 0,000211</td><td> 363</td><td> &lt; 0,000010</td>

<td> 133</td><td> 0,000055</td><td> 364</td><td> 0,000014</td>

<td> 134</td><td> 0,000181</td><td> 365</td><td> 0,004551</td>

<td> 135</td><td> 0,000068</td><td> 366</td><td> 0,006052</td>

<td> 136</td><td> 0,000177</td><td> 367</td><td> 0,000012</td>

<td> 137</td><td> 0,000021</td><td> 368</td><td> &lt; 0,000010</td>

<td> 138</td><td> 0,000016</td><td> 369</td><td> 0,000014</td>

<td> 139</td><td> 0,000125</td><td> 370</td><td> &lt; 0,000010</td>

<td> 140</td><td> 0,000223</td><td> 371</td><td> &lt; 0,000010</td>

<td> 141</td><td> 0,000482</td><td> 372</td><td> 0,014978</td>

<td> 142</td><td> 0,000071</td><td> 373</td><td> 1,195000</td>

<td> 143</td><td> 0,000053</td><td> 374</td><td> 0,005337</td>

<td> 144</td><td> 0,000028</td><td> 375</td><td> 0,327810</td>

<td> 145</td><td> 0,000057</td><td> 376</td><td> 0,057705</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 146</td><td> 0,00004</td><td> 377</td><td> 0,002323</td>

<td> 147</td><td> 0,000127</td><td> 378</td><td> &lt; 0,000010</td>

<td> 148</td><td> 0,000106</td><td> 379</td><td> 0,017948</td>

<td> 149</td><td> 0,00003</td><td> 380</td><td> 0,008274</td>

<td> 150</td><td> 0,000759</td><td> 381</td><td> 0,000020</td>

<td> 151</td><td> 0,006935</td><td> 382</td><td> 0,000114</td>

<td> 152</td><td> 0,018589</td><td> 383</td><td> 0,427490</td>

<td> 154</td><td> 0,000012</td><td> 384</td><td> 0,006233</td>

<td> 155</td><td> 0,000062</td><td> 385</td><td> 0,049293</td>

<td> 156</td><td> 0,000035</td><td> 386</td><td> &lt; 0,000010</td>

<td> 157</td><td> 0,00072</td><td> 387</td><td> &lt; 0,000010</td>

<td> 158</td><td> 0,000619</td><td> 388</td><td> 0,000020</td>

<td> 159</td><td> 0,000526</td><td> 389</td><td> &lt; 0,000010</td>

<td> 160</td><td> 0,000028</td><td> 390</td><td> &lt; 0,000010</td>

<td> 161</td><td> 0,000031</td><td> 391</td><td> &lt; 0,000010</td>

<td> 162</td><td> 0,000048</td><td> 392</td><td> &lt; 0,000010</td>

<td> 163</td><td> 0,000686</td><td> 393</td><td> &lt; 0,000010</td>

<td> 164</td><td> 0,000056</td><td> 394</td><td> 0,000018</td>

<td> 165</td><td> 0,00012</td><td> 395</td><td> 0,000077</td>

<td> 166</td><td> 0,000082</td><td> 396</td><td> &lt; 0,000010</td>

<td> 167</td><td> 0,001345</td><td> 397</td><td> 0,000137</td>

<td> 168</td><td> 0,028343</td><td> 398</td><td> 0,000175</td>

<td> 169</td><td> 0,000498</td><td> 399</td><td> &lt; 0,000010</td>

<td> 170</td><td> 0,000036</td><td> 400</td><td> 0,000082</td>

<td> 171</td><td> 0,000066</td><td> 401</td><td> 0,000035</td>

<td> 172</td><td> 0,000549</td><td> 402</td><td> 0,000039</td>

<td> 173</td><td> 0,000019</td><td> 403</td><td> 0,002136</td>

<td> 174</td><td> 0,000037</td><td> 404</td><td> 0,000069</td>

<td> 175</td><td> 0,000046</td><td> 405</td><td> 0,000354</td>

<td> 176</td><td> 0,00024</td><td> 406</td><td> 0,000166</td>

<td> 177</td><td> 0,000037</td><td> 407</td><td> 0,000946</td>

<td> 178</td><td> 0,000175</td><td> 408</td><td> 0,001160</td>

<td> 179</td><td> 0,000036</td><td> 409</td><td> 0,000686</td>

<td> 180</td><td> 0,000112</td><td> 410</td><td> &lt; 0,000010</td>

<td> 181</td><td> 0,000119</td><td> 411</td><td> 0,021291</td>

<td> 182</td><td> 0,000172</td><td> 412</td><td> 0,001125</td>

<td> 183</td><td> 0,00253</td><td> 413</td><td> 0,000739</td>

<td> 184</td><td> 0,000155</td><td> 414</td><td> 0,000014</td>

<td> 185</td><td> 0,000083</td><td> 415</td><td> 0,000013</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 186</td><td> 0,000035</td><td> 416</td><td> 0,007436</td>

<td> 187</td><td> 0,000054</td><td> 417</td><td> 0,006876</td>

<td> 188</td><td> 0,000073</td><td> 418</td><td> &lt; 0,000010</td>

<td> 189</td><td> 0,000036</td><td> 419</td><td> 0,000012</td>

<td> 190</td><td> 0,000077</td><td> 420</td><td> &lt; 0,000010</td>

<td> 191</td><td> 0,000552</td><td> 421</td><td> &lt; 0,000010</td>

<td> 192</td><td> 0,000024</td><td> 422</td><td> &lt; 0,000010</td>

<td> 193</td><td> 0,000064</td><td> 423</td><td> &lt; 0,000010</td>

<td> 194</td><td> 0,000317</td><td> 424</td><td> &lt; 0,000010</td>

<td> 195</td><td> 0,000684</td><td> 425</td><td> 0,000013</td>

<td> 197</td><td> 0,00022</td><td> 426</td><td> &lt; 0,000010</td>

<td> 198</td><td> &lt;0,000010</td><td> 427</td><td> &lt; 0,000010</td>

<td> 199</td><td> 0,000244</td><td> 428</td><td> &lt; 0,000010</td>

<td> 200</td><td> 0,000081</td><td> 429</td><td> &lt; 0,000010</td>

<td> 201</td><td> 0,00001</td><td> 430</td><td> &lt; 0,000010</td>

<td> 202</td><td> 0,020043</td><td> 431</td><td> &lt; 0,000010</td>

<td> 203</td><td> 0,000084</td><td> 432</td><td> &lt; 0,000010</td>

<td> 204</td><td> 0,000075</td><td> 433</td><td> &lt; 0,000010</td>

<td> 205</td><td> 0,000153</td><td> 434</td><td> &lt; 0,000010</td>

<td> 206</td><td> 0,000037</td><td> 435</td><td> 0,000010</td>

<td> 207</td><td> 0,000074</td><td> 436</td><td> &lt; 0,000010</td>

<td> 208</td><td> 0,000261</td><td> 437</td><td> &lt; 0,000010</td>

<td> 209</td><td> &lt;0,000010</td><td> 438</td><td> 0,000031</td>

<td> 210</td><td> 0,00002</td><td> 439</td><td> &lt; 0,000010</td>

<td> 211</td><td> 0,001338</td><td> 440</td><td> 0,000022</td>

<td> 212</td><td> 0,000375</td><td> 441</td><td> 0,000054</td>

<td> 213</td><td> 0,000031</td><td> 442</td><td> &lt; 0,000010</td>

<td> 214</td><td> 0,000221</td><td> 443</td><td> 0,000029</td>

<td> 215</td><td> 0,002954</td><td> 444</td><td> 0,000018</td>

<td> 216</td><td> 0,000027</td><td> 445</td><td> &lt; 0,000010</td>

<td> 217</td><td> 0,000174</td><td> 446</td><td> 0,000015</td>

<td> 218</td><td> 0,000175</td><td> 447</td><td> 0,000029</td>

<td> 219</td><td> 0,014857</td><td> 448</td><td> &lt; 0,000010</td>

<td> 220</td><td> 0,000127</td><td> 449</td><td> &lt; 0,000010</td>

<td> 221</td><td> 0,000227</td><td> 450</td><td> &lt; 0,000010</td>

<td> 222</td><td> &gt;1,195000</td><td> 451</td><td> &lt; 0,000010</td>

<td> 223</td><td> 0,010911</td><td> 452</td><td> 0,000112</td>

<td> 224</td><td> 0,005603</td><td> 453</td><td> &lt; 0,000010</td>

<td> 225</td><td> 0,003283</td><td> 454</td><td> 0,000024</td>

EP-2507211B1PL

<td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td><td>Example No.</td><td>Bcl-2 binding Ki by TR-FRET (μΜ)</td>

<td> 226</td><td> 0,007586</td><td> 455</td><td> 0,000011</td>

<td> 227</td><td> 0,000174</td><td> 456</td><td>bd</td>

<td> 229</td><td> 0,001085</td><td> 457</td><td>bd</td>

<td> 230</td><td> 0,002833</td><td> 458</td><td>bd</td>

<td> 231</td><td> 0,036946</td><td></td><td></td>

[0102] Braking constant (K_and) is the dissociation constant of the enzyme-inhibitor complex or protein-small molecule complex, where the small molecule inhibits the binding of one protein to another protein. Therefore, a large value of K_and indicates low binding affinity and low K value_and indicates high binding affinity.

[0103] The data in TABLE 2 show inhibition constants for inhibition of the Bak BH3 peptide probe to the Bcl-2 protein and indicate that the compounds have high binding affinities for the anti-apoptotic Bcl-2 protein. The compounds are therefore expected to have utility in the treatment of diseases in which the anti-apoptotic Bcl-2 protein is expressed.

[0104] It is expected that the above compounds bind to Bcl-2 because they may also have utility as binders to other anti-apoptotic proteins having close structural homology to Bcl-2, such as, for example, anti-Bcl-2 proteins. apoptotic Bcl-X_L, Bcl-w, Mcl-1 and Bfl-1 / Al. [0105] Bcl-2 protein involvement in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, lymphoma lymphoma. or B-cells, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, spleen cancer, and the like is described in PCT Application US 2004/36770, published as WO 2005/049593, and PCT Application US 2004/37911, published as WO 2005/024636.

[0106] The 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), 14091418.

[0107] The involvement of Bcl-2 proteins in arthritis is disclosed in application PCT / US2008 / 083478, published as WO 2009/064938.

[0108] The involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in US Patent Application Serial No. 12 / 464,685, published as US 2010/0087436 A1.

[0109] Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or their combination in various cancers and immune system diseases. Cancers include, but are not limited to, types of hematological tumors and solid tumors, such as auditory nerve neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, hemangiosarcoma, astrocytoma, myelomonocytic leukemia and promyeloma) from T cells, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer (including breast cancer

EP-2507211B1PL (estrogen receptors), bronchogenic carcinoma, Burkitt's lymphoma, cervical carcinoma, chondrosarcoma, string, malignant chorionic epithelium, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloma, leukemia anus, craniopharynx, cystic adenocarcinoma, non-proliferative changes (dysplasia and metaplasia), germ cell carcinoma, endometrial cancer, endothelial sarcoma, lining, epithelial cancer, di Gugliemo disease, esophageal cancer, breast cancer with estrogen receptors, excessive platelet count, Ewing sarcoma, fibrosarcoma, stomach cancer, testicular germ cell cancer, glioblastoma, trophoblastic disease, chain disease heavy immunoglobulins, embryonic hemangioma, hepatoma, hepatocellular carcinoma, hormone independent prostate cancer, smooth muscle cancer, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioma, endothelial lymphosarcoma, lymphosarcoma, lymphoblastic leukemia, lymphoma (including lymphoma, including large fuzzy B lymphoma, malignant lymphoma, and follicular lymphoma) disorders of excessive growth of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, malignant T or B lymphomas, leukemia, medullary carcinoma, spinal cord, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, oligoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic carcinoma, papilloma adenoma, papillomatous papilloma true, prostate cancer (including hormone insensitive (resistant) prostate cancer), rectal cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoid and sarcoma), gastric cancer, squamous cell carcinoma, synovialoma, sweat gland cancer, testicular cancer (including testicular germ cell carcinoma), thyroid cancer, Waldenstrom macroglobulinemia, testicular cancer, uterine cancer , Wilms' tumor and the like.

[0110] It is also expected that the compounds of the invention could inhibit the growth of cells expressing Bcl-2 proteins derived from pediatric cancer or cancer, such as embryonic rhabdomyosarcoma, childhood acute lymphocytic leukemia, childhood acute myeloid leukemia, childhood follicular rhabdomyosarcoma, childhood ependymoma. anaplastic, childhood large cell anaplastic lymphoma, childhood anaplastic medulla, pediatric atypical teratoid / rhabdoid neoplasm of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitt's lymphoma, pediatric carcinomas of the Ewing sarcoma family, such as primitive neuroectodermal tumors, pediatric fuzzy anaplastic Wilms tumor, pediatric Wilms tumor of favorable histoma , neuroblastoma, numerous myelocytic infiltrates from pediatric neuroblastoma, childhood B-cell precursor cancers (such as leukemia), childhood osteosarcoma, childhood rhabdomyosarcoma, childhood rhabdomyosarcoma, and childhood T-cell carcinomas such as lymphoma and skin cancer, and the like.

[0111] Autoimmune disorders include acquired immune deficiency syndrome (AIDS), Canale-Smith syndrome, hemolytic anemia, inflammatory diseases and thrombocytopenia, acute or chronic immune disease associated with organ transplantation, Addison's disease, allergic diseases, alopecia, alopecia areata, a disease atherosclerosis / arteriosclerosis, arteriosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme disease, psoriatic arthritis and reactive arthritis), pemphigus

EP-2507211B1EN autoimmune, abetalipoprotemia, diseases associated with acquired immunodeficiency, acute organ transplant immunological disease, acquired acocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute inflammation adenocarcinomas, extrasocular extrasystoles, adult respiratory distress syndrome (acute), dementia associated with AIDS, alcoholic cirrhosis, alcohol-induced liver damage, alcohol-induced liver inflammation, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis associated with lung disease, degeneration of anterior horn cells, antibody cytotoxicity, antiphospholipid syndrome, hypersensitivity reactions against receptors, aortic and peripheral aneurysms, aortic rupture, hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, weakness, asthma, ataxia, atopic allergy, atrial fibrillation or atrial fibrillation (persistent or atrial fibrillation) ), atrial flutter, atrioventricular block, atrophic autoimmune hypoplasia of the thyroid gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hepatitis 1 (classic autoimmune or lupus hepatitis), autoimmune hypoglycemia, autoimmune neutrophil deficiency, autoimmune thrombocytopenia, autoimmune thyroid disease, B lymphoma lymphoma, bone graft rejection, bone marrow rejection ), bronchiolitis obliterans, bundle branch block (His), burns, cachexia, cardiac arrhythmias, arrhythmia syndrome, heart tumors, cardiomyopathy, inflammatory response at cardiopulmonary bypass, cartilage transplant rejection, cerebral cortical degeneration, brain disorders, chaotic or multifocal atrial tachycardia, chemotherapy related disorders, chlamydia, cholestasis, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immune transplant disease, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucosal and skin candidiasis, chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, primary colorectal immunodeficiency (primary gamma-globulin deficiency in the blood) ), conjunctivitis, connective tissue disease associated with interstitial lung disease, contact dermatitis, haemolytic anemia resulting in a positive Coombs test, pulmonary heart, Creutzfeldt-Jakob disease, hidden cause autoimmune hepatitis, hidden cause fibrotic inflammation, septicemia with negative cultures, cystic fibrosis, disorders associated with cytokine therapy, Crohn's disease, Crohn's disease, boxing dementia, demyelinating diseases, dengue hemorrhagic fever, dermatitis, scleroderma, dermatological conditions, dermatomyositis / polymyositis associated with lung disease, diabetes mellitus, diabetic arteriosclerosis, diabetes mellitus, dementia with Lewy bodies, dilated cardiomyopathy, congestive cardiomyopathy, thyroid lupus erythematosus, cerebral base disorders, disseminated intravascular coagulation. in middle age, drug-induced interstitial lung disease, drug-induced hepatitis, drug-induced drug movement disorders, caused by drugs that block dopamine receptors in the CNS, sensitivity to drugs, eczema, encephalomyelitis, endocrine disorders, enterocolic synovitis, epiglottitis, Epstein-Barr virus infection, limb dysentery,

EP-2507211B1EN extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus rejection, Friedreich's ataxia, functional disorders of the peripheral arteries, female-type infertility, fibrosis, pulmonary fibrosis, fungal septicemia, bronchiolar ganglion, gastritis, ganglion kidney, glomerulonephritis, Goodpasture's syndrome, gout autoimmune hypoplasia of the parathyroid gland (Hashimoto's disease), gouty arthritis, rejection of any organ or tissue transplant, graft versus host disease, gram-negative sepsis, gram-positive sepsis, granulomas due to intracellular microorganisms, group B streptococcal disease, GBS disease, with hemosiderosis, hairy cell leukemia, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hematologic malignancies (leukemia and lymphoma), hemolytic anemia, hemorrhagic syndrome / thrombolytic thrombocytopenia, haemorrhage, Henon-Schochlein disease, hepatitis A, hepatitis B , HIV infection / HIV-related neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's chorea, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis assessment, idiopathic Addison's disease, idiopathic white blood cell deficiency, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, idiosyncratic liver disease, childhood spondylitis aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonia, iris and vitreous inflammation / uveitis / optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile pernicious anemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki disease, renal transplant rejection , leprosy, cortico-spinal disease, linear IgA disease, lipidemia, liver transplant rejection, Lyme disease, lymphoedema, lymphocytic infiltrative lung disease, malaria, spontaneous male infertility or unspecified, malignant histiocytosis, malignant melanoma, meningitis, meningococcal infection, small vasculitis, migraine headache, mixed mitochondrial disorder, mixed connective tissue disease, pneumonia associated with mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multi-system degeneration (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), chronic fatigue syndrome (described in the Royal Free Hospital), pregnant myasthenia gravis, inflammation of small vessels in the kidneys, mycobacterial infection (Lady Windermere syndrome), tuberculosis, myelodysplastic syndrome, myocardial infarction, ischemic heart disease, nasopharyngeal cancer, chronic neonatal lung disease, nephritis, non-inflammatory kidney disease, nephrotic syndrome, neurodegenerative diseases, neurogenic and muscular atrophy, fever associated with neutropenia, nonalcoholic fatty liver, closure of the abdominal aorta and its branches, arterial occlusive disorders, organ rejection rejection, orchitis / epididymitis, orchitis / vasectomy reversal procedures, abnormal enlargement of the organ, osteoarthritis , hypo-ovarian disease, pancreas transplant rejection, parasitic diseases, parathyroid transplant rejection, Parkinson's disease, Pelvic inflammatory disease, pemphigus vulgaris, pemphigus vulgaris, pemphigoid, persistent rhinitis, pericardial disease, peripheral arteriosclerosis, peripheral vascular disorders, peritonitis, pernicious anemia, glaucomatous inflammation

EP-2507211B1EN, pneumonia caused by Pneumocystis carinii, pneumonia, POEMS syndrome (syndrome including polyneuropathy, organ enlargement, endocrinopathy, monoclonal gammopathy, and skin lesions), post-perfusion syndrome, post-perfusion syndrome, post-cardiotomy syndrome after myocardial infarction, interstitial pneumonia after infection, premature loss of ovarian function, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, progressive spinal palsy, psoriasis, type 1 psoriasis, type 2 psoriasis, psoriatic arthritis, secondary pulmonary hypertension after connective tissue disease, pulmonary nodular arteritis disease, post-inflammatory interstitial lung disease, radiation fibrosis, radiation therapy, Raynaud's syndrome and disease, Raynoud's disease, Refsum's disease, regular tachycardia with narrow QRS, Reiter's disease, kidney disease not otherwise specified, renal hypertension, reperfusion injury, limiting cardiomyopathy, rheumatoid arthritis associated with interstitial lung disease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome, scleroderma, senile chorea, senile dementia ego, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell anemia, Sjógren's disease associated with lung disease, Sjórgren's syndrome, skin allograft rejection, skin lesions syndrome, small bowel transplant rejection, production of antibodies against own sperm, multiple sclerosis (all subtypes), spinal ataxia, spinal cord and cerebellar degeneration, arthritis involving the spine joints, arthritis involving the spine joints, sporadic type I glandular deficiencies, sporadic type II glandular deficiencies, Still's disease, streptococcal myocarditis, stroke, cerebellar lesions, subacute sclerosing encephalitis, sympathetic urethritis, syncope, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory response syndrome, systemic rheumatoid arthritis from adolescence, systemic lupus erythematosus, systemic lung disease lupus erythematosus, systemic sclerosis, interstitial lung disease associated with systemic sclerosis, T cell or FAB ALL diseases, Takayasu disease / arteritis, telangiectasia, Th2 and Th1 type diseases, thromboangiitis obliterans, thrombocytopenia, thyroiditis, toxicity, toxic shock syndrome, transplants, trauma / hemorrhage, autoimmune hepatitis 2 (hepatitis with anti-LKM antibodies), type B insulin resistance with dark keratosis, type III hypersensitivity reactions, type IV hypersensitivity, ulcerative colitis with arthritis, ulcerative colitis, unstable angina, uremia, diuretic sepsis, urticaria, uveitis, heart valve diseases, varicose veins, vasculitis, interstitial lung disease with vasculitis, vein disease, thrombosis, fibrosis ventricular, vitiligo acquired in acute liver disease, viral and fungal infections, viral encephalitis / aseptic meningitis, associated with viruses, hemafacitic syndrome, Wegener's granulomatosis, Wernicke-Korsakov syndrome, Wilson's disease, any organ or tissue xenograft rejection, joint disease associated with Yersinia and Salmonella infection, and the like.

Schemes and experimental data [0112] The following abbreviations have the meanings indicated. ADDP means 1,1 '- (azodicarbonyl) dipiperidine; AD-mix-e means mixture (DHQD)₂PHAL, K₃Fe (CN)₆, K₂WHAT₃, and K₂SO₄; 9-BBN means 9-borabicyclo [3.3.1] nonane; Boc is a tert-butoxycarbonyl group; (DHQD)₂Phal

EP-2507211B1PL is 1,4-phthalazinyl dihydroquinidine diether; DBU means 1,8-diazabicyclo [5.4.0] undec-7-ene;

DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means N, N-dimethylaminopyridine; DMF means N, N-dimethylformamide; dmpe means 1,2-bis (dimethylphosphine) ethane; DMSO means dimethyl sulfoxide; dppb means 1,4-bis (diphenylphosphine) butane; dppe means 1,2-bis (diphenylphosphine) ethane; dppf means 1,1'bis (diphenylphosphine) ferrocene; dppm means 1,1-bis (diphenylphosphine) methane; EDA &amp; HCl means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means O- (7-azabenzotriazol-1-yl) -N, N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; MPBH₃ is cyanoborohydride on macroporous triethylammonium methylpolystyrene; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh₃means triphenylphosphine.

[0113] The following schemes are presented to give what is believed to be the most useful and easily understood description of procedures and conceptual aspects of methods for making compounds disclosed herein. The compounds disclosed herein can be prepared by chemical synthesis methods, examples of which are shown herein. It should be understood that the order of steps in the methods can be varied, that reagents, solvents and reaction conditions can replace those that are specifically mentioned, and that sensitive moieties can be protected and deprotected as necessary.

[0114] The following schemes are suitable for the preparation of compounds of the invention as long as they lead to compounds of Examples 412-458.

DIAGRAM 1

<img file="PL2507211T3_D0001.tif" />

[0115] Compounds of formula (4) can be prepared as shown in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I) which are representative of the compounds disclosed herein. Compounds of formula (1) in which R is an alkyl group can be converted to compounds of formula (2) using Z³L¹MgX¹. where X¹ is a halide, in a solvent such as but not limited to ether or tetrahydrofuran. Compounds of formula (3) can be prepared from compounds of formula (2) using a strong base such as NaH and R⁵⁷X²where X²means halide. Compounds of formula (3), treated with aqueous NaOH or LiOH, will give compounds of formula (4).

EP-2507211B1PL

DIAGRAM 2

<img file="PL2507211T3_D0002.tif" />

[0116] As shown in Scheme 2, compounds of formula (5) can be reacted with compounds of formula (6) and a reducing agent to give compounds of formula (7). Examples of reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, polymer-based cyanoborohydride, and the like. The reaction is typically carried out in a solvent such as, but not limited to, methanol, tetrahydrofuran, and dichloromethane, or mixtures thereof. Compounds of formula (8) can be prepared from compounds of formula (7) as described in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I).

DIAGRAM 3

<img file="PL2507211T3_D0003.tif" />

[0117] Compounds of formula (9), reacted with a compound of formula (10), wherein X is a halide or trifluoromethanesulfonate, and a base, will give a compound of formula (11). Bases useful in the reaction include triethylamine, diisopropylethylamine, and the like. Compounds of formula (13) in which Y is a substituent on Z³, can be prepared from compounds of formula (11) and compounds of formula (12) using Suzuki coupling conditions known to those skilled in the art and readily available in the literature. Compounds of formula (14) can be prepared from compounds of formula (13) as described in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I).

DIAGRAM 4

<img file="PL2507211T3_D0004.tif" />

[0118] As shown in Scheme 4, compounds of formula (17) can be prepared from compounds of formula (15) and compounds of formula (16) wherein R is an alkyl group using Suzuki coupling conditions known to those skilled in the art and readily available in literature. Compounds of formula (17) can be reduced to compounds of formula (18) using a reducing agent such as LiAlH₄ in a solvent such as, but not limited to, diethyl ether or THF. Compounds of formula (19) can be prepared from compounds of formula (18) using Dess-Martin periodinate or Swern oxidation conditions known to those skilled in the art and readily available in the literature. Compounds of formula (19) can be reacted with a compound of formula (5) and a reducing agent to give compounds of formula (20). Examples of reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, polymer-based cyanoborohydride, and the like. The reaction is typically carried out in a solvent such as, but not limited to, methanol, tetrahydrofuran, 1,2-dichloroethane, and dichloromethane, or mixtures thereof. Compounds of formula (21) can be prepared from compounds of formula (20) as described in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I). DIAGRAM 5

<img file="PL2507211T3_D0005.tif" />

[0119] As shown in Scheme 5, compounds of formula (22) wherein R is an alkyl group can be converted to compounds of formula (23) by subjecting these first reactions where X¹ is Cl, Br, I, or CF3SO3-, and compounds of formula R⁴¹-OH and catalyst, with or without first base. Examples of catalysts include copper (I) -toluene trifluoromethanesulfonate complex, PdCl2, Pd (OAc)₂, and South₂(Dba)₃. Examples of the first bases include triethylamine, N, N-diisopropylethylamine, Cs₂WHAT₃, Na₂WHAT₃, K₃AFTER₄, and mixtures thereof.

[0120] Compounds of formula (22) can also be converted to compounds of formula (23) by subjecting these first reactions when X¹ is Cl, F, or NO2, and compounds of formula R⁴¹-OH with the first base. Examples of the first bases include triethylamine, N, N-diisopropylethylamine, Cs2CO₃, Na₂WHAT₃, K₃AFTER₄, and mixtures thereof.

EP-2507211B1PL

DIAGRAM 6

<img file="PL2507211T3_D0006.tif" />

[0121] Compounds of formula (18) can be reacted with methanesulfonyl chloride and a base such as, but not limited to, triethylamine followed by N-tert-butoxycarbonylpiperazine, to give compounds of formula (24). Compounds of formula (25) can be prepared by reacting compounds of formula (24) with triethylsilane and trifluoroacetic acid. Compounds of formula (25) can be reacted with compounds of formula (26) and HK₂AFTER₄ to give compounds of formula (27) in a solvent such as, but not limited to, dimethyl sulfoxide. Compounds of formula (28) can be prepared from compounds of formula (27) as described in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I).

DIAGRAM 7

<img file="PL2507211T3_D0007.tif" />

[0122] As shown in Scheme 7, compounds of formula (1) can be reacted with the appropriate triphenylphosphonium bromide of formula (29) and a base such as, but not limited to, sodium hydride or n-butyl lithium, to give compounds of formula (30). The reaction is typically carried out in a solvent such as THF or DMSO. Compounds of formula (31) can be prepared from compounds of formula (30) as described in Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I).

EP-2507211B1PL

<img file="PL2507211T3_D0008.tif" />

[0123] As shown in Scheme 8, compounds of formula (32), which can be prepared as described herein, can be converted to compounds of formula (33) by subjecting these first reactions to ammonia. Compounds of formula (33) can be converted into compounds of formula (I) by reacting the former and compounds of formula (4), (8), (14), (21), (28), (31), or ( 38), and the coupling agent, with or without the first base. Examples of coupling agents include 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, 1,1'-carbonyldiimidazole, and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Examples of the first bases include triethylamine, N, N10 diisopropylethylamine, 4- (dimethylamino) pyridine, and mixtures thereof.

DIAGRAM 9

<img file="PL2507211T3_D0009.tif" />

[0124] Compounds of formula (33), prepared as described in Scheme 8, can also be converted to compounds of formula (I) by reacting the first and compounds of formula (34) and the first base.

Examples of the first bases include, but are not limited to, sodium hydride, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, and mixtures thereof.

DIAGRAM 10

<img file="PL2507211T3_D0010.tif" />

[0125] As shown in Scheme 10, compounds of the formula (35) in which L is a bond, an alkyl group, O, S, S (O), S (O)₂, NH, etc., can be reacted with compounds of formula (36) to give compounds of formula (37). The reaction is typically conducted at elevated temperatures in a solvent such as, but not limited to, dimethyl sulfoxide, and may require the use of a base such as, but not limited to, potassium phosphate, potassium carbonate, and the like. Compounds of formula (38) can be prepared from compounds of formula (37) as described in

Scheme 1, and can be used as described in Scheme 8 for the preparation of compounds of formula (I).

EP-2507211B1PL

DIAGRAM 11

<img file="PL2507211T3_D0011.tif" />

[0126] Compounds of formula (39) wherein Y is as described herein for substituents on Z³, can be prepared from compounds of formula (39A) wherein X is a halide or triflate, and YB (OH)₂, using Suzuki coupling conditions known to those skilled in the art and readily available in the literature. Compounds of formula (39) can be reacted with tert-butyl piperazine-1-carboxylate and a reducing agent such as sodium triacetoxyborohydride to give compounds of formula (40). The reaction is typically carried out in a solvent such as, but not limited to, methylene chloride. Compounds of formula (41) can be prepared from compounds of formula (40) by reacting the latter with R⁵⁷X, where X is a halide, and NaH in a solvent such as N, N-dimethylformamide, and then the resulting material can be treated with triethylsilane and trifluoroacetic acid in dichloromethane. Compounds of formula (41) can be used as described in Scheme 10 where L¹-FROM³ has the meaning as shown in the formula (41).

DIAGRAM 12 _R37A

<td>OY^jΥγ ° (6)% -Yr⁵⁷ *</td><td>rT ° ΧΎ ' R37aT_FROM3</td><td>Λ -Yr⁵⁷r37aT₂3</td>

<td></td><td> (42)</td><td> (43)</td>

[0127] As shown in Scheme 12, substituted piperazin-2-ones in which R⁵⁷ is an alkyl group, can be reacted with compounds of formula (6) and a reducing agent such as sodium triacetoxyborohydride in dichloromethane to give compounds of formula (42). Compounds of formula (42) can be reduced to compounds of formula (43) using a reducing agent such as but not limited to lithium aluminum hydride in a solvent such as but not limited to tetrahydrofuran. Compounds of formula (43) can be used as described in Scheme 10, where L¹-FROM³has the meaning as shown in the formula (43).

[0128] The following examples are presented to give what is believed to be the most useful and easily understood description of the procedures and ideological aspects of the methods for making the compounds disclosed herein. The compounds shown in the examples were named using the ACD / ChemSketch programs, version 5.06 (June 5, 2001, Advanced Chemistry Development Inc., Toronto, Ontario), ACD / ChemSketch, version 12.01 (May 13, 2009). Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw®, version 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using ChemDraw®, version 9.0.5 (CambridgeSoft, Cambridge, MA).

[0129] Of the following examples, Examples 412-458 relate to compounds of the invention.

EXAMPLE 1

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

EXAMPLE 1A

Tert-butyl 4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazine-1-carboxylate [0130] 4'-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl piperazine-1-carboxylate ( 4.23 g) and sodium triacetoxyborohydride (5.61 g) in CH₂cl₂ (60 ml) was stirred for 24 hours. The mixture was treated with methanol and poured into ether. The extract was washed with water and brine and concentrated. The concentrate was chromatographed on silica gel using 2-25% ethyl acetate / hexane.

EXAMPLE 1B

1 - ((4'-chlorobiphenyl-2-yl) methyl) piperazine EXAMPLE 1A (3.0 g) and triethylsilane (1 ml) were stirred in dichloromethane (30 ml) and trifluoroacetic acid (30 ml) for 2 hours . The mixture was concentrated, dissolved in ether and concentrated again.

EXAMPLE 1C

Methyl 2-bromo-4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0132] Methyl 2-bromo-4-fluorobenzoate (3 g), EXAMPLE 1B (4 , 43 g), and K₂WHAT₃ (3.56 g) was stirred in DMSO (35 ml) at 125 ° C for 24 hours. The mixture was cooled, dissolved in ethyl acetate (500 ml), washed with water and brine, dried over Na₂SO₄, filtered and concentrated. The concentrate was chromatographed on silica gel with 5-25% ethyl acetate / hexane.

EXAMPLE 1D

3 - ((dimethylamino) methyl) phenol 3-Hydroxybenzaldehyde (1.0 g), 2M dimethylamine in THF (5 ml), and sodium triacetoxyborohydride (2 g) in CH₂cl₂ (10 ml) was stirred for 24 hours. The mixture was treated with methanol and chromatographed on silica gel with 2-25% ethyl acetate / hexane.

EXAMPLE 1E

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3 - ((dimethylamino) methyl) phenoxy) benzoate [0134] EXAMPLE 1C (400 mg), EXAMPLE 1D (260 mg), Cs₂WHAT₃ (570 mg), 1-naphthoic acid (2.96 g), copper (I) -toluene trifluoromethanesulfonate complex (245 mg), ethyl acetate (9 μΕ), and 4A sieves (30 mg) in toluene (2 ml) were mixed at 105 ° C for 24 hours. The mixture was cooled and dissolved in ethyl acetate (100 ml) and water (40 ml). The layers were separated and the extract was washed twice with Na solution₂WHAT₃ and brine, dried, and concentrated. The concentrate was chromatographed on silica gel with 25-50% ethyl acetate / hexane.

EXAMPLE 1F 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3 - ((dimethylamino) methyl) phenoxy) benzoic acid [0135] EXAMPLE 1E (750 mg ) was stirred in 25 ml of a 2: 1 dioxane / 1M NaOH mixture at 80 ° C for 4 hours. The solution was cooled and adjusted to pH 4 with NaH solution₂AFTER₄ and concentrated HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na₂SO₄), and concentrated.

EXAMPLE 1G

EP-2507211B1PL

3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonamide 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl) methylamine (1.14 g), and triethylamine (1 g) was stirred in THF (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH solution₂AFTER₄ and brine, and dried (Na₂SO₄), filtered and concentrated. The product was triturated with ethyl acetate.

EXAMPLE 1H

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3 - ((dimethylamino) methyl) phenoxy) -N- ((3 -nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 1F (128 mg), EXAMPLE 1G (73 mg), 1-ethyl-3- (3-hydrochloride) - (dimethylamino) propyl) carbodiimide (88 mg), and 4-dimethylaminopyridine (28 mg) was stirred in CH₂cl₂ (3 ml) for 24 hours. The mixture was cooled and chromatographed on silica gel with 0-10% methanol / ethyl acetate.¹H NMR (300 MHz, DMSO-d₆) δ 11.15 (br s, 1H), 8.63 (dd, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.44-7.53 (m, 5H ), 7.36 (m, 3H), 7.22 (m, 3H), 7.01 (s, 1H), 6.92 (d, 1H), 6.78 (d, 1H), 6.44 (s, 1H), 4.17 (m, 2H), 3.86 (dd, 2H), 3.33 (m, 6H), 3.16 (m, 4H), 2.66 (s, 6H) , 2.37 (br s, 4H), 1.91 (m, 1H), 1.63 (d, 2H), 1.29 (m, 2H).

EXAMPLE 2

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

EXAMPLE 2A

3- (methylamino) phenol [0138] Ethylamine was bubbled into a solution of 4-hydroxybenzaldehyde (2.0 g) and sodium triacetoxyborohydride (5.2 g) in CH₂cl₂ (60 ml) for 1 hour, and the mixture was capped and stirred for 24 hours. A 1M NaOH solution (10 ml) was added followed by addition of di-tert-butyl dicarbonate (3.57 g) and triethylamine (2.28 ml) and the mixture was stirred for 24 hours. The solution was cooled and adjusted to pH 4 with NaH solution₂AFTER₄ and concentrated HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na₂SO₄), and concentrated. The concentrate was chromatographed on silica gel with 20% ethyl acetate / hexane.

EXAMPLE 2B

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylamino) phenoxy) benzoate [0139] EXAMPLE 1C (457 mg), EXAMPLE 2A ( 225 mg), cesium carbonate (595 mg), copper (I) -toluene trifluoromethanesulfonate complex (41 mg), and ethyl acetate (0.016 mL) in toluene (5 mL) was stirred at 110 ° C for 72 hours. The mixture was cooled and chromatographed on silica gel with 5-25% ethyl acetate / hexane.

EXAMPLE 2C 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylamino) phenoxy) benzoic acid [0140] This EXAMPLE was performed by substituting EXAMPLE 2B for EXAMPLE 1E in EXAMPLE 1F.

2D EXAMPLE

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylamino) phenoxy) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0141] This EXAMPLE was carried out by substituting EXAMPLE 2C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, DMSO-d₆) δ 11.60 (brs, 1H), 8.37 (s, 1H), 7.69 (d, 1H), 7.58 (d,

EP-2507211B1PL

1H), 7.47 (m, 5H), 7.38 (m, 3H), 7.24 (m, 1H), 6.95 (d, 1H), 6.89 (dd, 1H), 6, 61 (d, 1H), 6.26 (s, 1H), 6.13 (d, 1H), 5.97 (s, 1H), 5.92 (d, 1H), 5.59 (br s, 1H), 3.84 (dd, 2H), 3.37 (m, 6H), 3.03 (m, 4H), 2.89 (m, 2H),

2.59 (br s, 3H), 2.36 (br s, 4H), 1.91 (m, 1H), 1.62 (d, 2H), 1.24 (m, 2H).

EXAMPLE 3

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((2-methyl1H-indol-5- yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 3A

Ethyl 4-fluoro-2- (2-methyl-1H-indol-5-yloxy) benzoate [0142] Ethyl 2,4-difluorobenzoate (1.14 g), K₃AFTER₄ (1.30 g) and 2-methyl-5-indolol (0.90 g) were stirred at 110 ° C in diglyme (12 ml) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. Then the solution was concentrated. The concentrate was chromatographed on silica gel using 10% ethyl acetate / hexane.

EXAMPLE 3B

Methyl 4,4-dimethyl-2- (trifluoromethylsulfonyloxy) cyclohex-1-enocarboxylate [0143] To a suspension of washed with hexane NaH (17 g) in dichloromethane (700 ml) was added 5.5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0 ° C. After 30 minutes of stirring, the mixture was cooled to -78 ° C and trifluoroacetic anhydride (40 ml) was added. The mixture was warmed to room temperature and stirred for 24 hours. The extract was washed with brine, dried and concentrated.

EXAMPLE 3C

Methyl 2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enocarboxylate EXAMPLE 3B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and tetrakis (triphenylphosphine) ) palladium (0) (2 g) in a 2: 1 dimethoxyethane / methanol mixture (600 ml) was heated to 70 ° C for 24 hours. The mixture was concentrated. Ether was added and the mixture was filtered and concentrated.

EXAMPLE 3D (2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methanol [0145] To a mixture of LiBH₄ (13 g), EXAMPLE 3C (53.8 g) and ether (400 ml) were slowly added with methanol (25 ml) by syringe. The mixture was stirred at room temperature for 24 hours. The reaction of the mixture was quenched with 1N HCl with ice cooling. The mixture was diluted with water and extracted with ether (3 x 100 mL). The extracts were dried, and concentrated. The concentrate was chromatographed on silica gel with 0-30% ethyl acetate / hexane.

EXAMPLE 3E

Tert-butyl 4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazine-1-carboxylate [0146] Methanesulfonyl chloride (7.5 mL) was added by syringe to EXAMPLE 3D (29 , 3 g) and triethylamine (30 ml) in CH₂cl₂ (500 ml) at 0 ° C, and the mixture was stirred for 1 minute. N-tert-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at room temperature for 24 hours. The suspension was washed with brine, dried, and concentrated. The concentrate was chromatographed on silica gel with 10-20% ethyl acetate / hexane.

EXAMPLE 3F

1 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazine [0147] This EXAMPLE was performed by substituting EXAMPLE 3E for EXAMPLE 1A in EXAMPLE 1B.

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EXAMPLE 3G

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methyl-1H-indol-5-yloxy) benzoate [ 0148] EXAMPLE 3F (1008 mg), EXAMPLE 3A (900 mg), and HK₂AFTER₄ (550 mg) was stirred in DMSO (7 ml) at 140 ° C for 24 hours. The mixture was diluted with ethyl acetate, washed three times with water, washed with brine, dried, and concentrated. The concentrate was chromatographed on silica gel with 30% ethyl acetate / hexane.

EXAMPLE 3H 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methyl 1H-indol-5-yloxy) acid benzoic [0149] This EXAMPLE was carried out by substituting EXAMPLE 3G for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 3I

4- (1-methylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0150] This EXAMPLE was performed by substituting 4-amino-N-methylpiperidine for 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 3J

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((2-methyl1H-indol-5- yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0151] This EXAMPLE was performed by substituting EXAMPLE 3H for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.50 (br s, 1H), 8.55 (dd, 1H), 8.17 (d, 1H), 7.88 (dd, 1H), 7, 51 (d, 1H), 7.34 (d, 2H), 7.24 (d, 1H), 7.14 (d, 1H), 7.05 (d, 2H), 7.00 (d, 1H) ), 6.72 (d, 1H), 6.55 (d, 1H), 6.08 (d, 2H), 3.85 (m, 1H), 3.45 (m, 4H), 2.98 (br s, 4H), 2.85 (m, 2H), 2.71 (br s, 2H), 2.63 (s, 2H), 2.38 (s, 2H), 2.15 (m, 6H), 1.95 (m, 4H), 1.80 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

EXAMPLE 4

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((2-methyl1H-indol-5- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 4A

4- (3-morpholinopropylamino) -3-nitrobenzenesulfonamide [0152] 4-Fluoro-3-nitrobenzenesulfonamide (550 mg), 3- (N-morpholinyl) -1-propylamine (1.00 g), and triethylamine (1 g) stirred in THF (30 mL) for 24 hours. The mixture was diluted with ethyl acetate, washed with NaH solution₂AFTER₄ and brine, and dried (Na₂SO₄), filtered and concentrated. The product was triturated with ethyl acetate.

EXAMPLE 4B

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((2-methyl1H-indol-5- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide This EXAMPLE was carried out by substituting EXAMPLE 4A for EXAMPLE 1F and EXAMPLE 3H instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (m, 2H), 8.80 (dd, 1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.34 (d, 2H), 7.27 (d, 1H), 7.05 (m, 4H), 6.75 (d, 1H), 6.62 (d, 1H), 6.10 (d, 1H) , 3.60 (m, 4H), 3.45 (m, 2H), 3.01 (br s, 4H), 2.71 (br s, 3H), 2.38 (m, 8H), 2, 14 (br s, 6H), 1.95 (m, 2H), 1.81 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

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EXAMPLE 5

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

EXAMPLE 5A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) benzoate [0154] This EXAMPLE was performed by substituting 2-chlorophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 5B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) benzoic acid [0155] This EXAMPLE was performed by substituting EXAMPLE 5A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 5C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0156] This EXAMPLE was performed by substituting EXAMPLE 5B for EXAMPLE 1F in EXAMPLE 1H. The crude product was purified by preparative HPLC using a 250 x 50 mm C18 column and eluting with 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. ¹H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 9.58 (v br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.79 (dd, 1H), 7.71 (br s, 1H), 7.52 (m, 5H), 7.35 (m, 4H), 7.15 (d, 1H), 7.13 (m, 1H), 6.99 ( m, 1H), 6.78 (dd, 1H), 6.65 (d, 1H), 6.40 (s, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H ), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 6

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

EXAMPLE 6A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoate [0157] This EXAMPLE was performed by substituting 3-chlorophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 6B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoic acid [0158] This EXAMPLE was performed by substituting EXAMPLE 6A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 6C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0159] This EXAMPLE was performed by substituting EXAMPLE 6B for EXAMPLE 5B in EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (br s, 1H), 9.60 (v br s, 1H), 8.63 (t, 1H), 8.43 (d, 1H), 7.72 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.19 (dd, 1H), 7.14 ( d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 6.56 (d, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 7

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

EXAMPLE 7A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-chlorophenoxy) benzoate [0160] This EXAMPLE was performed by substituting 4-chlorophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 7B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-chlorophenoxy) benzoic acid [0161] This EXAMPLE was performed by substituting EXAMPLE 7A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 7C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-chlorophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0162] This EXAMPLE was performed by substituting EXAMPLE 7B for EXAMPLE 5B in EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.58 (v br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.73 (dd, 1H), 7.71 (br s, 1H), 7.50 (m, 5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H), 7.15 ( d, 1H), 6.79 (m, 3H), 6.50 (d, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 8

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

EXAMPLE 8A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitrophenoxy) benzoate [0163] This EXAMPLE was performed by substituting 3-nitrophenol for EXAMPLE 1D in

EXAMPLE 1E.

EXAMPLE 8B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitrophenoxy) benzoic acid [0164] This EXAMPLE was performed by substituting EXAMPLE 8A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 8C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitrophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0165] This EXAMPLE was performed by substituting EXAMPLE 8B for EXAMPLE 5B in EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.59 (v br s, 1H), 8.60 (t, 1H), 8.39 (d, 1H), 7.70 (m, 3H), 7.50 (m, 6H), 7.38 (m, 4H), 7.23 (m, 1H), 7.10 (d, 1H), 6.85 (dd, 1H), 6.63 (d , 1H), 4.35 (v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3, 27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 9

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (hydroxymethyl) phenoxy) -N - ((4- ( (3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 9A

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Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (hydroxymethyl) phenoxy) benzoate [0166] This EXAMPLE was carried out by substituting 3- (hydroxymethyl) phenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 9B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (hydroxymethyl) phenoxy) benzoic acid [0167] This EXAMPLE was carried out by substituting EXAMPLE 9A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 9C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (hydroxymethyl) phenoxy) -N - ((4- ( (3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0168] This EXAMPLE was carried out by substituting EXAMPLE 9B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (br s, 1H), 9.60 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.67 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.35 (br s, 1H), 7.20 (m, 2H), 6.95 (d, 1H), 6.75 (m, 3H), 6.40 (s, 1H), 4.40 (s, 2H), 4.35-2.80 (m, 22H), 1.98 (m, 2H).

EXAMPLE 10

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) -N - ((4 - ((3- morpholin-4-propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0169] This EXAMPLE was performed by substituting EXAMPLE 5B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 9.62 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.71 (br s, 1H), 7.52 (m, 5H), 7.40 (m, 3H), 7.33 (br s, 1H), 7.16 (m, 2H), 7.02 (m, 1H), 6.79 (dd, 1H), 6.70 (d, 1H), 6.40 (s, 1H), 4.35-2.80 (m, 22H), 1.98 (m, 2H).

EXAMPLE 11

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) -N - ((4 - ((3- ( dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 11A

4- (3- (dimethylamino) propylamino) -3-nitrobenzenesulfonamide [0170] This EXAMPLE was accomplished by substituting 3- (dimethylamino) -1-propylamine for 3- (N-morpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 11B

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-chlorophenoxy) -N - ((4 - ((3- ( dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0171] This EXAMPLE was carried out by substituting EXAMPLE 5B for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSOd₆) δ 11.77 (br s, 1H), 9.38 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.65 (br s, 1H), 7.52 (m,

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5H), 7.40 (m, 3H), 7.33 (br s, 1H), 7.16 (m, 2H), 7.02 (m, 1H), 6.79 (dd, 1H), 6 , 70 (d, 1H), 6.40 (s, 1H),

4.35-2.80 (m, 12H), 2.80 (s, 3H), 2.78 (s, 3H), 1.98 (m, 2H).

EXAMPLE 12

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) -N - ((4 - ((3- morpholin-4-propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0172] This EXAMPLE was performed by substituting EXAMPLE 6B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (br s, 1H), 9.63 (v br s, 2H), 8.66 (t, 1H), 8.43 (d, 1H), 7.78 (dd, 1H), 7.67 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.20 (dd, 1H), 7.14 ( d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 6.53 (s, 1H), 4.35-2.80 (m, 22H), 1.98 (m, 2H).

EXAMPLE 13

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-chlorophenoxy) -N - ((4 - ((3- morpholin-4-propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0173] This EXAMPLE was carried out by substituting EXAMPLE 7B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.63 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.69 (br s, 1H), 7.50 (m, 5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H), 7.15 ( d, 1H), 6.79 (m, 3H), 6.50 (d, 1H), 4.35-2.80 (m, 22H), 1.98 (m, 2H).

EXAMPLE 14

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) -N - ((4 - ((3- ( dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0174] This EXAMPLE was carried out by substituting EXAMPLE 6B for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSOd₆) δ 11.85 (br s, 1H), 9.63 (v br s, 2H), 8.70 (t, 1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.20 (dd, 1H), 7.14 ( d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 6.56 (s, 1H), 4.35-2.80 (m, 12H), 2.52 (s, 3H), 2.50 (s, 3H), 2.00 (m, 2H).

EXAMPLE 15

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-chlorophenoxy) -N - ((4 - ((3- ( dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) benzamide This EXAMPLE was carried out by substituting EXAMPLE 7B for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSOd₆) δ 11.81 (br s, 1H), 9.38 (v br s, 1H), 8.68 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.69 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H), 7.15 ( d, 1H), 6.80 (m, 3H), 6.46 (s, 1H), 4.35-2.80 (m, 12H), 2.81 (s, 3H), 2.79 ( s, 3H), 1.98 (m, 2H).

EXAMPLE 16

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 nitrophenyl) sulfonyl) -2 - ((1-methyl-1H-indol-4-yl) oxy) benzamide

EXAMPLE 16A

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1- (triisopropylsilyl) -1H-indol-4-ol [0176] 4-Benzyloxyindole (1 g) was treated with a 60% suspension of NaH in oil (135 mg) and triisopropylsilyl chloride (1 g) in THF, purified by flash chromatography (98 (2 ethyl acetate / hexane), then debenzylation in ethanol (35 ml) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.

EXAMPLE 16B

Methyl 2- (1H-indol-4-yloxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0177] This EXAMPLE was carried out by substituting EXAMPLE 16A for EXAMPLE 1D in EXAMPLE 1E. The crude ether-forming material was desilylated using tetrabutylammonium fluoride in a THF / water 95/5 mixture for 1 hour before purification.

EXAMPLE 16C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (1-methyl-1H-indol-4-yloxy) benzoate [0178] EXAMPLE 16B (148 mg ), 60% NaH in oil (9 mg) and methyl iodide (57 mg) in THF (1 ml) was stirred at room temperature overnight. The mixture was chromatographed on silica gel using 20% ​​ethyl acetate in hexane.

EXAMPLE 16D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (1-methyl-1H-indol-4-yloxy) benzoic acid [0179] This EXAMPLE was carried out by substituting EXAMPLE 16C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 16E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2 - ((1-methyl-1H-indol-4-yl) oxy) benzamide [0180] This EXAMPLE was carried out by substituting EXAMPLE 11A for EXAMPLE 1G and EXAMPLE 16D for EXAMPLE 1F in EXAMPLE 1H. except that purification was carried out by HPLC according to EXAMPLE 5C.¹H NMR (300 MHz, DMSOd₆) δ 11.58 (br s, 1H), 9.42 (br s, 2H), 8.64 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H), 7 , 66 (br s, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.30 (m, 1H), 7.25 (d, 1H), 7.19 (d , 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 6.75 (dd, 1H), 6.40 (d, 1H), 6.38 (s, 1H), 6 , 23 (d, 1H), 4.35-2.80 (m, 12H), 3.80 (s, 3H), 2.79 (s, 3H), 2.77 (s, 3H), 1 , 96 (m, 2H).

EXAMPLE 17

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

EXAMPLE 17A

Methyl 2- (3-acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0181] This EXAMPLE was performed by substituting 3-acetamidophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 17B 2- (3-Acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0182] This EXAMPLE was performed by substituting EXAMPLE 17A for EXAMPLE 1E EXAMPLE 1F.

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EXAMPLE 17C

2- (3- (acetylamino) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0183] This EXAMPLE was carried out by substituting EXAMPLE 17B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 11.48 (s, 1H), 9.89 (s, 1H), 8.59 (m, 1H), 8.50 (d, 1H), 7.71 (dd, 1H), 7, 47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd, 1H), 6.50 (dd, 1H ), 6.39 (d, 1H), 3.86 (dd, 2H), 3.37 (m, 2H), 3.30 (m, 6H), 3.16 (m, 4H), 2.35 (s, 4H), 2.00 (s, 3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 18

2- (4-aminophenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 18A

Methyl 2- (4- (tert-butoxycarbonylamino) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0184] This EXAMPLE was carried out by substitution of N-tert-butoxycarbonyl -4-aminophenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 18B 2- (4- (tert-butoxycarbonylamino) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0185] This EXAMPLE was performed by substituting EXAMPLE 18A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 18C

4- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo ) phenoxy) tert-butyl phenylcarbamate [0186] This EXAMPLE was performed by substituting EXAMPLE 18B for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 18D

2- (4-aminophenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0187] This EXAMPLE was performed by substituting EXAMPLE 18C for EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.41 (s, 1H), 9.54 (s, 1H), 8.66 (t, 1H), 8.59 (d, 1H), 7.86 (dd, 1H), 7, 67 (m, 1H), 7.51 (dd, 5H), 7.38 (d, 2H), 7.31 (m, 1H), 7.25 (d, 1H), 6.82 (m, 4H ), 6.69 (dd, 1H), 6.24 (m, 1H), 4.26 (s, 2H), 3.85 (dd, 2H), 3.35 (m, 4H), 3.26 (td, 4H), 3.04 (m, 4H), 2.81 (m, 2H), 1.91 (m, 1H), 1.62 (dd, 2H), 1.26 (m, 2H) .

EXAMPLE 19

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

EXAMPLE 19A

Methyl 2- (3- (tert-butoxycarbonylamino) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0188] This EXAMPLE was carried out by substituting N-tert-butoxycarbonyl -3-aminophenol instead of EXAMPLE 1D in EXAMPLE 1E.

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EXAMPLE 19B 2- (3- (tert-butoxycarbonylamino) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0189] This EXAMPLE was performed by substituting EXAMPLE 19A for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 19C

3- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo ) phenoxy) tert-butyl phenylcarbamate [0190] This EXAMPLE was performed by substituting EXAMPLE 19B for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 19D

2- (3-aminophenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0191] This EXAMPLE was carried out by substituting EXAMPLE 19C for EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.39 (s, 1H), 9.50 (s, 1H), 8.64 (t, 1H), 8.54 (d, 1H), 7.75 (dd, 2H), 7, 51 (d, 5H), 7.38 (m, 2H), 7.31 (m, 1H), 7.16 (d, 1H), 6.92 (t, 1H), 6.73 (dd, 1H ), 6.38 (d, 1H), 6.28 (m, 1H), 6.09 (m, 1H), 6.02 (d, 1H), 5.24 (m, 1H), 4.36 (m, 1H), 3.86 (dd, 2H), 3.72 (m, 1H), 3.28 (m, 8H), 3.20 (m, 1H), 3.04 (m, 3H) , 2.85 (m, 1H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 20

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

EXAMPLE 20A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-methoxyphenoxy) benzoate [0192] This EXAMPLE was performed by substituting 3-methoxyphenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 20B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-methoxyphenoxy) benzoic acid [0193] This EXAMPLE was performed by substituting EXAMPLE 20A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 20C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-methoxy-phenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0194] This EXAMPLE was performed by substituting EXAMPLE 20B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 7.47 (m, 6H), 7, 36 (m, 2H), 7.24 (m, 1H), 7.11 (m, 2H), 6.76 (dd, 1H), 6.53 (ddd, 1H), 6.35 (m, 3H ), 3.86 (m, 2H), 3.66 (s, 3H), 3.32 (m, 6H), 3.17 (m, 4H), 2.36 (m, 4H), 1.92 (m, 1H), 1.64 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 21

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

EXAMPLE 21 A

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Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (dimethylamino) phenoxy) benzoate [0195] This EXAMPLE was carried out by substituting 3- (dimethylamino) phenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 21B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (dimethylamino) phenoxy) benzoic acid [0196] This EXAMPLE was performed by substituting EXAMPLE 21A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 21C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (dimethylamino) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0197] This EXAMPLE was performed by substituting EXAMPLE 21B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.36 (s, 1H), 8.63 (t, 1H), 8.51 (d, 1H), 7.79 (dd, 1H), 7.46 (m, 6H), 7, 36 (m, 2H), 7.24 (m, 1H), 7.15 (d, 1H), 7.04 (t, 1H), 6.72 (dd, 1H), 6.39 (dd, 1H ), 6.33 (d, 1H), 6.24 (t, 1H), 6.10 (dd, 1H), 3.86 (dd, 2H), 3.32 (m, 6H), 3.13 (m, 4H), 2.83 (s, 6H), 2.34 (m, 4H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H) .

EXAMPLE 22

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-cyanophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 22A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-cyanophenoxy) benzoate [0198] This EXAMPLE was carried out by substituting 3-cyanophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 22B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-cyanophenoxy) benzoic acid [0199] A mixture of EXAMPLE 22A (0.081 g) in pyridine (2 ml) in a microwave reactor vial equipped with a magnetic stirring element was treated with LiI (0.402 g), purged with nitrogen and heated in a CEM microwave reactor at 120 ° C for 30 minutes. The mixture was concentrated, acidified with 1N HCl, extracted with ethyl acetate and dried (MgSO₄), filtered and concentrated. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 0-10% methanol in dichloromethane.

EXAMPLE 22C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-cyanophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0200] This EXAMPLE was performed by substituting EXAMPLE 22B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.78 (s, 1H), 8.62 (t, 1H), 8.41 (d, 1H), 7.72 (dd, 1H), 7.48 (m, 6H), 7, 34 (m, 4H), 7.25 (m, 1H), 7.08 (m, 3H), 6.82 (dd, 1H), 6.54 (d, 1H), 3.87 (dd, 2H ), 3.33 (m, 6H), 3.22 (m, 4H), 2.38 (m, 4H), 1.93 (m, 1H), 1.65 (dd, 2H), 1.29 (m, 2H).

EXAMPLE 23

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((2-methyl-1,3-benzothiazol-6-yl) oxy) -N- ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide

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EXAMPLE 23A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-methylbenzo [d] thiazol-6-yloxy) benzoate [0201] This EXAMPLE was carried out by substitution 2-methylbenzothiazol-6-ol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 23B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-methylbenzo [d] thiazol-6-yloxy) benzoic acid [0202] This EXAMPLE was carried out by substituting EXAMPLE 23A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 23C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((2-methyl-1,3-benzothiazol-6-yl) oxy) -N ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0203] This EXAMPLE was performed by substituting EXAMPLE 23B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 11.78 (s, 1H), 8.56 (t, 1H), 8.40 (d, 1H), 7.71 (d,

2H), 7.64 (dd, 1H), 7.51 (m, 5H), 7.37 (d, 2H), 7.32 (m, 1H), 7.28 (d, 1H), 6, 98 (dd, 1H), 6.79 (dd, 1H),

6.51 (m, 1H), 4.33 (br s, 1H), 3.87 (dd, 2H), 3.69 (br s, 2H), 3.28 (m, 4H), 3.04 (br s, 2H), 2.84 (br s, 1H),

2.74 (s, 3H), 2.49 (m, 4H), 1.90 (br s, 1H), 1.63 (dd, 2H), 1.28 (m, 3H).

EXAMPLE 24

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((2-methyl-1,3-benzothiazol-5-yl) oxy) -N- ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 24A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-methylbenzo [d] thiazol-5-yloxy) benzoate [0204] This EXAMPLE was carried out by substitution 2-methylbenzothiazol-5-ol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 24B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-methylbenzo [d] thiazol-5-yloxy) benzoic acid [0205] This EXAMPLE was carried out by substituting EXAMPLE 24A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 24C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((2-methyl-1,3-benzothiazol-5-yl) oxy) -N ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0206] This EXAMPLE was performed by substituting EXAMPLE 24B and EXAMPLE 4A for EXAMPLE 1F and EXAMPLE 1G, respectively EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (s, 1H), 9.48 (br s, 1H), 8.64 (t, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7, 76 (dd, 1H), 7.50 (m, 5H), 7.37 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.04 (d, 1H ), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s, 1H), 4.35 (br s, 1H), 3.98 (m, 3H), 3 , 77 (br s, 2H), 3.60 (t, 4H), 3.49 (m, 2H), 3.15 (m, 4H), 3.04 (m, 4H), 2.75 (s , 3H), 2.56 (m, 2H), 1.94 (m, 2H).

EXAMPLE 25

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4- (4 - ((4'-chloro-l, 1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2 - ((2-methyl-1,3-benzothiazol-5-yl) oxy) benzamide [0207] This EXAMPLE was performed by substituting EXAMPLE 24B and EXAMPLE 11A for EXAMPLE 1F and EXAMPLE 1G, respectively 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.23 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.88 (d, 1H), 7, 77 (dd, 2H), 7.51 (m, 6H), 7.39 (m, 3H), 7.32 (br s, 1H), 7.19 (m, 1H), 7.04 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.49 (br s, 1H), 4.37 (br s, 1H), 3.76 (br s, 2H) , 3.49 (m, 4H), 3.11 (m, 4H), 2.79 (s, 3H), 2.77 (s, 3H), 2.76 (s, 3H), 1.94 ( m, 2H).

EXAMPLE 26

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) -3-oxopropyl) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 26A

3- (2-hydroxyphenyl) -N, N-dimethylpropanamide [0208] A solution of chroman-2-one (444 mg) in THF (1 mL) was treated with dimethylamine (7.5 mL) and stirred at room temperature for 5 hours. The solution was concentrated. The concentrate was filtered through a thin layer of silica gel.

EXAMPLE 26B

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) -3-oxopropyl) phenoxy) benzoate [0209] This EXAMPLE accomplished by substituting EXAMPLE 26A for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 26C 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) -3-oxopropyl) phenoxy) benzoic acid [0210] This EXAMPLE was performed by substituting EXAMPLE 26B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 26D

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) -3-oxopropyl) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0211] This EXAMPLE was performed by substituting EXAMPLE 26C for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 11.74 (s, 1H), 8.65 (t, 1H), 8.44 (d, 1H), 7.73 (dd, 2H), 7.52 (m, 5H), 7.35 (d, 3H), 7.13 (dd, 2H), 6.96 (t, 1H), 6.87 (t, 1H), 6.75 (dd, 1H), 6.44 (d, 1H) , 6.39 (d, 1H), 3.87 (dd, 2H), 3.67 (br, 8H), 3.34 (t, 2H), 3.28 (t, 2H), 3.00 ( br, 2H), 2.91 (s, 3H), 2.79 (s, 3H), 2.74 (t, 2H), 2.55 (t, 2H), 1.91 (m, 1H), 1.64 (d, 2H), 1.29 (m, 2H).

EXAMPLE 27

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) -2-oxoethyl) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 27A

2- (2-hydroxyphenyl) -N, N-dimethylacetamide [0212] This EXAMPLE was accomplished by substituting benzofuran-2 (3H) -one instead of chroman-2-one in EXAMPLE 26A.

EXAMPLE 27B

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Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) -2-oxoethyl) phenoxy) benzoate [0213] This EXAMPLE accomplished by substituting EXAMPLE 27A for EXAMPLE 1D in

EXAMPLE 1E.

EXAMPLE 27C 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) -2-oxoethyl) phenoxy) benzoic acid [0214] This EXAMPLE was performed by substituting EXAMPLE 27B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 27D

4- (4 - ((4'-chloro-1 '- biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) -2-oxoethyl) phenoxy) - N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0215] This EXAMPLE was performed by substituting EXAMPLE 27C for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (t, 1H), 8.52 (d, 1H), 7.82 (dd, 1H), 7.70 (s, 1H), 7.52 (dd, 5H), 7.37 (d, 2H), 7.33 (s, 1H), 7.19 (m, 2H), 7.14 (t, 1H), 7.03 (t, 1H), 6.70 (m, 2H) , 6.23 (s, 1H), 3.86 (dd, 2H), 3.64 (s, 2H), 3.40 (br, 12H), 3.25 (t, 2H), 2.92 ( s, 3H), 2.72 (s, 3H), 1.91 (s, 1H), 1.63 (d, 2H), 1.28 (m, 2H).

EXAMPLE 28

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

EXAMPLE 28A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) propyl) phenoxy) benzoate [0216] Solution of EXAMPLE 26B (211 mg) in THF (1.7 mL) at room temperature was treated with borane (689 μL) and stirred for 24 hours. The reaction of the mixture was quenched with 1N HCl and heated at 50 ° C overnight. The solution was concentrated. The concentrate was purified by flash chromatography (0-5% 7N NH₃ in 10% methanol / dichloromethane).

EXAMPLE 28B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) propyl) phenoxy) benzoic acid [0217] This EXAMPLE was carried out by substituting EXAMPLE 28A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 28C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (3- (dimethylamino) propyl) phenoxy) N- ( (3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0218] This EXAMPLE was carried out by substituting EXAMPLE 28B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (t, 1H), 8.44 (d, 1H), 7.75 (dd, 1H), 7.51 (m,

6H), 7.39 (d, 2H), 7.32 (s, 1H), 7.16 (m, 2H), 6.98 (m, 1H), 6.90 (t, 1H), 6, 76 (d, 1H), 6.48 (d, 1H), 6.37 (s,

1H), 3.87 (d, 2H), 3.35 (m, 2H), 3.29 (m, 2H), 3.07 (s, 2H), 2.79 (s, 6H), 2, 61 (t, 2H), 1.94 (s, 2H), 1.64 (d,

2H), 1.30 (m, 2H).

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EXAMPLE 29

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

EXAMPLE 29A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) ethyl) phenoxy) benzoate [0219] This EXAMPLE was carried out by substitution EXAMPLE 27B instead of EXAMPLE 26B in EXAMPLE 28A.

EXAMPLE 29B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) ethyl) phenoxy) benzoic acid [0220] This EXAMPLE was carried out by substituting EXAMPLE 29A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 29C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (2- (dimethylamino) ethyl) phenoxy) -N- ( (3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0221] This EXAMPLE was carried out by substituting EXAMPLE 29B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (t, 1H), 8.44 (d, 1H), 7.72 (m, 2H), 7.53 (m,

5H), 7.38 (d, 2H), 7.32 (m, 1H), 7.19 (dd, 1H), 7.15 (d, 1H), 7.01 (td, 1H), 6, 90 (t, 1H), 6.79 (dd, 1H), 6.49 (d, 1H), 6.42 (d, 1H), 3.88 (m, 2H), 3.60 (br, 10H ), 3.35 (t, 2H), 3.29 (t, 4H), 2.97 (m, 2H), 2.81 (m, 6H),

1.92 (s, 1H), 1.65 (m, 2H), 1.30 (m, 2H).

EXAMPLE 30

2- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo ) phenoxy) -N, N-dimethyl-benzamide

EXAMPLE 30A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (dimethylcarbamoyl) phenoxy) benzoate [0222] This EXAMPLE was carried out by substituting 2-hydroxy-N , N-dimethylbenzamide instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 30B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2- (dimethylcarbamoyl) phenoxy) benzoic acid [0223] This EXAMPLE was performed by substituting EXAMPLE 30A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 30C

2- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo ) phenoxy) -N, N-dimethylbenzamide [0224] This EXAMPLE was performed by substituting EXAMPLE 30B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (t, 1H), 8.52 (d, 1H), 7.83 (dd, 1H), 7.71 (s,

1H), 7.51 (m, 5H), 7.30 (m, 5H), 7.20 (d, 1H), 7.13 (t, 1H), 6.82 (d, 1H), 6, 74 (m, 1H), 6.24 (d, 1H), 4.30 (s, 1H), 3.80 (br, 11H), 3.34 (t, 2H), 3.27 (t, 2H ), 2.79 (s, 3H), 2.66 (s, 3H), 1.90 (s, 1H), 1.62 (d, 2H), 1.27 (ddd, 2H).

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EXAMPLE 31

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

EXAMPLE 31A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2 - ((dimethylamino) methyl) phenoxy) benzoate [0225] This EXAMPLE was carried out by substituting EXAMPLE 30A instead of EXAMPLE 26B in EXAMPLE 28A.

EXAMPLE 31B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2 - ((dimethylamino) methyl) phenoxy) benzoic acid [0226] This EXAMPLE was carried out by substitution EXAMPLE 31A instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 31C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (2 - ((dimethylamino) methyl) phenoxy) -N- ((3 -nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0227] This EXAMPLE was carried out by substituting EXAMPLE 31B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (m, 1H), 8.38 (d, 1H), 7.70 (dd, 1H), 7.61 (d,

1H), 7.51 (d, 4H), 7.39 (m, 4H), 7.33 (s, 1H), 7.15 (m, 2H), 6.97 (t, 1H), 6, 84 (d, 1H), 6.61 (s, 1H), 6.43 (d,

1H), 4.33 (s, 2H), 3.88 (d, 2H), 3.55 (br, 10H), 3.35 (m, 2H), 3.29 (m, 2H), 2, 78 (s, 6H), 1.92 (s, 1H), 1.64 (d, 2H), 1.31 (m, 2H).

EXAMPLE 32

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

EXAMPLE 32A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-morpholinophenoxy) benzoate [0228] This EXAMPLE was performed by substituting 3-morpholinophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 32B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-morpholinophenoxy) benzoic acid [0229] This EXAMPLE was performed by substituting EXAMPLE 32A for EXAMPLE 1E EXAMPLE 1F.

EXAMPLE 32C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2- (3-morpholin-4-ylphenoxy) benzamide [0230] This EXAMPLE was carried out by substituting EXAMPLE 32B for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (br s, 1H), 9.50 (br s, 1H), 8.69 (t, 1H), 8.51 (d, 1H), 7.83 (dd, 1H), 7 , 68 (m, 1H), 7.50 (m, 5H), 7.39 (m, 2H), 7.31 (m, 1H), 7.15 (d, 1H), 7.08 (m, 1H), 6.75 (dd, 1H), 6.59 (dd, 1H), 6.40 (m, 2H), 6.23 (m, 1H), 3.71 (m, 4H), 3, 52 (m, 4H), 3.40 (m, 4H), 3.13 (m, 4H), 3.00 (m, 6H), 2.78 (s, 6H), 1.96 (m, 2H ).

EXAMPLE 33

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4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2,4-dimethyl-1,3-thiazol- 5-yl) phenoxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 33A

Methyl 2- (3- (benzyloxy) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0231] This EXAMPLE was carried out by substituting 3- (benzyloxy) phenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 33B

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-hydroxyphenoxy) benzoate [0232] EXAMPLE 33A (510 mg) in CH₂cl₂ (5 ml) cooled to 0 ° C, treated with 1M BBr₃ in CH₂cl₂ (4 ml), and stirred at room temperature for 2 hours. The reaction of the mixture was quenched with saturated NaHCO solution₃ and extracted with ethyl acetate. The extract was washed with water and brine, dried over Na₂SO₄ and concentrated. The concentrate was purified by flash column chromatography on silica gel using 0-30% ethyl acetate in hexane.

EXAMPLE 33C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (trifluoromethylsulfonyloxy) phenoxy) benzoate [0233] EXAMPLE 33B (180 mg) in THF (5 ml) was cooled to -78 ° C, and 0.5 ml of 1M lithium hexadimethylsilazide in THF was added. The mixture was stirred for 15 minutes, then treated with 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (146 mg). The mixture was warmed to room temperature overnight, quenched with saturated NH solution₄Cl and extracted with ethyl acetate. The extract was washed with water and brine, dried over Na₂SO₄ and concentrated.

EXAMPLE 33D

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2,4-dimethylthiazol-5-yl) phenoxy) benzoate [0234] EXAMPLE 33C (60 mg), 2,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole (36 mg) and dichlorobis (triphenylphosphine) palladium (II) (2 mg) was dissolved in 5 ml of a mixture of dimethoxyethane: ethanol: 2M Na solution₂WHAT₃ (7: 2: 2). The mixture was heated at 130 ° C for 15 minutes in a microwave reactor and concentrated. The concentrate was purified by flash column chromatography using 0-30% ethyl acetate / hexane.

EXAMPLE 33E 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2,4-dimethylthiazol-5-yl) phenoxy) benzoic acid [0235] This EXAMPLE was performed by substituting EXAMPLE 33D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 33F

4- (4 - ((4'-chloro-l, 1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2,4-dimethyl-1,3-thiazol- 5-yl) phenoxy) N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide This EXAMPLE was carried out by substituting EXAMPLE 33E for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ

11.80 (br s, 1H), 9.67 (br s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.78 (dd, 1H), 7.68 (m, 1H), 7.52 (m, 5H),

7.35 (m, 4H), 7.10 (d, 1H), 7.05 (d, 1H), 6.77 (m, 3H), 6.57 (m, 1H), 3.95 (m , 2H), 3.60 (m, 6H), 3.45 (m,

6H), 3.16 (m, 4H), 3.07 (m, 4H), 2.51 (s, 3H), 2.26 (s, 3H), 1.95 (m, 2H).

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EXAMPLE 34

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 34A

Ethyl 2- (2-chlorophenoxy) -4-fluorobenzoate [0237] This EXAMPLE was carried out by substituting 2-chlorophenol instead of 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 34B

Ethyl 2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex -1-enyl) methyl) piperazin-1-yl) benzoate [0238] This EXAMPLE was carried out by substituting EXAMPLE 34A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 34C 2- (2-Chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0239] This EXAMPLE accomplished by substituting EXAMPLE 34B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 34D

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0240] This EXAMPLE was performed by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 8.37 (d, 1H), 8.08 (d, 1H), 7.76 (dd, 1H), 7.62 (d, 1H), 7.36 (d, 2H), 7.35 (d, 1H), 7.07 (d, 2H), 7.07-7.03 (m, 2H), 6.90 (td, 1H), 6.71 (dd, 1H), 6.55 ( dd, 1H), 6.26 (d, 1H), 3.81 (m, 1H), 3.21 (m, 2H), 3.08 (m, 4H), 2.86 (m, 2H), 2.76 (s, 2H), 2.63 (s, 3H), 2.28-2.04 (m, 8H), 1.97 (s, 2H), 1.76 (m, 2H), 1 , 40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 35

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (3,5-dichloro- phenoxy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 35A

Ethyl 2- (3,5-dichlorophenoxy) -4-fluorobenzoate [0241] This EXAMPLE was carried out by substituting 3,5-dichlorophenol instead of 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 35B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3,5-dichlorophenoxy) benzoate [0242] This EXAMPLE was carried out by substitution of EXAMPLE 35A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 35C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3,5-dichlorophenoxy) benzoic acid

[0243] This EXAMPLE was carried out by substituting EXAMPLE 35B for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 35D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (3,5-dichloro- phenoxy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0244] This EXAMPLE was performed by substituting EXAMPLE 35C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.14 (d, 1H), 8.53 (m, 1H), 8.31 (m, 1H), 7.95 (d, 1H), 7.46 (d, 2H), 7.11 (d, 2H), 6.99 (m, 3H), 6.81 (m, 2H), 3.73 (m, 1H), 3.22 (m, 4H), 3.05 (m, 2H) , 2.85 (s, 2H), 2.56 (m, 2H), 2.46 (s, 3H), 2.30 (m, 6H), 2.14 (m, 2H), 1.95 ( m, 4H), 1.42 (m, 2H), 0.97 (s, 6H).

EXAMPLE 36

2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 36A

Ethyl 2- (3-chlorophenoxy) -4-fluorobenzoate [0245] This EXAMPLE was carried out by substituting 2-chlorophenol instead of 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 36B

Ethyl 2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0246] This EXAMPLE was carried out by substituting EXAMPLE 36A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 36C 2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0247] This EXAMPLE accomplished by substituting EXAMPLE 36B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 36D

2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide This EXAMPLE was carried out by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ

9.12 (d, 1H), 8.51 (d, 1H), 8.31 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 1H), 7.11 (m , 3H), 7.02 (m, 2H), 6.91 (dd,

1H), 6.82 (dd, 1H), 6.68 (d, 2H), 4.05 (br s, 1H), 3.55 (br s, 2H), 3.31 (s, 6H), 2.99 (s, 2H), 2.85 (s, 3H),

2.51 (br s, 3H), 2.41 (s, 6H), 1.99 (s, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 37

4- (4 - ((4'-chloro-4- (2- (dimethylamino) ethoxy) -1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3chlorofenoksy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 37A

4'-chloro-4-hydroxybiphenyl-2-carboxaldehyde 2-Bromo-5-hydroxybenzaldehyde (20 g), 4-chlorophenylboronic acid (17.1 g) and dichlorobis (triphenylphosphine) palladium (II) (1.75 g) dissolved in 475 ml of dimethoxyethane: ethanol:

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2M solution Na₂WHAT₃ (7: 2: 2). The mixture was refluxed for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed thoroughly with water and brine, dried over

MgSO₄, filtered and concentrated. The resulting solid was suspended in 500 mL of hexane:

ether (2: 1). The title compound was collected by filtration.

EXAMPLE 37B

Tert-butyl 4 - ((4'-chloro-4-hydroxybiphenyl-2-yl) methyl) piperazine-1-carboxylate [0250] The title compound was prepared by substituting EXAMPLE 37A for 4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 37C

Tert-butyl 4 - ((4'-chloro-4- (2- (dimethylamino) ethoxy) biphenyl-2-yl) methyl) piperazine-1-carboxylate [0251] EXAMPLE 37B (2 g), 2-chloro salt N, N-dimethylethanamine with hydrochloric acid (2.15 g), and cesium carbonate (9.70 g) were combined in 10 ml of N, N-dimethylformamide. The resulting mixture was heated to 80 ° C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and poured into water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed thoroughly with water and brine, dried over MgSO₄, filtered and concentrated. The crude material was suspended in 100 ml of ether and the product was obtained by filtration.

EXAMPLE 37D

2- (4'-chloro-2- (piperazin-1-ylmethyl) biphenyl-4-yloxy) -N, N-dimethylethanamine [0252] The title compound was prepared by substituting EXAMPLE 37C for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 37E

Ethyl 4- (4 - ((4'-chloro-4- (2- (dimethylamino) ethoxy) biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoate [0253] The title compound was prepared by substituting EXAMPLE 36A for EXAMPLE 3A and EXAMPLE 37D instead of EXAMPLE 3F in EXAMPLE 3G.

EXAMPLE 37F 4- (4 - ((4'-chloro-4- (2- (dimethylamino) ethoxy) biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoic acid [0254] the title was made by substituting EXAMPLE 37E for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 37G

4- (4 - ((4'-chloro-4- (2- (dimethylamino) ethoxy) -1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3chlorofenoksy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0255] The title compound was prepared by substituting EXAMPLE 37F for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.88 (br s, 1H), 9.52 (br s, 1H), 9.30 (br s, 1H), 8.45 (m, 1H), 8.21 (d, 1H), 7.78 (dd, 1H), 7.50 (m, 3H), 7.38 (m, 2H), 7.18 (m, 3H), 6.95 (m, 1H), 6.81 (dd , 1H), 6.72 (dd, 1H), 6.68 (m, 1H), 6.53 (m, 1H), 4.35 (m, 2H), 3.53 (m, 2H), 3 , 28 (m, 2H), 3.21 (m, 4H), 3.08 (m, 2H), 2.88 (s, 6H), 2.73 (m, 2H), 2.64 (m, 1H), 2.43 (s, 3H), 2.27 (m, 4H), 1.83 (m, 2H).

EXAMPLE 38

2- (2-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl ) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

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EXAMPLE 38A

Methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate To a suspension of NaH hexane washed (0.72 g, 60%) in tetrahydrofuran (30 mL) was added a solution of 2,2-dimethyl dihydro-2H -pyran-4 (3H) -one (2.0 g) in tetrahydrofuran (20 ml). The suspension was stirred at room temperature for 30 minutes. Dimethyl carbonate (6.31 mL) was added dropwise by syringe. The mixture was refluxed for 4 hours. The mixture was acidified with 5% aqueous HCl and extracted with dichloromethane (100 mL x 3) and washed with water and brine, and dried over

On₂SO₄. After filtration and concentration, the crude product was applied to a column and eluted with 10% ethyl acetate in hexane to give the product.

EXAMPLE 38B

Methyl 6,6-dimethyl-4- (trifluoromethylsulfonyloxy) -5,6-dihydro-2H-pyran-3-carboxylate To a cooled (0 ° C) mixed NaH suspension (0.983 g 60% in mineral oil, washed three times with hexane) in ether (50 mL) EXAMPLE 38A (3.2 g) was added. The mixture was stirred at 0 ° C for 30 minutes and then trifluoromethanesulfonic anhydride (4.2 ml) was added. The mixture was then stirred at room temperature overnight. The mixture was diluted with ether (200 mL) and washed with 5% HCl, water and brine. After drying over Na₂SO₄, evaporation of the solvent gave a crude product which was used without further purification.

EXAMPLE 38C

Methyl 4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate [0258] To the solution of EXAMPLE 38B (2.88 g), 4-chlorophenyl boronic acid (1.88 g) and tetrakis (triphenylphosphine) palladium (0) (0.578 g) in toluene (40 ml) and ethanol (10 ml) 2N aqueous Na solution₂WHAT₃ (10 ml). The mixture was stirred at reflux overnight. The mixture was diluted with ether (300 mL) and washed with water, brine and dried over Na₂SO₄. After filtration and evaporation of the solvent, the residue was applied to a column and eluted with 3% ethyl acetate in hexane to give the product.

EXAMPLE 38D (4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methanol [0259] To a solution of EXAMPLE 38C (1.6 g) in ether (20 ml) ) LiAlH was added₄ (1.2 g). The mixture was stirred at room temperature for 4 hours. The mixture was acidified carefully with 5% aqueous HCl and extracted with ethyl acetate (100 mL × 3) and the combined organic layers were washed with water, brine and dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude product was applied to a column and eluted with 10% ethyl acetate in hexane to give the product. EXAMPLE 38E

4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxaldehyde [0260] To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 ml) at -78 ° C dimethyl sulfoxide (6.12 mL) was added. The mixture was stirred at -78 ° C for 30 minutes and then a solution of EXAMPLE 38D (1.2 g) in dichloromethane (10 mL) was added. The mixture was stirred at -78 ° C for 2 hours before adding triethylamine (10 mL). The mixture was stirred overnight and allowed to rise to room temperature. The mixture was diluted with ether (300 mL) and washed with water, brine and dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude product was loaded onto a column and eluted with 5% ethyl acetate in hexane to give the product.

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EXAMPLE 38F

Methyl 2- (2-chlorophenoxy) -4- (piperazin-1-yl) benzoate [0261] This EXAMPLE was performed by substituting piperazine instead of EXAMPLE 3F and

EXAMPLE 34A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 38G

2- (2-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) benzoate methyl [0262] To a solution of EXAMPLE 38E (100 mg) and EXAMPLE 38F (177 mg) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (154 mg). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2 wt. aqueous NaOH, water and brine. After drying over Na₂SO₄ and filtration, the solvent was evaporated under reduced pressure and the residue was applied to a column and eluted with 30% ethyl acetate in hexane to give the product.

EXAMPLE 38H 2- (2-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazinic acid 1-yl) benzoic [0263] To a solution of EXAMPLE 38G (254 mg) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added LiOH^.H₂O (126 mg). The mixture was stirred at room temperature overnight. The mixture was then neutralized with 5% aqueous HCl and diluted with ethyl acetate (200 mL). After washing with brine, it was dried over Na₂SO₄. Filtration and evaporation of the solvent gave the product.

EXAMPLE 38I

2- (2-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl ) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0264] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 38H and EXAMPLE 3I. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.33 (d, 1H), 8.06 (d, 1H), 7.71 (dd, 1H), 7.64 (d, 1H), 7.38 (d, 2H), 7.33 (dd, 1H), 7.16 (d, 2H), 7.02 (m, 2H), 6.86 (m, 1H), 6.69 (dd, 1H), 6.49 (dd, 1H) , 6.25 (d, 1H), 4.14 (m, 2H), 3.73 (m, 1H), 3.04 (m, 10H), 2.87 (m, 2H), 2.42 ( m, 4H), 2.22 (m, 6H), 1.69 (m, 2H), 1.21 (s, 6H).

EXAMPLE 39

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

EXAMPLE 39A

2- (3- (benzyloxy) phenoxy) -N, N-dimethylethanamine [0265] A solution of 3- (benzyloxy) phenol (2.002 g), 2-chloro-N, N-dimethylethanamine (1.459 g) in N, N-dimethylformamide (50 ml) was treated with cesium carbonate (3.91 g) and stirred at 50 ° C overnight. The mixture was diluted with ethyl acetate and 1N aqueous NaOH and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography (5% 7N NH₃ in methanol - dichloromethane) to give the desired product.

EXAMPLE 39B

3- (2- (dimethylamino) ethoxy) phenol

[0266] EXAMPLE 39A (450 mg) was dissolved in ethyl acetate (10 ml). The flask was flushed with nitrogen three times and then 10% Pd / C (45 mg) was added. The reaction mixture was kept under 1 atm of hydrogen at room temperature overnight. The mixture was filtered and concentrated. The residue was filtered through a thin silica gel pad and used in the next step without further purification.

EXAMPLE 39C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) ethoxy) phenoxy) benzoate [0267] The title compound was prepared by substitution EXAMPLE 39B instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 39D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) ethoxy) phenoxy) benzoic acid [0268] The title compound was prepared by substituting EXAMPLE 39C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 39E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) ethoxy) phenoxy) N- ( (3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0269] The title compound was prepared by substituting EXAMPLE 39D for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.69 (m, 1H), 9.60 (m, 1H), 8.64 (s,

1H), 8.50 (d, 1H), 7.80 (d, 1H), 7.72 (s, 1H), 7.52 (d, 5H), 7.38 (d, 2H), 7, 33 (s, 1H), 7.19 (m, 2H), 6.78 (d,

1H), 6.65 (d, 1H), 6.45 (dd, 3H), 4.24 (s, 2H), 3.86 (d, 2H), 3.67 (s, 10H), 3, 48 (s, 2H), 3.35 (t, 2H), 3.27 (t, 2H), 2.85 (s, 6H), 1.91 (s, 1H), 1.63 (d, 2H) ), 1.27 (d, 2H).

EXAMPLE 40

2- (4-amino-3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 40A

Ethyl 2- (4-amino-3-chlorophenoxy) -4-fluorobenzoate [0270] The title compound was prepared by substituting 4-amino-3-chlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 40B

Ethyl 2- (4-amino-3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0271] The title compound was prepared by substituting EXAMPLE 40A for methyl 2-bromo-4-fluoro benzoate and EXAMPLE 3F for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 40C 2- (4-Amino-3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0272] The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 40D

EP-2507211B1PL

2- (4-amino-3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0273] The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.70 (br s, 1H), 8.60 (s, 1H), 8.20 (dd, 1H), 7.90 (dd, 1H), 7.45 (d, 1H), 7, 35 (d, 2H), 7.24 (d, 1H), 7.06 (d, 2H), 6.91 (d, 1H), 6.78 (s, 2H), 6.64 (d, 1H ), 6.14 (d, 1H), 5.24 (s, 2H), 4.03 (m, 1H), 3.52 (m, 2H), 3.10 (m, 6H), 2.80 (m, 4H), 2.73 (s, 3H), 2.18 (m, 6H), 1.99 (m, 2H), 1.82 (m, 2H), 1.38 (m, 2H) , 0.94 (s, 6H).

EXAMPLE 41

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-isopropylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 41 A

4- (1-Isopropyl-piperidin-4-ylamino) -3-nitrobenzenesulfonamide [0274] A suspension of 4-chloro-3-nitrobenzenesulfonamide (1.664 g) triethylamine (2 ml) and 1-isopropylpiperidine-4-amine (1 g) in dioxane ( 10 ml) was stirred for 16 hours at 90 ° C. The reaction mixture was cooled to room temperature and the solid material was filtered off. The solid material was washed with 20% methanol / dichloromethane, and the mixture was dried under reduced pressure to give the product.

EXAMPLE 41B

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-isopropylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0275] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 41A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.18 (d, 1H), 8.51 (d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.40 - 7.49 (m, 3H) , 7.10 (d, 2H), 7.00 - 7.06 (m, 2H), 6.94 - 6.99 (m, 1H), 6.86 (dd, 1H), 6.80 (dd , 1H), 6.54 (d, 2H), 3.90-3.99 (m, 1H), 3.41-3.55 (m, 3H), 3.10-3.21 (m, 6H ), 2.87 (s, 2H), 2.24 - 2.45 (m, 10H), 1.99 (s, 2H), 1.41 (t, 2H), 1.25 (d, 6H) , 0.95 (s, 6H).

EXAMPLE 42

2- (2-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 42A

Ethyl 2- (2-bromophenoxy) -4-fluorobenzoate [0276] The title compound was prepared by substituting 2-bromophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 42B

Ethyl 2- (2-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0277] The title compound was prepared by substituting EXAMPLE 42A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 42C 2- (2-Bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid

EP 0 2507211B1EN [0278] The title compound was prepared by substituting EXAMPLE 42B for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 42D

2- (2-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0279] The title compound was prepared by substituting EXAMPLE 42C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.81 (s, 1H), 9.24 - 9.76 (m, 2H), 8.48 (d, 1H), 8.21 (d, 1H), 7.84 (dd, 1H) , 7.50 - 7.60 (m, 2H), 7.41 (d, 2H), 7.25 (d, 1H), 7.18 (t, 1H), 7.11 (d, 2H), 6.95 (t, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.39 (s, 1H), 4.03 - 4.13 (m, 1H), 3 , 47 - 3.65 (m, 5H), 3.20 - 3.40 (m, 3H), 3.01 - 3.19 (m, 4H), 2.70 2.91 (m, 5H), 2.14 - 2.26 (m, 4H), 2.04 (s, 2H), 1.73 - 1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 43

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1- piperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 43A

Ethyl 2- (trifluoromethylsulfonyloxy) cyclohex-1-enocarboxylate [0280] The title compound was prepared as described in EXAMPLE 38B by replacing EXAMPLE 38A with ethyl 2-oxocyclohexane carboxylate.

EXAMPLE 43B

Ethyl 2- (4-chlorophenyl) cyclohex-1-enocarboxylate [0281] The title compound was prepared as described in EXAMPLE 38C by replacing EXAMPLE 38B with EXAMPLE 43A.

EXAMPLE 43C (2- (4-chlorophenyl) cyclohex-1-enyl) methanol [0282] The title compound was prepared as described in EXAMPLE 38D by replacing EXAMPLE 38C with EXAMPLE 43B.

EXAMPLE 43D

2- (4-chlorophenyl) cyclohex-1-enocarboxaldehyde [0283] The title compound was prepared as described in EXAMPLE 38E by replacing EXAMPLE 38D with EXAMPLE 43C.

EXAMPLE 43E

Methyl 2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0284] The title compound was prepared as described in EXAMPLE 38G by replacement of EXAMPLE 38E with EXAMPLE 43D.

EXAMPLE 43F 2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0285] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 43E.

EXAMPLE 43 G

EP-2507211B1PL

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4 - ((methyl -4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0286] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 43F and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.36 (d, 1H), 8.07 (d, 1H), 7.74 (dd, 1H), 7.62 (d, 1H), 7.35 (d, 2H), 7.09 (d, 2H), 7.04 (d, 1H), 6.89 (m, 1H), 6.70 (dd, 1H), 6.54 (dd, 1H), 6.25 (d, 1H) , 3.80 (m, 1H), 3.11 (m, 8H), 2.77 (m, 4H), 2.59 (m, 4H), 2.15 (m, 8H), 1.70 ( m, 8H).

EXAMPLE 44

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1 H-indazol-4- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 44A

4-methoxy-3-methyl-1H-indazole [0287] A solution of 1- (2-fluoro-6-methoxyphenyl) ethanone (1 g), hydrazine (1.04 g), and sodium acetate (0.49 g) was stirred for 72 hours in toluene (10 ml). The mixture was concentrated, dissolved in DMSO (8 mL), and heated to 135 ° C for 24 hours. The mixture was cooled, poured into ethyl acetate (200 ml), and washed 3 x with water, and brine. The organic layer was concentrated and chromatographed on silica gel with 10-100% ethyl acetate / hexane.

EXAMPLE 44B

3-methyl-1H-indazol-4-ol [0288] 1M solution BBr₃ (6.57 mL) was added to a solution of EXAMPLE 44A (0.71 g) in dichloromethane (30 mL), and the reaction was stirred for 18 hours. The reaction was stopped by the slow addition of methanol, and the mixture was concentrated and chromatographed on silica gel using 10% methanol / ethyl acetate.

EXAMPLE 44C

Ethyl 4-fluoro-2- (3-methyl-1H-indazol-4-yloxy) benzoate [0289] The title compound was prepared by substituting EXAMPLE 44B for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 44D

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methyl-1H-indazol-4-yloxy) benzoate [ 0290] The title compound was prepared by substituting EXAMPLE 44C for methyl 2-bromo-4-fluoro benzoate and EXAMPLE 3F for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 44E 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methyl 1H-indazol-4-yloxy) acid benzoic [0291] The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 44F

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1 H-indazol-4- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0292] The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,

Dimethyl sulfoxide-d₆) δ 11.95 (br s, 2H), 8.47 (m, 1H), 8.27 (d, 1H), 7.62 (d, 1H), 7.36 (d, 2H), 7, 07 (d,

2H), 6.95 (m, 2H), 6.72 (m, 2H), 6.36 (s, 1H), 5.92 (d, 1H), 3.61 (m, 4H), 3, 04 (m, 4H), 2.75 (m, 2H), 2.39 (m, 4H), 2.18 (m, 6H), 1.99 (s, 3H), 1.90 (m, 6H ), 1.77 (m, 2H), 1.41 (m, 2H), 0.94 (s, 6H).

EXAMPLE 45

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3difluorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 45A

Ethyl 2- (2,3-difluorophenoxy) -4-fluorobenzoate [0293] The title compound was prepared by substituting 2,3-difluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 45B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2,3-difluorophenoxy) benzoate [0294] The title compound was prepared by substitution of EXAMPLE 45A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 45C [0295] This EXAMPLE was performed by substituting EXAMPLE 45B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 45D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3difluorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0296] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) 9.17 (d, 1H), 8.49 (d, 1H), 8.38 (dd, 1H), 7.99 (d, 1H), 7.46 (d, 2H), 7.10 ( d, 2H), 7.01 (d, 1H), 6.85 (m, 3H), 6.69 (m, 2H), 3.70 (m, 1H), 3.21 (m, 4H), 3.05 (m, 2H), 2.84 (s, 2H), 2.57 (m, 2H), 2.46 (s, 3H), 2.28 (m, 6H), 2.11 (m , 2H), 1.94 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H).

EXAMPLE 46

2- (3-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 46A

Ethyl 2- (3-bromophenoxy) -4-fluorobenzoate [0297] The title compound was prepared by substituting 3-bromophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 46B

Ethyl 2- (3-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0298] The title compound was prepared by substituting EXAMPLE 46A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 46C 2- (3-Bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid

[0299] The title compound was prepared by substituting EXAMPLE 46B for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 46D

2- (3-bromophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0300] The title compound was prepared by substituting EXAMPLE 46C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.97 (s, 1H), 9.46 (s, 1H), 9.38 (s, 1H), 8.39 - 8.48 (m, 1H), 8.21 (d, 1H) , 7.78 (dd, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 7.08 - 7.24 (m, 5H), 6.75 - 6.86 (m , 3H), 6.58 (d, 1H), 4.08 (s, 1H), 3.62 (s, 3H), 3.55 (d, 4H), 3.23 - 3.39 (m, 3H), 3.05 - 3.20 (m, 4H), 2.78 - 2.91 (m, 5H), 2.70 - 2.78 (m, 1H), 2.13 - 2.28 ( m, 4H), 2.05 (s, 2H), 1.78 - 1.92 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 47

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-ethyl-piperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 47A

4- (1-ethylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0301] The title compound was prepared by substituting 1-ethylpiperidin-4-amine for 1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 47B

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-ethylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0302] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 47A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.18 (d, 1H), 8.50 (d, 1H), 8.36 (dd, 1H), 8.01 (d, 1H), 7.39 - 7.47 (m, 3H) , 7.10 (d, 5H), 7.03 - 7.06 (m, 2H), 7.02 (dd, 1H), 6.96 (td, 2H), 6.85 (dd, 1H), 6.80 (dd, 1H), 6.54 (d, 1H), 3.93 - 4.00 (m, 1H), 3.55 (s, 2H), 3.13 - 3.21 (m, 5H), 3.10 (q, 2H), 2.90 (s, 2H), 2.28 - 2.37 (m, 8H), 2.22 - 2.28 (m, 2H), 1.98 (s, 2H), 1.40 (t, 2H), 1.26 (t, 3H), 0.95 (s, 6H).

EXAMPLE 48

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((3- nitro-4 - ((1,2,2,6,6-pentamethylpiperidin-4-yl) amino) phenyl) sulfonyl) benzamide EXAMPLE 48A

4- (1,2,2,6,6-Pentamethylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0303] The title compound was prepared by substituting 1,2,2,6,6-pentamethylpiperidin-4-ylamine for 1-isopropylpiperidine -4-amines in EXAMPLE 41A.

EXAMPLE 48B

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((3- nitro-4 - ((1,2,2,6,6-pentamethylpiperidin-4-yl) amino) phenyl) sulfonyl) benzamide [0304] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 48A for EXAMPLE 1G 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.19 (d, 1H), 8.45 (d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.45 (d, 3H), 7.09 (d, 2H), 7.06 (s, 1H), 7.02 7.05 (m, 2H), 6.99 (td, 1H), 6.86 (dd, 2H), 6.80 (dd , 1H), 6.53 (d, 1H), 4.16 - 4.25 (m, 1H), 3.16 - 3.23 (m,

EP-2507211B1PL

4H), 2.90 (s, 2H), 2.82 (s, 3H), 2.45 - 2.54 (m, 2H), 2.31 (d, 6H), 2.17 (dd, 2H ), 1.98 (s, 2H), 1.55 (s, 6H),

1.46 (s, 6H), 1.40 (t, 2H), 0.95 (s, 6H).

EXAMPLE 49

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3difluorofenoksy) -N - (( 3-nitro-4 - ((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino) phenyl) sulfonyl) benzamide

EXAMPLE 49A

Tert-butyl 1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylcarbamate [0305] Mixture of tert-butyl piperidin-4-ylcarbamate (45 g) and dihydro-2H-pyran-4 (3H) -one (24.74 g) in dichloromethane (1000 mL) was treated with sodium triacetoxyborohydride (61.9 g), stirred at room temperature for 16 hours, washed with 1M sodium hydroxide solution and dried with anhydrous sodium sulfate, filtered and concentrated. The concentrate was subjected to flash column chromatography on silica gel using 10-20% methanol / dichloromethane. EXAMPLE 49B 1- (Tetrahydro-2H-pyran-4-yl) piperidin-4-amine dihydrochloride [0306] A solution of EXAMPLE 49A (52.57 g) in dichloromethane (900 mL) was treated with 4M aqueous HCl (462 mL), stirred vigorously at room temperature for 16 hours and concentrated.

EXAMPLE 49C

3-nitro-4- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) benzenesulfonamide [0307] A mixture of EXAMPLE 49B (22.12 g), water (43 ml), and triethylamine (43 , 6 ml) in 1,4-dioxane (300 ml) was stirred at room temperature until EXAMPLE 49B completely dissolved. The solution was then treated with 4-chloro-3-nitrobenzenesulfonamide (20.3 g), heated at 90 ° C for 16 hours, cooled and concentrated. 10% methanol in dichloromethane was added, and the solution was stirred vigorously at room temperature until a fine suspension formed, and then the mixture was filtered.

EXAMPLE 49D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3difluorofenoksy) -N - (( 3-nitro-4 - ((1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino) phenyl) sulfonyl) benzamide [0308] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.18 (d, 1H), 8.53 (d, 1H), 8.40 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 2H), 7.10 (d, 2H), 7.03 (d, 1H), 6.85 (m, 3H), 6.69 (m, 2H), 4.02 (m, 2H), 3.72 (m, 1H) , 3.31 (t, 2H), 3.21 (m, 4H), 3.11 (m, 2H), 2.83 (m, 3H), 2.66 (m, 2H), 2.30 ( m, 6H), 2.16 (m, 2H), 1.93 (m, 4H), 1.74 (m, 4H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 50

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((7-fluoro-1H-indol-5- yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 50A ((3-fluoro-4-nitrophenoxy) methylene) dibenzene [0309] Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolved in N, N-dimethylformamide (30 ml) and then K₂WHAT₃ (4.2 g) and the reaction stirred at room temperature for 60 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with 2M aqueous solution

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On₂WHAT₃ and brine, then dried over Na₂SO₄. After filtration and concentration, the crude material was purified by column chromatography using 1.5-2.0% ethyl acetate in hexane.

EXAMPLE 50B

5- (benzhydryloxy) -7-fluoro-1H-indole [0310] EXAMPLE 50A (2.0 g) was dissolved in tetrahydrofuran (60 ml) and then this solution was cooled to -40 ° C. A 1.0 M solution of vinyl magnesium bromide in tetrahydrofuran (21 ml) was then added dropwise, keeping the temperature below -30 ° C. The reaction was stirred at 40 ° C for 90 minutes, and partitioned between saturated NH solution₄Cl and ethyl acetate. The organic layer was washed with brine and dried over Na₂SO₄. After filtration and concentration, the crude material was purified by column chromatography using 2.5-3.0% ethyl acetate in hexane.

EXAMPLE 50C

7-fluoro-1H-indol-5-ol [0311] EXAMPLE 50B (240 mg) was dissolved in ethyl acetate (1 ml) and methanol (9 ml), then palladium hydroxide on carbon (35 mg) was added and the reaction stirred in room temperature in a hydrogen atmosphere from the balloon for 90 minutes. The reaction was filtered through celite and concentrated to give the crude product, which was carried on to the next step without further purification.

EXAMPLE 50D

Ethyl 4-fluoro-2- (7-fluoro-1H-indol-5-yloxy) benzoate [0312] The title compound was prepared by substituting EXAMPLE 50C for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 50E

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (7-fluoro-1H-indol-5-yloxy) benzoate [ 0313] The title compound was prepared by substituting EXAMPLE 50D for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 50F 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (7-fluoro-1H-indol-5-yloxy) benzoic acid [0314] The title compound was prepared by substituting EXAMPLE 50E for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 50G bis (2,2,2-trifluoroacetate) 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) - 2 - ((7-fluoro-1H-indol-5-yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0315] EXAMPLE 50F (35 mg), EXAMPLE 3I (17 mg), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (21 mg), and 4-dimethylaminopyridine (14 mg) was stirred in CH₂cl₂ (1.5 ml) overnight. The reaction was concentrated and the crude material was purified by preparative HPLC using a 250 x 50 mm C18 column and eluting with 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.62 (br s, 1H), 9.65, 9.45 (both v br s, together 2H), 8.55 (d, 1H), 8.17 (br d, 1H), 7, 84 (dd, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.39 (d, 2H), 7.20 (d, 1H), 7.08 (d, 2H ), 6.90 (d, 1H), 6.66 (m, 2H), 6.44 (m, 1H), 6.28 (d,

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1H), 4.02, 3.82 (both br s, together 2H), 3.60 (v br m, 4H), 3.05 (v br m, 5H), 2.85, 2.80 (br m, br s, together

5H), 2.20 (br m, 5H), 2.00 (br s, 3H), 1.80 (v br m, 2H) 1.44 (br t, 2H), 0.95 (s, 6H ).

EXAMPLE 51

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3difluorofenoksy) -N - (( 4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0316] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.21 (d, 1H), 9.00 (m, 1H), 8.36 (dd, 1H), 7.97 (d, 1H), 7.45 (d, 2H), 7.10 (d, 2H), 6.97 (d, 1H), 6.85 (d, 3H), 6.69 (d, 2H), 3.82 (m, 4H), 3.38 (q, 2H) , 3.21 (m, 4H), 2.86 (s, 2H), 2.45 (m, 6H), 2.28 (m, 6H), 1.99 (s, 2H), 1.80 ( m, 2H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 52

2- (4-amino-3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0317] The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.10 (br s, 1H), 8.80 (t, 1H), 8.56 (s, 1H), 7.82 (dd, 1H), 7.45 (d, 1H), 7, 35 (d, 2H), 7.17 (d, 1H), 7.06 (d, 2H), 6.89 (d, 1H), 6.77 (s, 2H), 6.63 (d, 1H ), 6.14 (d, 1H), 5.20 (br s, 2H), 3.61 (m, 4H), 3.46 (m, 2H), 3.07 (m, 4H), 2, 75 (m, 2H), 2.44 (m, 6H), 2.20 (m, 6H), 1.97 (m, 2H), 1.81 (m, 2H), 1.40 (m, 2H ), 0.94 (s, 6H).

EXAMPLE 53

2- (3-chlorophenoxy) -4- (4 - ((4'-chloro-4- (2-pyrrolidin-1-ylethyl) -1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) - N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide

EXAMPLE 53A

Methyl 5-formyl-2- (trifluoromethylsulfonyloxy) benzoate [0318] Trifluoromethanesulfonic anhydride (7.74 mL) was added to methyl 5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH₂cl₂ at 0 ° C, and the reaction mixture was stirred and allowed to warm to room temperature over 3 hours. The reaction mixture was diluted with CH₂cl₂ (150 ml), washed 3 x brine, dried over Na₂SO₄, filtered, and concentrated. The product was used without further purification.

EXAMPLE 53B

Methyl 4'-chloro-4-formylbiphenyl-2-carboxylate EXAMPLE 53A (14.5 g), 4-chlorophenyl boronic acid (6.88 g), CsF (12.2 g), and tetrakis (triphenylphosphine) palladium (0) was stirred at 70 ° C for 24 hours. The reaction mixture was cooled, filtered, and concentrated. The crude product was dissolved in ethyl acetate (250 mL), washed with 3 x aqueous 1M NaOH, and brine, concentrated, and chromatographed on silica gel with 10% ethyl acetate / hexane.

EXAMPLE 53C

Methyl 4'-chloro-4- (2-oxoethyl) biphenyl-2-carboxylate [0320] To a solution of (methoxymethyl) diphenylphosphine oxide (1.62 g) in 40 ml tetrahydrofuran at -78 ° C was added lithium diisopropylamide (2M, 3.3 ml), and after 3 minutes stirring EXAMPLE 53B (1.57 g), and the solution was warmed to room temperature. NaH (230 mg), and 40 ml N, N-dimethylformamide were added, and the mixture was heated to 60 ° C for 1 hour. Reaction mixture

The mixture was cooled and poured into saturated aqueous NaH solution₂AFTER₄. The resulting solution was extracted twice with ether, and the combined extracts were washed twice with water, and brine, and concentrated. The crude mixture of enol ethers was dissolved in 1M aqueous HCl (50 mL) and dioxane (50 mL), and stirred at 60 ° C for 3 hours. The reaction was cooled and poured into NaHCO solution₃. The resulting solution was extracted twice with ether, and the combined extracts were washed with water, and brine, and concentrated. The product was used without further purification.

EXAMPLE 53D

Methyl 4'-chloro-4- (2- (pyrrolidin-1-yl) ethyl) biphenyl-2-carboxylate [0321] The title compound was prepared by substituting EXAMPLE 53C for 4'-chlorobiphenyl-2-carboxaldehyde and pyrrolidine instead of piperazine-1-carboxylate tert-butyl in EXAMPLE 1A.

EXAMPLE 53E (4'-chloro-4- (2- (pyrrolidin-1-yl) ethyl) biphenyl-2-yl) methanol [0322] Diisobutylaluminum hydride (1M in hexane, 7.8 mL) was added to the solution of EXAMPLE 53D ( 0.89 g) in dichloromethane (30 ml) at 0 ° C, and the reaction was stirred for 20 minutes. The reaction was quenched by the slow addition of methanol and then poured into 1M aqueous NaOH (50 mL). The mixture was extracted twice with ethyl acetate, and the extracts were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated.

EXAMPLE 53F

4'-chloro-4- (2- (pyrrolidin-1-yl) ethyl) biphenyl-2-carboxaldehyde EXAMPLE 53E (0.85 g) and Dess-Martin periodinane (1.26 g) were stirred in dichloromethane ( 40 ml) for 90 minutes. The reaction was quenched with methanol (5 mL), concentrated, and silica gel chromatography using 10-50% ethyl acetate / hexane.

EXAMPLE 53G

Tert-butyl 4- (3- (3-chlorophenoxy) -4- (ethoxycarbonyl) phenyl) piperazine-1-carboxylate [0324] The title compound was prepared by substituting EXAMPLE 36A for methyl 2-bromo-4-fluoro benzoate and piperazine tert-butoxide -butyl instead of EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 53H

Ethyl 2- (3-chlorophenoxy) -4- (piperazin-1-yl) benzoate [0325] The title compound was prepared by substituting EXAMPLE 53G for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 53I

Ethyl 4- (4 - ((4'-chloro-4- (2- (pyrrolidin-1-yl) ethyl) biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoate [0326] The title compound was prepared by substituting EXAMPLE 53F for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 53H for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 53J 4- (4 - ((4'-chloro-4- (2- (pyrrolidin-1-yl) ethyl) biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-chlorophenoxy) benzoic acid [0327] The title compound was prepared by substituting EXAMPLE 53I for EXAMPLE 1E in EXAMPLE 1F.

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EXAMPLE 53K

2- (3-chlorophenoxy) -4- (4 - ((4'-chloro-4- (2-pyrrolidin-1-ylethyl) -1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) - N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0328] The title compound was prepared by substituting EXAMPLE 53J for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.80 (br s, 1H), 8.66 (t, 1H), 8.45 (s, 1H), 8.00 (m, 1H), 7.72 (dd, 1H), 7, 52 (d, 2H), 7.35 (m, 4H), 7.16 (m, 2H), 6.94 (d, 1H), 6.80 (d, 1H), 6.66 (d, 2H ), 6.55 (m, 1H), 4.32 (m, 1H), 3.85 (m, 2H), 3.56 (m, 2H), 3.33 (m, 8H), 3.07 (m, 6H), 2.85 (m, 2H), 2.43 (m, 2H), 2.02 (m, 2H), 1.91 (m, 4H), 1.63 (m, 2H) , 1.27 (m, 2H).

EXAMPLE 54

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3dichlorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 54A

Ethyl 2- (2,3-dichlorophenoxy) -4-fluorobenzoate [0329] The title compound was prepared by substituting 2,3-dichlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 54B

Ethyl 2- (2,3-dichlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0330] The title compound was prepared by substitution of EXAMPLE 54A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 54C 2- (2,3-dichlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0331] The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 54D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,3dichlorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0332] The title compound was prepared by substituting EXAMPLE 54C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.16 (d, 1H), 8.50 (d, 1H), 8.33 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 2H), 7.11 (t, 3H), 7.04 (d, 1H), 6.95 (t, 1H), 6.84 (dd, 1H), 6.74 (d, 1H), 6.68 (d, 1H) , 3.90 - 3.98 (m, 1H), 3.51 (d, 2H), 3.20 - 3.27 (m, 4H), 3.15 (t, 2H), 2.90 (s , 2H), 2.80 (s, 3H), 2.33 (d, 9H), 2.17 - 2.26 (m, 2H), 1.99 (s, 2H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 55

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1 H-indazol-4- yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0333] The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.95 (br s, 2H), 8.30 (d, 1H), 8.02 (d, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7, 07 (d, 2H), 6.94 (m, 2H), 6.69 (m, 2H), 6.36 (s, 1H), 5.92 (d, 1H), 3.27 (m, 4H ), 3.04 (m, 7H), 2.75 (m, 4H), 2.49 (m, 4H), 2.22 (m, 8H), 1.99 (s, 3H), 1.77 (m, 2H), 1.39 (m, 2H), 0.94 (s, 6H).

EXAMPLE 56

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2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohept-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4 - ((1metylopiperydyn -4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 56A (Z) -2- (Trifluoromethylsulfonyloxy) methyl cyclohept-1-enocarboxylate [0334] The title compound was prepared as described in EXAMPLE 38B by replacing EXAMPLE 38A with methyl 2-oxocycloheptanecarboxylate.

EXAMPLE 56B (Z) -2- (4-chlorophenyl) cyclohept-1-enocarboxylate [0335] The title compound was prepared as described in EXAMPLE 38C by replacing EXAMPLE 38B with EXAMPLE 56A.

EXAMPLE 56C (Z) - (2- (4-chlorophenyl) cyclohept-1-enyl) methanol [0336] The title compound was prepared as described in EXAMPLE 38D by replacing EXAMPLE 38C with EXAMPLE 56B.

EXAMPLE 56D (Z) -2- (4-chlorophenyl) cyclohept-1-enocarboxaldehyde [0337] The title compound was prepared as described in EXAMPLE 38E by replacing EXAMPLE 38D with EXAMPLE 56C.

EXAMPLE 56E (Z) -2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohept-1-enyl) methyl) piperazin-1-yl) benzoate [0338] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38E with EXAMPLE 56D.

EXAMPLE 56F (Z) -2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohept-1-enyl) methyl) piperazin-1-yl) benzoic acid [0339] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 56E.

EXAMPLE 56G

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) cyclohept-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4 - ((1metylopiperydyn -4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0340] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 56F and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.63 (d, 1H), 7.35 (d, 2H), 7.04 (m, 4H), 6.88 (m, 1H), 6.69 (dd, 1H), 6.52 (dd, 1H), 6.25 (d, 1H), 3.78 (m, 1H) , 3.06 (m, 6H), 2.70 (m, 4H), 2.38 (m, 4H), 2.26 (m, 5H), 2.07 (m, 4H), 1.73 ( m, 5H), 1.52 (m, 5H).

EXAMPLE 57

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4 - ((1-methylpiperidin-4- yl) amino) -3-nitrophenyl) sulfonyl) -2- (3- (trifluoromethyl) phenoxy) benzamide EXAMPLE 57A

Ethyl 4-fluoro-2- (3- (trifluoromethyl) phenoxy) benzoate

[0341] The title compound was prepared by substituting 3- (trifluoromethyl) phenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 57B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (trifluoromethyl) phenoxy) benzoate [0342] The title compound prepared by substituting EXAMPLE 57A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 57C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (trifluoromethyl) phenoxy) benzoic acid [0343] This EXAMPLE was performed by substituting EXAMPLE 57B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 57D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4 - ((1-methylpiperidin-4- yl) amino) -3-nitrophenyl) sulfonyl) -2- (3- (trifluoromethyl) phenoxy) benzamide [0344] The title compound was prepared by substituting EXAMPLE 57C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.32 (d, 1H), 8.04 (m, 1H), 7.66 (m, 2H), 7.35 (m, 3H), 7.16 (d, 1H), 7.06 (d, 2H), 6.95 (m, 3H), 6.73 (dd, 1H), 6.42 (d, 1H), 3.80 (m, 1H), 3.11 (m, 4H) , 2.83 (m, 4H), 2.63 (m, 3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.97 (m, 5H), 1.76 ( m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 58

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 nitrophenyl) sulfonyl) -2 - ((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl) oxy) benzamide

EXAMPLE 58A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy) benzoate [0345] Compound the title was prepared by substituting 3,4-dihydro-5-hydroxy-1H-quinolin-2-one instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 58B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy) benzoic acid [0346 ] The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 58C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2 - ((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl) oxy) benzamide [0347] The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.68 (s, 1H), 10.08 (s, 1H), 8.64 (t, 1H), 8.48 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 6H), 7.39 (m, 2H), 7.29 (m, 1H), 7.14 (d, 1H), 6.93 (t, 1H), 6.75 (dd, 1H) , 6.51 (d, 1H), 6.39 (m, 1H), 6.13 (d, 1H), 4.36 (m, 1H), 3.72 (m, 1H), 3.40 ( m, 6H), 3.13 (m, 4H), 2.80 (m, 4H), 2.78 (d, 6H), 2.40 (t, 2H), 1.96 (m, 2H).

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EXAMPLE 59

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3 - ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide [0348] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 131D instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.99 (d, 1H), 7.88 (m, 1H), 7.62 (d, 1H), 7.38 (m, 3H), 7.06 (d, 3H), 7.01 (d, 1H), 6.93 (t, 1H), 6.69 (m, 1H), 6.56 (d, 1H), 6.50 (s, 1H), 6.24 (d, 1H) , 3.25 (m, 10H), 3.07 (s, 2H), 3.07 (s, 3H), 2.77 (d, 3H), 2.20 (d, 5H), 2.04 ( s, 2H), 1.96 (d, 2H), 1.63 (s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 60

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,5dichlorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 60A

Ethyl 2- (2,5-dichlorophenoxy) -4-fluorobenzoate [0349] The title compound was prepared by substituting 2,5-dichlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 60B

Ethyl 2- (2,5-dichlorophenoxy) -4- (piperazin-1-yl) benzoate [0350] The title compound was prepared by substituting piperazine instead of EXAMPLE 3F and EXAMPLE 60A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 60C

2-chloro-4,4-dimethylcyclohex-1-enocarboxaldehyde [0351] To a 250 mL round bottom flask was added N, N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a colorless solution. The mixture was cooled to -10 ° C, and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was refluxed overnight. The reaction was quenched with a solution (0 ° C) of sodium acetate (25 g in 50 ml water). The aqueous layer was extracted with ether (3 x 200 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and dried under reduced pressure. EXAMPLE 60D

2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enocarboxaldehyde [0352] EXAMPLE 60C (6.8 g), 4-chlorophenylboronic acid (6.5 g) and palladium acetate (II) were added to a 1 L round bottom flask. ) (0.2 g) in water (100 ml) to give a suspension. Potassium carbonate (15 g) and tetrabutylammonium bromide (10 g) were added. After degassing by reducing pressure and admitting nitrogen, the mixture was stirred at 45 ° C for 4 hours. After filtration through silica gel, ether (4 x 200 mL) was used to extract the product. The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated and purified by flash chromatography on silica using 0 to 10% ethyl acetate in hexane to afford the title compound.

EXAMPLE 60E

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2,5-dichlorophenoxy) benzoate

[0353] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 60B for tert-butyl piperazine-1-carboxylate in

EXAMPLE 1A.

EXAMPLE 60F 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2,5-dichlorophenoxy) benzoic acid [0354] The title compound prepared by substituting EXAMPLE 60E for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 60G

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,5dichlorofenoksy) -N - (( 4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0355] The title compound was prepared by substituting EXAMPLE 60F for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 12.01 (br.s, 1H), 9.92 (br.s, 1H), 9.68 (br.s, 1H), 8.43 (m, 1H), 8.19 (d, 1H), 7.80 (dd, 1H), 7.55 (d, 1H), 7.39 (m, 3H), 7.23 (d, 1H), 7.11 (d, 2H), 6, 97 (dd, 1H), 6.85 (dd, 1H), 6.55 (m, 2H), 3.58 (m, 5H), 3.25 (m, 6H), 2.83 (m, 4H ), 2.21 (m, 4H), 2.05 (s, 2H), 1.87 (m, 2H), 1.48 (t, 2H), 0.96 (s,

6H).

EXAMPLE 61

2- (2-chloro-4-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 61 A

Ethyl 2- (2-chloro-4-fluorophenoxy) -4-fluorobenzoate [0356] The title compound was prepared by substituting 2-chloro-4-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 61B

Ethyl 2- (2-chloro-4-fluorophenoxy) -4- (piperazin-1-yl) benzoate [0357] The title compound was prepared by substituting piperazine for EXAMPLE 3F and EXAMPLE 61A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 61C

Ethyl 2- (2-chloro-4-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0358] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 61B for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 61D 2- (2-Chloro-4-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0359] The title compound was prepared by substituting EXAMPLE 61C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 61E

2- (2-chloro-4-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

[0360] The title compound was prepared by substituting EXAMPLE 61D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.40 (m, 1H), 8.08 (m, 1H), 7.78 (dd, 1H), 7.59 (d, 1H), 7.33 (m, 3H), 7.07 (m,

3H), 6.92 (m, 1H), 6.69 (dd, 1H), 6.59 (m, 1H), 6.25 (d, 1H), 3.84 (m, 1H), 3, 08 (m, 4H), 2.77 (m, 8H),

2.16 (m, 8H), 1.97 (s, 2H), 1.75 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 62

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 62A

Methyl 4,4-dimethyl-2-oxocyclopropanecarboxylate [0361] An compound was prepared according to WO 2006/035061 (page 53).

EXAMPLE 62B

Methyl 4,4-dimethyl-2- (trifluoromethylsulfonyloxy) cyclopent-1-enocarboxylate [0362] The title compound was prepared as described in EXAMPLE 38B by replacing EXAMPLE 38A with EXAMPLE 62A.

EXAMPLE 62C

Ethyl 2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-enocarboxylate [0363] The title compound was prepared as described in EXAMPLE 38C by replacing EXAMPLE 38B with EXAMPLE 62B.

EXAMPLE 62D (2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-enyl) methanol [0364] The title compound was prepared as described in EXAMPLE 38D by replacing EXAMPLE 38C with EXAMPLE 62C.

EXAMPLE 62E

2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-enocarboxaldehyde [0365] The title compound was prepared as described in EXAMPLE 38E by replacing EXAMPLE 38D with EXAMPLE 62D.

EXAMPLE 62F

Methyl 2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-enyl) methyl) piperazin-1-yl) benzoate [0366] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38E with EXAMPLE 62E.

EXAMPLE 62G 2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-enyl) methyl) piperazin-1-yl) benzoic acid [0367] Title compound prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 62F.

EXAMPLE 62H

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclopent-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0368] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 62G and EXAMPLE 3I, respectively. ¹H NMR (300 MHz,

Dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.33 (m, 5H), 7.04 (m,

2H), 6.88 (m, 1H), 6.72 (dd, 1H), 6.52 (dd, 1H), 6.28 (d, 1H), 3.78 (d, 1H), 3, 07 (d, 4H), 2.71 (m, 6H), 2.33 (m, 8H), 2.06 (m, 4H), 1.74 (m, 4H), 1.10 (m, 6H ).

EXAMPLE 63

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1-indol-4- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 63A

Ethyl 4-fluoro-2- (3-methyl-1H-indol-4-yloxy) benzoate [0369] The title compound was prepared by substituting 3-methyl-4-indolol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 63B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methyl-1H-indol-4-yloxy) benzoate [ 0370] The title compound was prepared by substituting EXAMPLE 63A for methyl 2-bromo-4-fluoro benzoate and EXAMPLE 3F instead of EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 63C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methyl 1H-indol-4-yloxy) acid benzoic [0371] The title compound was prepared by substituting EXAMPLE 63B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 63D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1-indol-4- yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0372] The title compound was prepared by substituting EXAMPLE 63C for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.92 (br s, 2H), 8.77 (m, 1H), 8.57 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7, 33 (d, 2H), 7.15 (m, 2H), 7.03 (d, 2H), 6.99 (m, 2H), 6.67 (d, 1H), 6.45 (d, 1H ), 6.12 (d, 1H), 3.68 (m, 4H), 3.47 (m, 2H), 3.02 (m, 6H), 2.73 (m, 4H), 2.43 (m, 2H), 2.14 (m, 8H), 1.99 (s, 3H), 1.91 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H) .

EXAMPLE 64

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2-chloro-3- (trifluoromethyl) phenoxy ) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide EXAMPLE 64A [0373] 2- (2-Chloro-3- (trifluoromethyl) phenoxy) -4- ethyl fluorobenzoate. The title compound was prepared by substituting 2-chloro-3- (trifluoromethyl) phenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 64B

Ethyl 2- (2-chloro-3- (trifluoromethyl) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [0374 ] The title compound was prepared by substituting EXAMPLE 64A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 64C

2- (2-chloro-3- (trifluoromethyl) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) acid EP-2507211B1EN benzoic [0375] The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 64D

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2-chloro-3- (trifluoromethyl) phenoxy ) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0376] The title compound was prepared by substituting EXAMPLE 64C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H . ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 12.02 (s, 1H), 9.76 (s, 1H), 9.52 (s, 1H), 8.42 (m, 1H), 8.17 (d, 1H), 7.82 (dd, 1H), 7.58 (d, 1H), 7.41 (m, 3H), 7.27 (m, 2H), 7.11 (d, 2H), 6.93 (d, 1H) , 6.84 (dd, 1H), 6.57 (d, 1H), 3.15 (m, 6H), 2.83 (m, 8H), 2.11 (m, 8H), 1.83 ( m, 2H), 1.47 (t, 2H), 0.96 (s, 6H).

EXAMPLE 65

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-cyclopropyl-piperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 65A

4- (1-cyclopropylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0377] To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 ml ) N, N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35 mg) were added. The mixture was stirred at reflux overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCO₃, water, and brine, and dried over Na₂SO₄. After filtration and concentration, the residue was dissolved in dichloromethane and loaded onto a column and eluted with dichloromethane (500 ml), 5% 7N NH₃ in 10% methanol in dichloromethane (1.5 L) to give the product.

EXAMPLE 65B

2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((4- ((1-cyclopropylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0378] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 34C and EXAMPLE 65A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.46 (dd, 1H), 8.22 (t, 1H), 7.81 (m, 2H), 7.53 (d, 1H), 7.37 (m, 4H), 7.14 (m, 1H), 7.07 (m, 1H), 6.99 (m, 1H), 6.72 (m, 1H), 6.29 (d, 1H), 3.75 (m, 1H) , 3.13 (s, 3H), 2.93 (d, 3H), 2.78 (s, 1H), 2.20 (m, 5H), 1.97 (m, 5H), 1.59 ( m, 5H), 0.94 (s, 6H), 0.42 (m, 5H).

EXAMPLE 66

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2 - ((3-methyl-1-indol-4- yl) oxy) -N - ((4 - ((1-methylpiperidin-4-yl) amino) -3-nitrophenyl) sulfonyl) benzamide [0379] The title compound was prepared by substituting EXAMPLE 63C for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.86 (br s, 2H), 8.51 (br s, 1H), 8.15 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7 , 33 (d, 2H), 7.15 (m, 2H), 7.03 (d, 2H), 6.94 (m, 2H), 6.62 (d, 1H), 6.38 (d, 1H), 6.12 (d, 1H), 3.82 (m, 1H), 3.09 (m, 2H), 2.98 (m, 6H), 2.88 (m, 2H), 2, 71 (m, 3H), 2.66 (m, 2H), 2.11 (m, 8H), 1.99 (s, 3H), 1.82 (m, 2H), 1.38 (m, 2H ), 0.92 (s, 6H).

EXAMPLE 67

EP-2507211B1PL

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (2,5dichlorofenoksy) -N - (( 4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0380] The title compound was prepared by substituting EXAMPLE 60D for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.71 (m, 1H), 8.43 (d, 1H), 7.75 (dd, 1H), 7.54 (d, 1H), 7.36 (m, 3H), 7.07 (m, 3H), 6.94 (dd, 1H), 6.79 (dd, 1H), 6.46 (dd, 2H), 3.67 (m, 4H), 3.48 (q, 2H) , 3.20 (m, 4H), 2.83 (s, 2H), 2.65 (m, 6H), 2.24 (m, 6H), 1.98 (s, 2H), 1.88 ( m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 68

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((1-methyl-1H-indol-4-yl) oxy) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0381] The title compound was prepared by substituting EXAMPLE 16D for EXAMPLE 50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.58 (br s, 1H), 9.78 (br s, 1H), 8.67 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H), 7 , 66 (br s, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.30 (m, 1H), 7.25 (d, 1H), 7.19 (d , 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 6.75 (dd, 1H), 6.40 (d, 1H), 6.38 (s, 1H), 6 , 23 (d, 1H), 4.35-2.80 (br m series, total 22 H), 3.80 (s, 3H), 1.96 (m, 2H).

EXAMPLE 69

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-morpholin-4-yl-phenoxy) -N - ((4- ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0382] The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.63 (s, 1H), 9.86 (s, 1H), 8.71 (t, 1H), 8.50 (d, 1H), 7.83 (dd, 1H), 7.70 (s, 1H), 7.50 (m, 5H), 7.39 (d, 2H), 7.32 (m, 1H), 7.16 (d, 1H), 7.08 (m, 1H) , 6.74 (dd, 1H), 6.59 (dd, 1H), 6.40 (m, 2H), 6.23 (dd, 1H), 4.24 (m, 2H), 3.97 ( m, 2H), 3.70 (m, 4H), 3.63 (m, 4H), 3.54 (m, 4H), 3.18 (m, 4H), 3.07 (m, 4H), 3.00 (m, 4H), 2.83 (m, 2H), 1.98 (m, 2H).

EXAMPLE 70

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2 - ((3- (3-morpholin-4-yl-3-oxopropyl) -1H-indol-5-yl) oxy) benzamide EXAMPLE 70A (Z) -5- (benzyloxy) -3 - tert-butyl (3-morpholine-3-oxoprop-1-enyl) -1H-indole-1-carboxylate mixture of tert-butyl 5- (benzyloxy) -3-bromo-1H-indole-1H-carboxylate ( 2.011 g), 1-morpholinoprop-2-en-1-one (0.776 g), palladium acetate (31 mg), tri-o-tolylphosphine (187 mg) and triethylamine (1.14 mL) in N, N-dimethylformamide (14 mL) under nitrogen was stirred at 100 ° C overnight. The mixture was diluted with ethyl acetate and saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography (80% ethyl acetate-hexane) to afford the desired product.

EXAMPLE 70B

Tert-butyl 5-hydroxy-3- (3-morpholine-3-oxopropyl) -1H-indole-1-carboxylate [0384] The title compound was prepared by substituting EXAMPLE 70A for EXAMPLE 39A in EXAMPLE 39B.

EXAMPLE 70C

EP-2507211B1PL

5- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (methoxycarbonyl) phenoxy) -3- (3morfolino-3-oxopropyl) -1H-indole Tert-butyl 1-carboxylate [0385] The title compound was prepared by substituting EXAMPLE 70B for EXAMPLE 1D in

EXAMPLE 1E.

EXAMPLE 70D

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3-morpholine-3-oxopropyl) -1H-indol-5-yloxy) benzoate [0386 ] A solution of EXAMPLE 70C (300 mg) in dioxane (2 mL) was treated with concentrated aqueous hydrochloric acid (0.378 mL) and stirred at room temperature overnight. The solution was concentrated and the residue was used for the next step without further purification.

EXAMPLE 70E 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3-morpholine-3-oxopropyl) -1H-indol-5-yloxy) benzoic acid [0387] The title compound was prepared by substituting EXAMPLE 70D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 70F

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2 - ((3- (3-morpholin-4-yl-3-oxopropyl) -1H-indol-5-yl) oxy) benzamide [0388] The title compound was prepared by substituting EXAMPLE 70E for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.37 (s, 1H), 10.88 (s, 1H), 9.33 (s, 1H), 8.64 (m, 2H), 7.88 (d, 1H), 7.66 (s, 1H), 7.51 (dd, 5H), 7.35 (dd, 3H), 7.29 (s, 1H), 7.21 (s, 1H), 7.13 (d, 2H) , 6.82 (dd, 1H), 6.67 (d, 1H), 6.21 (s, 1H), 3.42 (s, 20H), 3.12 (s, 2H), 2.85 ( m, 2H), 2.78 (d, 6H), 2.61 (m, 2H), 1.95 (m, 2H).

EXAMPLE 71

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

EXAMPLE 71A 2- (3- (benzyloxy) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0389] The title compound was prepared by substituting EXAMPLE 33A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 71B

2- (3- (benzyloxy) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0390] The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.69 (m, 1H), 8.62 (m, 1H), 8.48 (d,

1H), 7.76 (dd, 1H), 7.65 (m, 1H), 7.50 (m, 5H), 7.38 (m, 6H), 7.32 (m, 2H), 7, 11 (m, 2H), 6.77 (dd, 1H),

6.62 (dd, 1H), 6.41 (m, 2H), 6.35 (m, 1H), 4.98 (s, 2H), 3.83 (m, 2H), 3.28 (m , 12H), 3.17 (m, 2H), 1.89 (m, 1H), 1.59 (m, 2H), 1.26 (m, 2H).

EXAMPLE 72

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

EXAMPLE 72A

EP-2507211B1PL

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-cyanophenoxy) benzoate [0391] The title compound was prepared by substituting 4-cyanophenol for EXAMPLE 1D in

EXAMPLE 1E.

EXAMPLE 72B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-cyanophenoxy) benzoic acid [0392] The title compound was prepared by substituting EXAMPLE 72A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 72C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4-cyanophenoxy) -N - ((3-nitro-4 ( (tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0393] The title compound was prepared by substituting EXAMPLE 72B for EXAMPLE 1G in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.97 (s, 1H), 9.54 (s, 1H), 8.62 (t, 1H), 8.44 (d, 1H), 7.66 (m, 4H), 7.53 (m, 5H), 7.37 (m, 3H), 7.12 (d, 1H), 6.82 (m, 3H), 6.64 (d, 1H), 4.37 (m, 1H) , 3.86 (dd, 2H), 3.49 (m, 2H), 3.26 (m, 8H), 3.10 (m, 2H), 2.84 (s, 1H), 1.92 ( m, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).

EXAMPLE 73

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((3- (3-morpholin-4-yl-3-oxopropyl ) -1Hindol-5-yl) oxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0394] The title compound was prepared by substituting EXAMPLE 70E instead of EXAMPLE 1F in

EXAMPLE 1H. 1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.38 (s, 1H), 10.87 (s, 1H), 8.59 (m, 2H), 7.79 (dd, 1H), 7.68 (s, 1H), 7.51 (dd, 5H), 7.34 (dd, 4H), 7.20 (s, 1H), 7.10 (d, 2H), 6.81 (dd, 1H), 6.68 (d, 1H) , 6.23 (s, 1H), 3.85 (d, 2H), 3.44 (s, 18H), 3.28 (m, 4H), 2.84 (m, 2H), 2.60 ( t, 2H), 1.89 (s, 1H), 1.63 (m, 2H), 1.27 (m, 2H).

EXAMPLE 74

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((3- (3-morpholin-4-yl-propyl) -1H- indol-5-yl) oxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 74A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3-morpholinopropyl) -1H-indol-5-yloxy) benzoate [0395] EXAMPLE 70C ( 107 mg) was dissolved in anhydrous tetrahydrofuran (0.7 mL), followed by the addition of a 1M solution of borane in tetrahydrofuran (0.57 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1N HCl aqueous solution (1.5 mL). The resulting solution was heated at 50 ° C overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate in hexane to give the product.

EXAMPLE 74B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3-morpholinopropyl) -1H-indol-5-yloxy) benzoic acid [0396] Compound the title was made by substituting EXAMPLE 74A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 74C

EP-2507211B1PL

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((3- (3-morpholin-4-yl-propyl) -1H- indol-5-yl) oxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0397] The title compound was prepared by substituting EXAMPLE 74B for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.35 (m, 1H), 10.95 (s, 1H), 9.58 (m, 1H), 8.60 (m, 2H), 7.86 (dd, 1H), 7.63 (m, 1H), 7.50 (dd, 5H), 7.35 (t, 3H), 7.28 (s, 1H), 7.22 (dd, 2H), 7.17 (d, 1H) , 6.84 (d, 1H), 6.65 (d, 1H), 6.16 (s, 1H), 3.93 (s, 1H), 3.84 (d, 2H), 3.50 ( m, 15H), 3.32 (m, 2H), 3.26 (m, 2H), 3.13 (m, 2H), 3.03 (s, 2H), 2.68 (t, 2H), 1.97 (d, 2H), 1.89 (s, 1H), 1.61 (d, 2H), 1.27 (m, 2H).

EXAMPLE 75

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

EXAMPLE 75A

4 - ((dimethylamino) methyl) phenol [0398] The title compound was prepared by substituting 4-hydroxybenzaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and dimethylamine instead of tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 75B

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4 - ((dimethylamino) methyl) phenoxy) benzoate [0399] The title compound was prepared by substituting EXAMPLE 75A instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 75C 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4 - ((dimethylamino) methyl) phenoxy) benzoic acid [0400] The title compound was prepared by substitution EXAMPLE 75B instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 75D

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4 - ((dimethylamino) methyl) phenoxy) -N- ((3 -nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0401] The title compound was prepared by substituting EXAMPLE 75C for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.80 (br s, 1H), 9.60 (br s, 1H), 8.59 (m, 1H), 8.48 (m, 1H), 7.80 (d, 1H), 7 , 50 (d, 2H), 7.46 (m, 2H), 7.36 (m, 4H), 7.24 (m, 2H), 6.90 (d, 2H), 6.77 (d, 1H), 6.44 (d, 1H), 4.16 (m, 2H), 3.84 (dd, 2H), 3.30 (m, 8H), 3.15 (m, 4H), 2, 68 (m, 4H), 2.35 (m, 4H), 1.88 (m, 1H), 1.61 (dd, 2H), 1.23 (m, 2H).

EXAMPLE 76

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

EXAMPLE 76A

Methyl 2- (4- (1H-imidazol-1-yl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0402] The title compound was prepared by substitution of 4- (1H-imidazol-1-yl) phenol for EXAMPLE 1D in EXAMPLE 1E.

EP-2507211B1PL

EXAMPLE 76B 2- (4- (1H-Imidazol-1-yl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0403] The title compound prepared by substituting EXAMPLE 76A for EXAMPLE 1E in

EXAMPLE 1F.

EXAMPLE 76C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (1H-imidazol-1-yl) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0404] The title compound was prepared by substituting EXAMPLE 76B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.50 (s, 1H), 8.17 (d, 1H), 7.78 (m, 1H),

7.66 (m, 1H), 7.40-7.58 (m, 8H), 7.37 (d, 2H), 7.25 (m, 1H), 7.10 (d, 2H), 6 , 94 (d, 1H), 6.75 (d, 1H), 6.63 (d, 1H), 6.43 (d, 1H), 3.82 (m, 2H), 3.37 (m, 4H), 3.08-3.21 (m, 6H), 2.35 (m, 4H), 1.82 (m, 1H), 1.58 (m,

2H), 1.40 (m, 2H).

EXAMPLE 77

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitrophenoxy) -N - ((4 - ((tetrahydro- 2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide

EXAMPLE 77A

4 - ((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonamide 4-aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium triacetoxyborohydride (16.74 g) ) in tetrahydrofuran (300 ml) and acetic acid (15 ml) were stirred at room temperature for 24 hours. The reaction was concentrated and dissolved in ethyl acetate. The resulting solution was washed with water and brine, concentrated, and chromatographed on silica gel with 50% ethyl acetate / hexane.

EXAMPLE 77B

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitrophenoxy) -N ((2,2-trifluoroacetate) 4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0406] The title compound was prepared by substituting EXAMPLE 8B for EXAMPLE 50F and EXAMPLE 77A instead of EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.58 (br s, 1H), 9.58 (br s, 1H), 7.86 (m, 1H), 7.71 (br s, 1H), 7.52 (m, 7H), 7.40 (m, 5H), 7.30 (m, 1H), 6.82 (dd, 1H), 6.71 (br s, 1H), 6.60 (d, 1H), 6.47 ( d, 2H), 4.37 (v br s, 1H), 3.83 (dd, 2H), 3.70 (v br s, 1H), 3.50-3-40 (envelope, 6H), 3 , 26, (m, 2H), 3.05, 2.96, 2.94, 2.85 (all br s, together 4H), 1.79 (m, 1H), 1.65 (m, 2H) , 1.22 (m, 2H).

EXAMPLE 78

4- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4- ((tetrahydro- 2-t-butyl 2-pyran-4-methyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) benzyl (ethyl) carbamate EXAMPLE 78A tert-butyl ethyl (4-hydroxybenzyl) carbamate [0407] Gas diethylamine was bubbled into a solution of 4-hydroxybenzaldehyde ( 2.0 g) and sodium triacetoxyborohydride (5.2 g) in dichloromethane (60 ml) until saturation. The reaction flask was capped and the reaction stirred for 24 hours. Then 1M NaOH (10 mL) was added, followed by di-tert-butyl dicarbonate (3.57 g) and triethylamine (2.28 mL), and the reaction was stirred for 24 hours. The reaction was acidified with saturated NaH solution₂AFTER₄, extracted twice with ethyl acetate, and

The combined extracts were washed with brine and concentrated. The crude product was chromatographed on silica gel using 20% ​​ethyl acetate / hexane as the eluent to give the product.

EXAMPLE 78B

Methyl 2- (4 - ((tert-butoxycarbonyl (ethyl) amino) methyl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0408] Compound the title was made by substituting EXAMPLE 78A for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 78C 2- (4 - ((tert-butoxycarbonyl (ethyl) amino) methyl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0409 ] The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 78D

4- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo tert-butyl benzyl (ethyl) carbamate [0410] The title compound was prepared by substituting EXAMPLE 78C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 79

3- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4 - ((tetrahydro -2H-pyran-4-methyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) tert-butyl benzyl (ethyl) carbamate EXAMPLE 79A tert-butyl ethyl (4-hydroxybenzyl) carbamate [0411] The title compound was prepared by substitution of 3-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in EXAMPLE 78A.

EXAMPLE 79B

Methyl 2- (3 - ((tert-butoxycarbonyl (ethyl) amino) methyl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0412] Compound the title was made by substituting EXAMPLE 79A for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 79C 2- (3 - ((tert-butoxycarbonyl (ethyl) amino) methyl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0413 ] The title compound was prepared by substituting EXAMPLE 79B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 79D

3- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) fenylosulfonylokarbamoilo tert-butyl benzyl (ethyl) carbamate [0414] The title compound was prepared by substituting EXAMPLE 79C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 80

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

[0415] The title compound was prepared by substituting EXAMPLE 78D for EXAMPLE 1A in

EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.63 (br s, 1H), 8.52 (br s, 1H), 8.43 (s,

1H), 7.78 (dd, 1H), 7.60 (d, 1H), 7.46 (s, 4H), 7.35 (d, 2H), 7.31 (m, 1H), 7, 24 (d, 1H), 7.13 (d, 1H), 6.84 (d, 2H), 6.72 (d, 1H), 6.36 (s, 1H), 4.04 (s, 2H ), 3.84 (dd, 2H), 3.27 (m, 6H), 3.11 (m, 4H), 2.94 (m, 2H),

2.36 (m, 4H), 1.91 (m, 1H), 1.62 (dd, 2H), 1.23 (m, 2H), 1.17 (t, 3H).

EXAMPLE 81

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3 - ((ethylamino) methyl) phenoxy) -N - (( 3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0416] The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE 1A in

EXAMPLE 1B, 1H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.60 (br s, 1H), 8.80 (br s, 1H), 8.62 (br s, 1H), 8.51 (s, 1H), 7.82 (dd, 1H), 7.30-7.55 (m, 7H), 7.24 (m, 2H), 7.19 (d, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6 , 77 (d, 1H), 6.36 (s, 1H), 4.06 (s, 2H), 3.86 (dd, 2H), 3.27 (m, 6H), 3.11 (m, 4H), 2.96 (m, 2H), 2.34 (m, 4H), 1.90 (m, 1H), 1.61 (dd, 2H), 1.24 (m, 2H), 1, 19 (t, 3H).

EXAMPLE 82

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

EXAMPLE 82A

Methyl 2- (4-acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0417] The title compound was prepared by substituting 4-acetamidophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 82B 2- (4-Acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid. The title compound was prepared by substituting EXAMPLE 82A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 82C

2- (4- (acetylamino) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0418] The title compound was prepared by substituting EXAMPLE 82B for EXAMPLE 1G in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.58 (s, 1H), 9.91 (s, 1H), 8.62 (t, 1H), 8.54 (d, 1H), 7.76 (dd, 1H), 7.68 (m, 1H), 7.51 (m, 7H), 7.34 (m, 3H), 7.16 (d, 1H), 6.85 (d, 2H), 6.72 (dd, 1H) , 6.30 (m, 1H), 4.35 (s, 1H), 3.85 (dd, 2H), 3.68 (m, 1H), 3.27 (m, 9H), 3.02 ( m, 2H), 2.83 (m, 1H), 2.04 (s, 3H), 1.89 (m, 1H), 1.62 (dd, 2H), 1.24 (m, 2H).

EXAMPLE 83

4- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4 - ((tetrahydro Tert-butyl -2H-pyran-4-methyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) phenylcarbamate [0419] This EXAMPLE was performed by substituting EXAMPLE 18B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.37 (s, 1H), 9.32 (s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.81 (dd, 1H), 7.44 (m, 8H), 7.34 (m, 2H), 7.22 (m, 2H), 6.88 (d, 2H), 6.69 (dd, 1H), 6.20 (d, 1H) , 3.85 (m, 2H), 3.28 (m, 6H), 3.09 (m, 4H), 2.33 (m, 4H), 1.90 (m, 1H), 1.63 ( m, 2H), 1.47 (m, 9H),

1.26 (m, 2H).

EXAMPLE 84

EP-2507211B1PL

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

EXAMPLE 84A

Methyl 2- (biphenyl-2-yloxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0420] The title compound was prepared by substituting 2-phenylphenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 84B 2- (Biphenyl-2-yloxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0421] The title compound was prepared by substituting EXAMPLE 84A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 84C

2- (1,1'-biphenyl-2-yloxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl 2,2,2-trifluoroacetate ) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0422] The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE 50F and EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.56 (v br s, 1H), 9.50 (v br s, 1H), 8.62 (t, 1H), 8.45 (d, 1H), 7.76 (dd, 1H) , 7.70 (br s, 1H), 7.50 (m, 7H), 7.37 (d, 2H), 7.27 (m, 5H), 7.12 (m, 2H), 7.04 (m, 1H), 6.70 (dd, 1H), 6.64 (d, 1H), 6.27 (s, 1H), 4.35 (v br s, 1H), 3.83 (dd, 2H), 3.70 (v br s, 1H), 3.40 (m, 4H), 3.25, 3.20 (both m, 4H together), 3.00, 2.80 (both br s, total 4H), 1.83 (m, 1H), 1.59 (m, 2H), 1.24 (m, 2H).

EXAMPLE 85

3- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4 - ((tetrahydro Tert-butyl -2H-pyran-4-methyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) phenylcarbamate [0423] The title compound was prepared as described in EXAMPLE 19C. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) 811.45 (s, 1H), 9.34 (s, 1H), 8.62 (t, 1H), 8.52 (d, 1H), 7.75 (dd, 1H), 7.46 ( m, 6H), 7.36 (m, 2H), 7.23 (m, 1H), 7.11 (m, 4H), 6.74 (dd, 1H), 6.42 (m, 1H), 6.36 (d, 1H), 3.86 (dd, 2H), 3.30 (m, 6H), 3.15 (m, 4H), 2.35 (m, 4H), 1.90 (qd , 1H), 1.63 (dd, 2H), 1.45 (s, 9H), 1.27 (m, 2H).

EXAMPLE 86

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

EXAMPLE 86A

Methyl 2- (biphenyl-3-yloxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0424] The title compound was prepared by substituting 3-phenylphenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 86B 2- (Biphenyl-3-yloxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0425] The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 86C

2- (1,1'-biphenyl-3-yloxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl 2,2,2-trifluoroacetate ) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0426] The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE 50F and EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,

Dimethyl sulfoxide-d₆) δ 11.82 (v br s, 1H), 9.60 (v br s, 1H), 8.72 (t, 1H), 8.42 (d, 1H), 7.70 (br s, 1H) )

7.69 (dd, 1H), 7.55-7.20 (m, 15H), 7.00 (d, 1H), 6.96 (s, 1H), 6.80 (m, 2H), 6 , 53 (d, 1H), 4.35 (v br s, 1H),

3.83 (dd, 2H), 3.70 (v br s, 1H), 3.40 (m, 4H), 3.25, 3.20 (both m together 4H), 3.00, 2, 80 (both br s, together

4H), 1.81 (m, 1H), 1.58 (m, 2H), 1.22 (m, 2H).

EXAMPLE 87

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

EXAMPLE 87A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) ethyl) phenoxy) benzoate [0427] The title compound was prepared by substitution 4- (2- (dimethylamino) ethyl) phenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 87B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) ethyl) phenoxy) benzoic acid [0428] The title compound was prepared by substituting EXAMPLE 87A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 87C

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) ethyl) phenoxy) -N- ( (3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0429] The title compound was prepared by substituting EXAMPLE 87B for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.67 (s, 1H), 9.51 (s, 1H), 8.66 (t, 1H),

8.52 (d, 1H), 7.84 (dd, 1H), 7.70 (s, 1H), 7.51 (dd, 5H), 7.36 (m, 3H), 7.22 (m , 3H), 6.84 (d, 2H), 6.76 (m,

1H), 6.42 (s, 1H), 3.85 (m, 2H), 3.52 (s, 10H), 3.35 (m, 2H), 3.26 (dd, 4H), 2, 90 (m, 2H), 2.83 (d, 6H),

1.91 (s, 1H), 1.61 (d, 2H), 1.27 (dt, 2H).

EXAMPLE 88

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

EXAMPLE 88A

Methyl 2- (4- (benzyloxy) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0430] The title compound was prepared by substituting 4- (benzyloxy) phenol instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 88B 2- (4- (benzyloxy) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0431] The title compound was prepared by substituting EXAMPLE 88A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 88C

2- (4- (benzyloxy) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0432] The title compound was prepared by substituting EXAMPLE 88B for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.50 (m, 1H), 8.63 (t, 1H), 8.55 (d,

EP-2507211B1PL

1H), 7.82 (dd, 1H), 7.66 (m, 1H), 7.41 (m, 13H), 7.20 (m, 1H), 6.96 (d, 2H), 6, 88 (d, 2H), 6.70 (dd, 1H),

6.25 (m, 1H), 5.04 (m, 2H), 3.27 (m, 10H), 2.90 (m, 6H), 1.88 (m, 1H), 1.57 (m , 2H), 1.23 (m, 2H).

EXAMPLE 89

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3-morpholin-4-yl-phenoxy) -N - ((3- nitro-4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0433] The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.58 (s, 1H), 8.63 (t, 1H), 8.49 (d, 1H), 7.78 (dd, 1H), 7.69 (m, 1H), 7.52 (m, 5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.07 (m, 1H), 6.74 (dd, 1H) , 6.58 (dd, 1H), 6.40 (m, 2H), 6.22 (dd, 1H), 4.29 (m, 2H), 3.86 (m, 2H), 3.70 ( m, 6H), 3.30 (m, 6H), 3.00 (m, 6H), 2.83 (m, 2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.28 (m, 2H).

EXAMPLE 90

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((2-methyl-1,3-benzothiazol-5-yl) oxy) -N ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0434] The title compound was prepared by substituting EXAMPLE 24B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.83 (s, 1H), 9.48 (br s, 1H), 8.64 (t,

1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.76 (dd, 1H), 7.50 (m, 5H), 7.37 (m, 2H), 7, 30 (m, 1H), 7.18 (m, 1H), 7.04 (d, 1H), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s, 1H), 3.84 (dd, 2H), 3.37 (m, 6H), 3.23 (m, 4H), 2.89 (m,

2H), 2.75 (s, 3H), 2.36 (m, 3H), 1.62 (d, 2H), 1.24 (m, 2H).

EXAMPLE 91

4- (3- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4- tert-butyl ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) phenyl) piperazine-1-carboxylate

EXAMPLE 91 A

Tert-butyl 4- (3- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (methoxycarbonyl) phenoxy) phenyl) piperazine-1-carboxylate [0435 ] The title compound was prepared by substituting 1- (3-hydroxy-phenyl) -piperazine-4-carboxylic acid tert-butyl ester for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 91B 2- (3- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0436] The title compound was prepared by substituting EXAMPLE 91A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 91C

4- (3- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((3-nitro-4- tert-butyl ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) amino) carbonyl) phenoxy) phenyl) piperazine-1-carboxylate [0437] The title compound was prepared by substituting EXAMPLE 91B for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.65 (s, 1H), 8.65 (t, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 7.72 (m, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H), 6.75 (dd, 1H) , 6.57 (dd, 1H), 6.41 (m, 2H), 6.21 (dd, 1H), 4.31 (m, 2H), 3.86 (dd, 2H), 3.41 ( m, 6H), 3.34 (t, 2H),

3.27 (m, 4H), 3.00 (m, 6H), 2.85 (m, 2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.40 (m , 9H), 1.28 (m, 2H).

EXAMPLE 92

EP-2507211B1PL

2- (3- (benzyloxy) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4- ( (3- (Dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0438] The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.72 (s, 1H), 9.52 (s, 1H), 8.69 (t, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.65 (s, 1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32 (m, 2H), 7.13 (m, 2H), 6.77 (dd, 1H) , 6.64 (dd, 1H), 6.42 (s, 2H), 6.38 (m, 1H), 4.99 (s, 2H), 3.50 (m, 10H), 3.11 ( m, 4H), 2.77 (s, 6H), 1.95 (m, 2H).

EXAMPLE 93

2- (3- (benzyloxy) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4- ( (3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0439] The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.74 (m, 1H), 9.78 (s, 1H), 8.71 (m, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.67 (s, 1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32 (m, 2H), 7.13 (m, 1H), 6.77 (dd, 1H) , 6.64 (dd, 1H), 6.39 (m, 3H), 4.99 (s, 2H), 3.96 (m, 2H), 3.60 (s, 2H), 3.51 ( m, 6H), 3.17 (m, 10H), 2.67 (m, 2H), 1.94 (m, 2H).

EXAMPLE 94

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

EXAMPLE 94A

4- (2- (4- (benzyloxy) phenoxy) ethyl) morpholine [0440] The title compound was prepared by substituting 4- (2-chloroethyl) morpholine for 2-chloroN, N-dimethylethanamine and 4- (benzyloxy) phenol instead of 3- (benzyloxy) phenol in EXAMPLE 39A.

EXAMPLE 94B

4- (2-morpholinoethoxy) phenol [0441] The title compound was prepared by substituting EXAMPLE 94A for EXAMPLE 39A in EXAMPLE 39B.

EXAMPLE 94C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2-morpholinoethoxy) phenoxy) benzoate [0442] The title compound was prepared by substituting EXAMPLE 94B for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 94D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2-morpholinoethoxy) phenoxy) benzoic acid [0443] The title compound was prepared by substituting EXAMPLE 94C instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 94E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2-morpholin-4-yl-ethoxy) phenoxy) -N ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0444] The title compound was prepared by substituting EXAMPLE 94D for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.46 (m, 1H), 9.98 (m, 1H), 8.64 (d, 1H), 8.55 (d, 1H), 7.87 (d, 1H), 7.49 (m, 5H), 7.39 (d, 2H), 7.31 (s, 1H), 7.25 (d, 1H), 6.96 (m, 5H), 6.71

EP-2507211B1PL (d, 1H), 6.29 (s, 1H), 4.30 (s, 2H), 3.98 (s, 2H), 3.85 (d, 2H), 3.72 (s , 2H), 3.42 (s, 16H), 3.27 (m, 2H),

1.91 (s, 1H), 1.62 (d, 2H), 1.28 (m, 2H).

EXAMPLE 95

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((3-nitro-4 - ((tetrahydro-2H-piran- 4-methylmethyl) amino) phenyl) sulfonyl) -2 - ((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl) oxy) benzamide [0445] The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE 1F in

EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.50 (s, 1H), 10.07 (s, 1H), 8.60 (t, 1H), 8.47 (d, 1H), 7.74 (dd, 1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H), 7.14 (d, 1H), 6.92 (t, 1H), 6.74 (dd, 1H) , 6.51 (d, 1H), 6.35 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.36 (m, 4H), 3.25 ( m, 2H), 3.16 (m, 4H), 2.83 (t, 2H), 2.41 (dd, 2H), 2.35 (m, 4H), 1.90 (in, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).

EXAMPLE 96

2- (4- (benzyloxy) phenoxy) -4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4- ( (3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0446] The title compound was prepared by substituting EXAMPLE 88B for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.53 (s, 1H), 9.74 (s, 1H), 8.69 (m, 1H), 8.59 (d, 1H), 7.90 (dd, 1H), 7.67 (m, 1H), 7.41 (m, 13H), 7.21 (d, 1H), 6.99 (m, 2H), 6.91 (m, 2H), 6.70 (dd, 1H) , 6.23 (s, 1H), 5.07 (s, 2H),

4.28 (m, 2H), 3.95 (s, 2H), 3.51 (m, 6H), 3.16 (m, 10H), 2.73 (d, 2H), 1.98 (m , 2H).

EXAMPLE 97

4- (4- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((4 - ((3- tert-butyl morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) amino) carbonyl) phenoxy) phenyl) piperazine-1-carboxylate

EXAMPLE 97A

Tert-butyl 4- (4- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (methoxycarbonyl) phenoxy) phenyl) piperazine-1-carboxylate [0447 ] The title compound was prepared by substituting 1- (4-hydroxyphenyl) -piperazine-4-carboxylic acid tert-butyl ester for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 97B 2- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0448] The title compound was prepared by substituting EXAMPLE 97A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 97C

4- (4- (5- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((((4 - ((3- morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) amino) carbonyl) phenoxy) phenyl) piperazine-tert-butyl 1-carboxylate [0449] The title compound was prepared by substituting EXAMPLE 97B for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.44 (m, 1H), 9.67 (s, 1H), 8.70 (t, 1H), 8.59 (d, 1H), 7.91 (dd, 1H), 7.69 (s, 1H), 7.49 (m, 7H), 7.30 (m, 1H), 7.21 (d, 1H), 6.91 (m, 4H), 6.69 (dd, 1H) , 6.24 (s, 1H), 3.95 (m, 2H), 3.67 (m, 4H), 3.52 (m, 10H), 3.17 (s, 4H), 3.04 ( m, 10H), 1.97 (d, 2H), 1.43 (s, 9H).

EXAMPLE 98

EP-2507211B1PL

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-pyridin-4-yl-phenoxy) benzamide

EXAMPLE 98A

4- (3- (benzyloxy) phenyl) pyridine [0450] The title compound was prepared by substituting 1- (benzyloxy) -3-bromobenzene for EXAMPLE 33C and pyridin-4-ylboronic acid instead of 2,4-dimethyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole in EXAMPLE 33D.

EXAMPLE 98B

3- (pyridin-4-yl) phenol [0451] The title compound was prepared by substituting EXAMPLE 98A for EXAMPLE 33A in EXAMPLE 33B.

EXAMPLE 98C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (pyridin-4-yl) phenoxy) benzoate [0452] The title compound was prepared by substituting EXAMPLE 98B instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 98D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (pyridin-4-yl) phenoxy) benzoic acid [0453] The title compound was prepared by substitution of EXAMPLE 98C instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 98E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-pyridin-4-ylphenoxy) benzamide [0454] The title compound was prepared by substituting EXAMPLE 98D for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.87 (m, 1H), 8.68 (d, 2H), 8.58 (m, 1H), 8.42 (d, 1H), 7.73 (m, 4H), 7.52 (m, 5H), 7.36 (m, 6H), 7.14 (s, 1H), 7.03 (d, 1H), 6.91 (m, 1H), 6.80 (dd, 1H) , 6.55 (d, 1H), 4.22 (m, 2H), 3.89 (m, 7H), 3.41 (m, 4H), 3.15 (m, 4H), 2.91 ( m, 4H), 1.94 (m, 2H).

EXAMPLE 99

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-pyridin-4-ylphenoxy) benzamide EXAMPLE 99A

4- (4- (benzyloxy) phenyl) pyridine [0455] The title compound was prepared by substituting 1- (benzyloxy) -4-bromobenzene for EXAMPLE 33C and pyridin-4-ylboronic acid instead of 2,4-dimethyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole in EXAMPLE 33D.

EXAMPLE 99B

4- (pyridin-4-yl) phenol [0456] The title compound was prepared by substituting EXAMPLE 99A for EXAMPLE 33A in EXAMPLE 33B.

EXAMPLE 99C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (pyridin-4-yl) phenoxy) benzoate

EP 0 2507211B1EN [0457] The title compound was prepared by substituting EXAMPLE 99B for EXAMPLE 1D in

EXAMPLE 1E.

EXAMPLE 99D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (pyridin-4-yl) phenoxy) benzoic acid [0458] The title compound was prepared by substitution of EXAMPLE 99C instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 99E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-pyridin-4-ylphenoxy) benzamide [0459] The title compound was prepared by substituting EXAMPLE 99D for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.80 (d, 2H), 8.55 (m, 1H), 8.49 (d, 1H), 7.93 (m, 5H), 7.74 (m, 1H), 7.53 (m, 5H), 7.36 (m, 3H), 7.13 (m, 2H), 6.93 (d, 1H), 6.83 (dd, 1H), 6.62 (d, 1H) , 4.60 (s, 4H), 4.29 (m, 2H), 3.67 (s, 4H), 3.42 (m, 4H), 3.13 (m, 4H), 2.92 ( m, 4H), 1.90 (m, 2H).

EXAMPLE 100

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-pyridin-3-yl-phenoxy) benzamide

EXAMPLE 100A

3- (4- (benzyloxy) phenyl) pyridine [0460] The title compound was prepared by substituting 1- (benzyloxy) -4-bromobenzene for EXAMPLE 33C and pyridin-3-ylboronic acid instead of 2,4-dimethyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole in EXAMPLE 33D.

EXAMPLE 100B

4- (pyridin-4-yl) phenol [0461] The title compound was prepared by substituting EXAMPLE 100A for EXAMPLE 33A in EXAMPLE 33B.

EXAMPLE 100C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (pyridin-4-yl) phenoxy) benzoate [0462] The title compound was prepared by substituting EXAMPLE 100B instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 100D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (pyridin-4-yl) phenoxy) benzoic acid [0463] The title compound was prepared by substitution of EXAMPLE 100C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 100E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-pyridin-3-ylphenoxy) benzamide [0464] The title compound was prepared by substituting EXAMPLE 100D for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.84 (s, 1H), 8.95 (d, 1H), 8.66 (d, 1H), 8.57 (m, 1H), 8.52 (d, 1H), 8.24 (d,

1H), 7.83 (dd, 1H), 7.72 (m, 5H), 7.53 (m, 5H), 7.35 (m, 3H), 7.11 (m, 1H), 6, 93 (d, 2H), 6.81 (dd, 1H),

6.57 (d, 1H), 4.31 (s, 2H), 3.80 (m, 8H), 3.42 (m, 4H), 3.14 (m, 8H), 1.94 (m , 2H).

EP-2507211B1PL

EXAMPLE 101

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

EXAMPLE 101 A.

2- (4- (benzyloxy) phenoxy) -N, N-dimethylacetamide [0465] The title compound was prepared by substituting 2-chloro-N, N-dimethylacetamide for 2-chloro-N, N-dimethylethanamine and 4- (benzyloxy) phenol instead of 3 - (benzyloxy) phenol in EXAMPLE 39A.

EXAMPLE 101B

2- (4-hydroxyphenoxy) -N, N-dimethylacetamide [0466] The title compound was prepared by substituting EXAMPLE 101A for EXAMPLE 39A in EXAMPLE 39B.

EXAMPLE 101C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) -2-oxoethoxy) phenoxy) benzoate [0467] Title compound prepared by substituting EXAMPLE 101B for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 101D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) -2-oxoethoxy) phenoxy) benzoic acid [0468] The title compound was prepared by substituting EXAMPLE 101C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 101E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (4- (2- (dimethylamino) -2-oxo-ethoxy) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0469] The title compound was prepared by substituting EXAMPLE 101D for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.68 (t, 1H), 8.57 (d, 1H), 7.87 (dd, 1H), 7.72 (s, 1H), 7.53 (dd, 4H), 7.34 (m, 4H), 7.16 (d, 1H), 6.84 (m, 4H), 6.71 (dd, 1H), 6.34 (d, 1H), 4.60 (s, 2H) , 3.84 (d, 2H), 3.51 (s, 10H), 3.36 (m, 2H), 3.26 (m, 2H), 2.81 (d, 6H), 1.91 ( s, 1H), 1.62 (d, 2H),

1.28 (m, 2H).

EXAMPLE 102

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((1-methyl-1H-benzimidazol-5-yl) oxy) N - ((4 - ((3-morpholin-4-ylpropyl) amino) -3-nitrophenyl) sulfonyl) benzamide

EXAMPLE 102A

Methyl 4-bromo-2- (1-methyl-1H-benzo [d] imidazol-5-yloxy) benzoate [0470] 1-Methyl-1H-benzo [d] imidazol-5-ol (296 mg), 4- methyl bromo-2-fluorobenzoate (311 mg) and potassium carbonate (553 mg) were combined in dimethyl sulfoxide and heated to 90 ° C overnight. The reaction mixture was diluted with ethyl acetate and washed thoroughly with water and brine, dried over MgSO₄, filtered and concentrated.

EXAMPLE 102B

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (1-methyl-1H-benzo [d] imidazol-5-yloxy ) methyl benzoate

[0471] EXAMPLE 102A (480 mg) and EXAMPLE 1B (457 mg) were dissolved in dimethoxyethane (7.5 ml) in a microwave reactor vial. Tris (dibenzylideneacetone) dipalladium (0) (37 mg), 2- (di-tert-butylphosphine) biphenyl (48 mg) and tribasic potassium phosphate (423 mg) were added. The vial was sealed and heated in a CEM Discover microwave reactor for 30 minutes at 150 ° C. The crude reaction mixture was filtered through celite and concentrated. The material was dissolved in a 1: 1 dimethyl sulfoxide: methanol mixture and purified by HPLC.

EXAMPLE 102C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (1-methyl 1H-benzo [d] imidazol- 5-yloxy) benzoic [0472] The title compound was prepared by substituting EXAMPLE 102B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 102D

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((1-methyl-1H-benzimidazol-5-yl) oxy) N - ((4 - ((3-morpholin-4-yl-propyl) amino) -3-nitrophenyl) sulfonyl) benzamide [0473] The title compound was prepared by substituting EXAMPLE 102C for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.34 (d, 1H), 8.99 (t, 1H), 8.91 (s, 1H), 8.55 (s, 1H), 8.48 (dd, 1H), 7.94 (t, 1H), 7.50 (m, 4H), 7.42 (m, 3H), 7.35 (m, 3H), 7.05 (s, 1H), 7.02 (d, 1H) , 6.70 (m, 2H), 3.79 (t, 4H), 3.39 (s, 3H), 3.35 (m, 2H), 3.15 (m, 4H), 2.36 ( m, 12H), 1.74 (m, 2H).

EXAMPLE 103

4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylcarbamoyl) phenoxy) -N- (4- (3morfolinopropyloamino) -3-nitrophenylsulfonyl) benzamide

EXAMPLE 103A

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylcarbamoyl) phenoxy) benzoate [0474] The title compound was prepared by substitution of 3-hydroxy-N -methylbenzamide instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 103B 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylcarbamoyl) phenoxy) benzoic acid [0475] The title compound was prepared by substituting EXAMPLE 103A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 103C bis (2,2,2-trifluoroacetate) 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (methylcarbamoyl) phenoxy) -N- (4- (3-morpholinopropylamino) -3-nitrophenylsulfonyl) benzamide [0476] The title compound was prepared by substituting EXAMPLE 103B for EXAMPLE 50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.79 (v br s, 1H), 9.38 (v br s, 1H), 8.65 (t, 1H), 8.48 (d, 1H), 8.37 (q, 1H) , 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 6H), 7.35 (m, 4H), 7.26 (s, 1H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.43 (s, 1H), 4.35 (v br s, 1H), 3.99 (br m , 2H), 3.70 (v br s, 1H), 3.60, 3.50, 3.40 (all br m, together 10H), 3.20, 310, 2.80 (all br s, together 8H), 2.79, 2.77 (both s, together 3H), 1.99 (m, 2H).

EXAMPLE 104

EP-2507211B1PL

4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -N- (4- (3- (dimethylamino) propylamino) -3nitrofenylosulfonylo) -2- (3- (methylcarbamoyl) phenoxy) benzamide [0477] The title compound was prepared by substituting EXAMPLE 103B for EXAMPLE 50F and EXAMPLE 11A instead of EXAMPLE 3I in EXAMPLE 50G. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.79 (v br s, 1H), 9.38 (v br s, 1H), 8.65 (t, 1H), 8.48 (d, 1H), 8.37 (q, 1H) , 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 6H), 7.39 (m, 2H), 7.31 (m, 2H), 7.26 (s, 1H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.43 (s, 1H), 4.35 (v br s, 1H), 3.80 (v br s, 1H), 3.50, (br m, 8H), 3.10, 3.05 (m, br s, 4H), 2.81, 2.80 (both s, 6H), 2.78, 2.77 (both s, 3H), 1.96 (m, 2H).

EXAMPLE 105

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) -2-oxo-ethoxy) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 105A

2- (3- (benzyloxy) phenoxy) -N, N-dimethylacetamide [0478] The title compound was prepared by substituting 2-chloro-N, N-dimethylacetamide for 2-chloro-N, N-dimethylethanamine in EXAMPLE 39A.

EXAMPLE 105B

2- (3-hydroxyphenoxy) -N, N-dimethylacetamide [0479] The title compound was prepared by substituting EXAMPLE 105A for EXAMPLE 39A in EXAMPLE 39B.

EXAMPLE 105C

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) -2-oxoethoxy) phenoxy) benzoate [0480] Title compound prepared by substituting EXAMPLE 105B for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 105D 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) -2-oxoethoxy) phenoxy) benzoic acid [0481] The title compound was prepared by substituting EXAMPLE 105C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 105E

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (2- (dimethylamino) -2-oxo-ethoxy) phenoxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0482] The title compound was prepared by substituting EXAMPLE 105D for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.66 (d, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.72 (s, 1H), 7.51 (m, 5H), 7.35 (m, 3H), 7.28 (t, 1H), 7.16 (dd, 2H), 6.75 (dd, 1H), 6.46 (m, 3H), 4.60 (s, 2H) , 3.83 (d, 2H), 3.48 (s, 10H), 3.34 (m, 2H), 3.24 (m, 2H), 2.78 (s, 6H), 1.89 ( s, 1H), 1.60 (d, 2H), 1.26 (m, 2H).

EXAMPLE 106

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((3- (3- (dimethylamino) propyl) -1H-indol-5 -yl) oxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 106A (Z) -5- (benzyloxy) -3- ( Tert-butyl 3- (dimethylamino) -3-oxoprop-1-enyl) -1H-indole-1-carboxylate

[0483] The title compound was prepared by substituting N, N-dimethylacrylamide for 1-morpholinoprop-2-en-1-one in EXAMPLE 70A.

EXAMPLE 106B

Tert-butyl 3- (3- (dimethylamino) -3-oxopropyl) -5-hydroxy-1H-indole-1-carboxylate [0484] The title compound was prepared by substituting EXAMPLE 106A for EXAMPLE 39A in EXAMPLE 39B.

EXAMPLE 106C

5- (5- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (methoxycarbonyl) phenoxy) -3- (3- (dimethylamino) -3-oxopropyl) -1 tert-butyl indole-1-carboxylate [0485] The title compound was prepared by substituting EXAMPLE 106B for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 106D

Methyl 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3- (dimethylamino) propyl) -1H-indol-5-yloxy) benzoate [0486] The title compound was prepared by substituting EXAMPLE 106C for EXAMPLE 70C in EXAMPLE 74A.

EXAMPLE 106E 4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2- (3- (3- (dimethylamino) propyl) -1H-indol-5-yloxy) benzoic acid [ 0487] The title compound was prepared by substituting EXAMPLE 106D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 106F

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((3- (3- (dimethylamino) propyl) -1H-indol-5 -yl) oxy) -N - ((3-nitro-4 - ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0488] The title compound was prepared by substituting EXAMPLE 106E for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.97 (d, 1H), 9.34 (s, 1H), 8.61 (m, 2H), 7.86 (dd, 1H), 7.54-7.36 (m, 8H) , 7.22 (m, 4H), 6.86 (m, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 3.83 (m, 2H), 3.34- 3.24 (m, 8H), 3.07 (m, 6H), 2.76 (s, 6H), 2.67 (m, 2H), 1.95 (m, 3H), 1.65 (m , 2H), 1.29 (m, 4H), 0.88 (m, 2H).

EXAMPLE 107

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -N - ((4 - ((3- (dimethylamino) propyl) amino) 3 -nitrophenyl) sulfonyl) -2- (3- (hydroxymethyl) phenoxy) benzamide [0489] The title compound was prepared by substituting EXAMPLE 9A for EXAMPLE 50F and EXAMPLE 11A for EXAMPLE 3I in EXAMPLE 50G. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.60 (v br s, 1H), 9.40 (v br s, 1H), 8.76 (t, 1H), 8.51 (d, 1H), 7.80 (dd, 1H) , 7.65 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.30 (br s, 1H), 7.20 (dd, 1H), 7, 16 (d, 1H), 6.96 (d, 1H), 6.82 (s, 1H), 6.65 (d, 1H), 6.60 (d, 1H), 6.40 (s, 1H ), 4.41 (s, 2H), 3.55 (m 4H), 3.40 (m, 6H), 3.13 (m, 4H), 2.80, 2.79 (both s, together 6H ), 1.98 (m, 2H).

EXAMPLE 108

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((4-methoxybenzyl) oxy) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide EXAMPLE 108A

4-Fluoro-2- (4-methoxy-benzyloxy) benzoic acid methyl ester [0490] Methyl 4-Fluoro-2-hydroxybenzoate (1661 mg) was added to N, N-dimethylformamide (50 mL). Sodium hydride (60% in mineral oil, 430 mg) was added, the solution was stirred for 15 minutes at room temperature, and 1- (bromomethyl) -4-methoxybenzene (2061 mg) was added. The solution was stirred at room temperature for three days, added to 0.01M aqueous HCl, and extracted with ethyl acetate. The organic phase was washed with water twice, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure.

EXAMPLE 108B 4- [4- (4'-chloro-biphenyl-2-ylmethyl) -piperazin-1-yl] -2- (4-methoxybenzyloxy) benzoic acid methyl ester [0491] The title compound was prepared by substituting EXAMPLE 108A for 2 methyl bromo-4-fluorobenzoate in EXAMPLE 1C.

EXAMPLE 108C 4- [4- (4'-chloro-biphenyl-2-ylmethyl) -piperazin-1-yl] -2- (4-methoxy-benzyloxy) benzoic acid [0492] The title compound was prepared by substituting EXAMPLE 108B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 108D

4- (4 - ((4'-chloro-1,1'-biphenyl-2-yl) methyl) piperazin-1-yl) -2 - ((4-methoxybenzyl) oxy) -N - ((3-nitro -4 ((tetrahydro-2H-pyran-4-ylmethyl) amino) phenyl) sulfonyl) benzamide [0493] The title compound was prepared by substituting EXAMPLE 108C for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.79 (br s, 1H), 8.65 (t, 1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.53-7.41 (m, 7H ), 7.38 (m, 2H), 7.27-7.19 (m, 2H), 6.98 (d, 2H), 6.69 (br s, 1H), 6.55 (dd, 1H ), 5.16 (s, 2H), 3.84 (dd, 2H), 3.78 (s, 3H), 3.40 (s, 2H), 3.37-3.32 (m, 8H) , 2.38 (m, 4H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.26 (m, 2H).

EXAMPLE 109

N - [(4 - {[(4-Aminotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] -2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) benzamide

EXAMPLE 109A

4 - ((4-aminotetrahydro-2H-pyran-4-yl) methylamino) -3-nitrobenzenesulfonamide. A mixture of 4-chloro-3-nitrobenzenesulfonamide, 4- (aminomethyl) tetrahydro-2H-pyran-4-amine, acid hydrochloric acid and triethylamine in dioxane (10 mL) was heated at 110 ° C overnight. After cooling, the mixture was diluted with water (10 mL), and filtered.

EXAMPLE 109B

N- (4 - ((4-Aminotetrahydro-2H-pyran-4-yl) methylamino) -3-nitrophenylsulfonyl) -2- (3-chlorophenoxy) 4- (4 - ((2- (4-chlorophenyl) -4 , 4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzamide [0495] This EXAMPLE was performed by substituting EXAMPLE 6B instead of EXAMPLE 1F and EXAMPLE 109A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.35 (d, J = 1.83 Hz, 1H), 7.70 (dd, J = 9.0, 1.98 Hz, 1H), 7.64 (d, J = 8.85 Hz, 1H), 7.36 (d, J = 8.54 Hz, 2H), 7.11-7.18 (m, 2H), 7.07 (d, J = 8.24 Hz, 2H), 6.91 (dd, J = 7.93, 1.22 Hz, 1H), 6.77 (dd, J = 8.85, 2.14 Hz, 1H), 6, 65 (dd, J = 8.09, 1.98 Hz, 1H), 6.61-6.62 (m, 1H), 6.38 (d, J = 2.14 Hz, 1H),

EP-2507211B1PL

3.67-3.71 (m, 6H), 3.11 (m, 3H), 2.77 (s, 2H), 2.18-2.24 (m, 6H), 1.97-1, 99 (m, 2H), 1.76-1.79 (m, 2H),

1.65-1.67 (m, 2H), 1.39-1.42 (m, 2H), 0.94 (s, 6H).

EXAMPLE 110

4- {4- [1- (4'-chloro-1,1'-biphenyl-2-yl) ethyl] piperazine-1-yl} -2- (2-chlorophenoxy) -N - ({3-nitro- 4 [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 110A

1- (4'-Chlorobiphenyl-2-yl) ethanone [0496] A mixture of 1- (2-bromophenyl) ethanone (3.1 g), 4-chlorophenylboronic acid (2.92 g), bis (triphenylphosphine) palladium dichloride ( II) (1.202 g) and Na₂WHAT₃ (3.30 g) in a 7: 2: 3 dimethoxyethane / ethanol / water mixture (50 ml) was heated at 100 ° C for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and filtered. The filtrate was applied to a silica gel column and subjected to flash chromatography using 0% -50% dichloromethane / hexane.

EXAMPLE 110B

Tert-butyl 4- (1- (4'-chlorobiphenyl-2-yl) ethyl) piperazine-1-carboxylate A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with a 1M solution of titanium chloride (IV ) in dichloromethane (9.06 ml), cooled to 0 ° C, treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH₃ (0.828 g) in methanol (5 mL), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in a methanol / trifluoroacetic acid / dimethyl sulfoxide mixture, loaded onto a C18 reverse phase column and eluted with 0-80% acetonitrile in a solution of 0.1% trifluoroacetic acid in water for 70 minutes.

EXAMPLE 110C

1- (1- (4'-chlorobiphenyl-2-yl) ethyl) piperazine [0498] To a solution of EXAMPLE 110B (650 mg) in dichloromethane (6 mL) at 0 ° C, trifluoroacetic acid (6 mL) was added. The mixture was stirred at 0 ° C for 50 minutes and concentrated. The concentrate was dissolved in dichloromethane, washed with aqueous NaHCO₃ and dried over

On₂SO₄, filtered and concentrated.

EXAMPLE 110D

Ethyl 4- (4- (1- (4'-chlorobiphenyl-2-yl) ethyl) piperazin-1-yl) -2- (2-chlorophenoxy) benzoate [0499] EXAMPLE 110C (252 mg) and 2- (2 ethyl-chlorophenoxy) -4-fluorobenzoate (272 mg) in dimethyl sulfoxide (15 mL) was treated with potassium hydrogen phosphate (219 mg), stirred at 135 ° C overnight, cooled, diluted with dichloromethane, washed with water and concentrated. The concentrate was dissolved in dichloromethane, applied to a silica gel column and eluted with a 5 % solution (10M ammonia in methanol) in dichloromethane.

EXAMPLE 110E 4- (4- (1- (4'-chlorobiphenyl-2-yl) ethyl) piperazin-1-yl) -2- (2-chlorophenoxy) benzoic acid [0500] A mixture of EXAMPLE 110D (300 mg) in tetrahydrofuran (10 ml) and methanol (10 ml) at 50 ° C treated with 10% NaOH (2085 μΗ), stirred overnight, neutralized

EP-2507211B1PL using HCl and concentrated. The concentrate was dissolved in water and extracted with dichloromethane.

The organic layer was dried over Na₂SO₄, filtered and concentrated.

EXAMPLE 110F

4- {4- [1- (4'-chloro-1,1'-biphenyl-2-yl) ethyl] piperazine-1-yl} -2- (2-chlorophenoxy) -N - ({3-nitro- 4 [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0501] To a mixture of EXAMPLE 110E (65 mg), EXAMPLE 1G (74.9 mg) and 4-dimethylaminopyridine (58 mg) in dichloromethane (5 mL) 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (45.5 mg) was added. The mixture was stirred at ambient temperature overnight and concentrated. The concentrate was purified by RP HPLC (10-70% acetonitrile in a solution of 0.1% trifluoroacetic acid in water / 70 min). The product containing fractions were concentrated, and the concentrate was diluted with dichloromethane, neutralized with an aqueous NaHCO solution₃, dried over Na₂SO₄, filtered, and concentrated. ¹H NMR (500 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.64 (t, 1H), 8.47 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H), 7.45 -7.52 (m, 3H), 7.38-7.43 (m, 2H), 7.27-7.33 (m, 3H), 7.11-7.19 (m, 3H), 6 , 99 (t, 1H), 6.706.77 (m, 2H), 6.28 (d, 1H), 3.86 (dd, 2H), 3.33-3.37 (m, 1H), 3, 24-3.31 (m, 4H), 3.12 (s, 4H), 2.33-2.47 (m, 2H), 2.20-2.31 (m, 2H), 1.85- 1.96 (m, 1H), 1.64 (d, 2H), 1.17-1.33 (m, 5H).

EXAMPLE 111

N - {[4- {4 - [(4'-chloro-1,1'-biphenyl-2-yl) methyl] piperazin-1-yl} -2- (3,5-dichlorophenoxy) phenyl] sulfonyl} - 4 - [(1-methylpiperidin-4-yl) amino] -3-nitrobenzamide

EXAMPLE 111 A 4- (1-Methylpiperidin-4-ylamino) -3-nitrobenzoic acid [0502] To a solution of ethyl 4-fluoro-3-nitrobenzoate (2.13 g) and 1-methylpiperidin-4-amine (1.14 g) N, N-diisopropylethylamine (5 ml) was added in tetrahydrofuran (40 ml). The mixture was then stirred at reflux overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (300 ml) and washed with aqueous NaHCO₃, water and brine. After evaporation of the solvent, the residue was dissolved in tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml). Then LiOH H was added₂O (2 g). The mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue neutralized with 5% aqueous HCl. The precipitate was filtered off, washed with brine, and dried under reduced pressure to give the product.

EXAMPLE 111B

4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2-fluorobenzenesulfonamide [0503] To a solution of 2,4-difluorobenzenesulfonamide (1.56 g) and 1 - ((4 '-chlorobiphenyl-2-yl) methyl) piperazine (2.32 g) in dimethyl sulfoxide (20 ml) added N, N-diisopropylethylamine (5 ml). The mixture was stirred at 120 ° C overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3 x) brine and dried over Na₂SO₄. After filtration and evaporation of the solvent, the residue was applied to a column and eluted with 40% ethyl acetate in hexane to afford the title compound.

EXAMPLE 111C

N- (4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) -2-fluorophenylsulfonyl) -4- (1-methylpiperidin-4-ylamino) -3-nitrobenzamide [0504 ] The title compound was prepared as described in EXAMPLE 1G by replacing EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 111A and EXAMPLE 111B, respectively.

EXAMPLE 111D

[0505] N - {[4- {4 - [(4'-chloro-1,1'-biphenyl-2-yl) methyl] piperazin-1-yl} -2- (3,5-dichlorophenoxy ) phenyl] sulfonyl} -4 - [(1-methylpiperidin-4-yl) amino] -3-nitrobenzamide To a solution of 3,5-dichlorophenol (81 mg) and EXAMPLE 111C (72 mg) in diglyme (3 ml) was added K₂HPO₄ (53 mg). The mixture was stirred at 200 ° C in a CEM Discover microwave reactor for 2 hours. The mixture was filtered and purified by RP HPLC (10-70% acetonitrile in a solution of 0.1% trifluoroacetic acid in water / 70 min). The product containing fractions were concentrated, and the concentrate was diluted with dichloromethane, neutralized with an aqueous NaHCO solution₃, dried over Na₂SO₄, filtered, and concentrated. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.56 (d, 1H), 8.12 (d, 1H), 7.94 (m, 1H), 7.84 (m, 2H), 7.51 (m, 5H), 7.36 (m, 4H), 7.17 (d, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 4.36 (m, 1H) , 3.92 (m, 2H), 3.15 (m, 4H), 2.79 (m, 6H), 2.22 (m, 8H), 1.29 (m, 2H).

EXAMPLE 112

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 112A

Ethyl 4-fluoro-2- (3-fluorophenoxy) benzoate [0506] The title compound was prepared by substituting 3-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 112B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-fluorophenoxy) benzoate [0507] The title compound was prepared by substituting EXAMPLE 112A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 112C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-fluorophenoxy) benzoic acid [0508] The title compound was prepared by substitution of EXAMPLE 112B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 112D 4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide d₆) δ 8.34 (d, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.14 (m, 1H), 7.06 (d, 2H), 7.03 (d, 1H), 6.72 (dd, 1H), 6.65 (m, 1H), 6.49 (dd, 1H) , 6.41 (m, 2H), 3.81 (m, 1H), 3.22 (m, 2H), 3.11 (m, 4H), 2.88 (m, 2H), 2.77 ( m, 2H), 2.64 (s, 3H), 2.22 (m, 6H), 2.10 (m, 2H), 1.98 (m, 2H), 1.79 (m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).

EXAMPLE 113

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - ({ 3-nitro-4 - [(1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0510] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,

Dimethyl sulfoxide-d₆) δ 8.34 (d, 1H), 8.10 (d, 1H), 7.67 (dd, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.14 (m,

1H), 7.06 (d, 2H), 7.01 (d, 1H), 6.72 (dd, 1H), 6.65 (m, 1H), 6.49 (dd, 1H), 6, 41 (m, 2H), 3.93 (dd, 2H),

3.77 (br s, 2H), 3.30 (m, 2H), 3.10 (m, 6H), 2.77 (s, 2H), 2.69 (m, 2H), 2.24 ( m, 4H), 2.18 (t, 2H), 2.06 (d,

2H), 1.98 (s, 2H), 1.80 (d, 2H), 1.68 (m, 2H), 1.52 (m, 2H), 1.41 (t, 2H), 0, 94 (s, 6H).

EXAMPLE 114

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - ({4- [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0511] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.74 (br m, 1H), 8.43 (d, 1H), 7.73 (dd, 1H), 7.52 (d, 1H), 7.35 (m, 2H), 7, 19 (m, 1H), 7.06 (m, 3H), 6.73 (m, 2H), 6.50 (m, 2H), 6.44 (d, 1H), 3.64 (t, 4H ), 3.45 (m, 2H), 3.18 (m, 5H), 2.79 (m, 2H), 2.58 (m, 3H), 2.22 (m, 7H), 1.98 (m, 3H), 1.83 (m, 2H), 1.41 (m, 2H), 0.94 (s, 6H).

EXAMPLE 115

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3- nitro-4 - [(1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0512] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.33 (d, 1H), 8.09 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.34 (m, 3H), 7.03 (m, 4H), 6.87 (t, 1H), 6.69 (m, 1H), 6.50 (d, 1H), 6.25 (d, 1H), 3.91 (d, 2H) , 3.57 (s, 4H), 3.30 (m, 6H), 3.06 (s, 4H), 2.20 (d, 6H), 1.96 (d, 4H), 1.73 ( s, 2H), 1.63 (s, 2H), 1.48 (s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 116

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0513] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.70 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.40 (dd, 1H), 7.35 (m, 2H), 7.12 (m, 1H), 7.06 (m, 3H), 6.98 (td, 1H), 6.73 (dd, 1H), 6.68 (dd, 1H) , 6.26 (d, 1H), 4.62 (s, 2H), 3.62 (m, 4H), 3.46 (dd, 2H), 3.11 (s, 4H), 2.75 ( d, 2H), 2.47 (m, 4H), 2.20 (d, 6H), 1.97 (s, 2H), 1.82 (p, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 117

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-cyclopentyl-piperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 117A

4- (1-cyclopentylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0514] The title compound was prepared by substituting 1-cyclopentylpiperidin-4-amine for 3- (N-morpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 117B

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-cyclopentylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0515] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 117A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.63 (d, 1H), 7.35 (m, 3H), 7.04 (m,

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4H), 6.88 (td, 1H), 6.69 (dd, 1H), 6.53 (dd, 1H), 6.25 (d, 1H), 4.57 (s, 1H), 3, 29 (s, 8H), 3.05 (d, 4H), 2.75 (s, 2H), 2.62 (s, 2H), 2.20 (d, 5H), 2.07 (s, 1H ), 1.95 (d, 3H), 1.66 (s, 3H), 1.53 (s, 3H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 118

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (4-fluorophenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 118A

Ethyl 4-fluoro-2- (4-fluorophenoxy) benzoate [0516] The title compound was prepared by substituting 4-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 118B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4-fluorophenoxy) benzoate [0517] The title compound was prepared by substituting EXAMPLE 118A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 118C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4-fluorophenoxy) benzoic acid [0518] The title compound was prepared by substitution of EXAMPLE 118B instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 118D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (4-fluorophenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0519] The title compound was prepared by substituting EXAMPLE 118C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.39 (d, 1H), 8.08 (d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 7.36 (d, 2H), 7.06 (m, 3H), 6.98 (m, 2H), 6.73 (m, 2H), 6.67 (dd, 1H), 6.29 (d, 1H), 3.82 (m, 1H) , 3.18 (m, 2H), 3.08 (m, 4H), 2.80 (m, 4H), 2.60 (m, 3H), 2.22 (m, 6H), 2.07 ( m, 2H), 1.97 (m, 2H), 1.77 (m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).

EXAMPLE 119

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-cyclopropylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0520] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 36C and EXAMPLE 65A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.17 (d, 1H), 7.66 (dd, 1H), 7.58 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.05 (m, 3H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.64 (m, 2H), 6.41 (d, 1H) , 3.69 (m, 1H), 3.16 (m, 4H), 2.97 (m, 4H), 2.77 (m, 2H), 2.72 (s, 2H), 2.44 ( m, 3H), 2.21 (m, 3H), 1.96 (m, 2H), 1.58 (m, 3H), 0.94 (s, 6H), 0.40 (m, 5H).

EXAMPLE 120

2- (2-chloro-4-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide

101

[0521] The title compound was prepared by substituting EXAMPLE 61D for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.73 (m, 1H), 8.48 (d, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.36 (m, 3H), 7.07 (m,

4H), 6.75 (m, 2H), 6.25 (d, 1H), 3.63 (m, 4H), 3.47 (m, 2H), 3.12 (m, 4H), 2, 77 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.82 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H) ).

EXAMPLE 121

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2- (2,3-difluorophenoxy) benzamide [0522] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 65A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.42 (d, 1H), 8.21 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.35 (d, 2H), 7.15 (d, 1H), 7.06 (d, 2H), 6.89 (m, 2H), 6.75 (dd, 1H), 6.44 (m, 2H), 3.76 (m, 1H) , 3.17 (m, 4H), 3.00 (m, 2H), 2.81 (s, 2H), 2.59 (m, 2H), 2.24 (m, 6H), 1.92 ( m, 5H), 1.61 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H), 0.46 (m, 4H).

EXAMPLE 122

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2fluorofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 122A

Methyl 4-fluoro-2- (2-fluorophenoxy) benzoate [0523] The title compound was prepared by substituting 2-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 122B

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-fluorophenoxy) benzoate [0524] The title compound was prepared by substituting EXAMPLE 122A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 122C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-fluorophenoxy) benzoic acid [0525] The title compound was prepared by substitution of EXAMPLE 122B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 122D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2fluorofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0526] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.87 (s, 1H), 9.54 (s, 1H), 8.50 (d, 1H), 8.20 (d, 1H), 7.86 (dd, 1H), 7.52 (d, 1H), 7.40 (d, 2H), 7.24 (m, 2H), 7.10 (d, 2H), 7.03 (m, 2H), 6.78 (m, 2H) , 6.42 (s, 1H), 3.62 (m, 10H), 3.10 (m, 4H), 2.82 (m, 2H), 2.82 (s, 3H), 2.21 ( m, 4H), 2.03 (s, 2H), 1.85 (m, 1H), 1.46 (t, 2H), 0.96 (s, 6H).

EXAMPLE 123

4- (4 - {([2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2- (2-fluorophenoxy) benzamide

102

[0527] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 65A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.51 (d, 1H), 8.19 (s, 1H), 7.87 (dd, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.24 (m,

2H), 7.11 (d, 2H), 7.03 (m, 2H), 6.78 (m, 2H), 6.43 (d, 1H), 3.97 (m, 4H), 3, 21 (s, 8H), 3.21 (s, 4H), 2.83 (m, 4H), 2.22 (m, 4H), 2.06 (m, 2H), 1.81 (m, 1H ), 1.47 (t, 2H), 0.96 (s, 6H).

EXAMPLE 124

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2-fluorophenoxy) -N - ({ 3-nitro-4 - [(1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0528] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.90 (s, 1H), 9.59 (s, 1H), 8.51 (m, 1H), 8.20 (d, 1H), 7.87 (dd, 1H), 7.53 (d, 1H), 7.39 (d, 2H), 7.24 (m, 2H), 7.10 (d, 2H), 7.03 (m, 2H), 6.78 (m, 2H) , 6.42 (s, 1H), 4.01 (m, 2H), 3.71 (m, 4H), 3.34 (m, 6H), 3.17 (m, 4H), 2.78 ( m, 2H), 2.24 (m, 4H), 1.94 (m, 8H), 1.70 (m, 2H), 1.46 (t, 2H), 0.96 (s, 6H).

EXAMPLE 125

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2fluorofenoksy) -N - ({4- [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0529] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.85 (s, 1H), 9.94 (s, 1H), 9.63 (s, 1H), 8.71 (m, 1H), 8.53 (d, 1H), 7.86 (dd, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.26 (m, 1H), 7.19 (d, 1H), 7.07 (m, 4H) , 6.80 (m, 2H), 6.41 (d, 1H), 3.97 (m, 2H), 3.54 (m, 6H), 3.31 (m, 4H), 3.19 ( m, 8H), 2.22 (m, 2H), 1.99 (m, 4H), 1.47 (t, 2H), 0.97 (s, 6H).

EXAMPLE 126

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2fluorofenoksy) -N - ({4- [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 126A

4- (2-morpholinoethylamino) -3-nitrobenzenesulfonamide [0530] The title compound was prepared by substituting 2- (N-morpholinyl) -2-ethylamine for 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 126B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2fluorofenoksy) -N - ({4- [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0531] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.81 (s, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 7.23 (m, 1H), 7.04 (m, 5H), 6.79 (m, 1H), 6.73 (dd, 1H), 6.31 (d, 1H), 3.62 (m, 4H) , 3.50 (q, 2H), 3.32 (m, 6H), 3.14 (m, 4H), 2.79 (s, 2H), 2.67 (m, 2H), 2.20 ( m, 6H), 1.99 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 127

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3- nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

103

[0532] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.38 (m, 1H), 8.13 (m, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.36 (d, 2H), 7.16 (m, 1H), 7.05 (m, 3H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.61 (m, 1H) , 6.42 (m, 1H), 3.94 (m, 2H), 3.26 (m, 6H), 3.15 (m, 6H), 2.78 (m, 2H), 2.18 ( m, 9H), 1.98 (m, 3H), 1.86 (m, 2H), 1.74 (m, 2H), 1.57 (m, 2H), 1.41 (m, 2H), 0.93 (s, 6H).

EXAMPLE 128

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0533] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.75 (t, 1H), 8.41 (d, 1H), 7.71 (dd, 1H), 7.52 (d, 1H), 7.36 (d, 2H), 7.18 (m, 1H), 7.06 (m, 3H), 6.93 (dd, 1H), 6.77 (dd, 1H), 6.69 (m, 2H), 6.46 (d, 1H) , 3.65 (t, 4H), 3.47 (q, 2H), 3.29 (m, 2H), 3.18 (m, 4H), 2.79 (s, 2H), 2.56 ( m, 4H), 2.22 (m, 6H), 1.98 (m, 2H), 1.85 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 129

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - ({4- [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0534] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.48 (m, 1H), 8.81 (t, 1H), 8.45 (d, 1H), 7.75 (dd, 1H), 7.49 (d, 1H), 7.36 (d, 2H), 7.19 (m, 1H), 7.06 (m, 3H), 6.77 (dd, 1H), 6.72 (m, 1H), 6.54 (m, 2H) , 6.47 (d, 1H), 3.62 (m, 4H), 3.50 (q, 2H), 3.32 (m, 4H), 3.19 (m, 4H), 2.82 ( s, 2H), 2.69 (t, 2H), 2.27 (m, 4H), 2.18 (s, 2H), 1.99 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 130

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-cyclopentylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0535] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 117A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 7.35 (d, 2H), 7.14 (m, 1H), 7.04 (m, 3H), 6.88 (dd, 1H), 6.72 (dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H) , 6.39 (d, 1H), 3.87 (s, 1H), 3.11 (m, 6H), 2.93 (m, 2H), 2.77 (s, 2H), 2.21 ( m, 8H), 1.98 (m, 5H), 1.69 (m, 4H), 1.56 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 131

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

EXAMPLE 131 A (2-fluorophenyl) (trifluoromethyl) sulfane [0536] Methylvinylene hydrochloride (1.17 g) in N, N-dimethylformamide (80 ml) at 25 ° C saturated with trifluoromethyl iodide, treated with 2-fluorobenzeniol ml) and triethylamine (20 ml), stirred for 24 hours, diluted with water (240 ml) and extracted with diethyl ether.

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The extract was washed with 1M aqueous NaOH, saturated ammonium chloride and brine, and concentrated.

EXAMPLE 131B

1-fluoro-2- (trifluoromethylsulfonyl) benzene. EXAMPLE 131A (17.06 g) in a 1: 1: 2 mixture of carbon tetrachloride: acetonitrile: water (800 mL) at 25 ° C treated with sodium periodate (56.8 g) and ruthenium (III) chloride hydrate (183 mg), stirred for 18 hours, diluted with dichloromethane (100 mL) and filtered through diatomaceous earth (Celite®). The filtrate was washed with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with brine and dried (MgSO₄), filtered and concentrated. The concentrate was filtered through silica gel.

EXAMPLE 131C

4-fluoro-3- (trifluoromethylsulfonyl) benzenesulfonamide EXAMPLE 131B (37.3 g) in chlorosulfonic acid (32.8 ml) at 120 ° C was stirred for 18 hours, cooled to 25 ° C and pipetted to the broken ice. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine and dried (MgSO₄), filtered and concentrated. The crude product was dissolved in isopropanol (706 mL) at -78 ° C, treated with ammonium hydroxide (98 mL) for 1 hour, stirred for 1 hour, quenched with 6M aqueous HCl (353 mL), heated to 25 ° C and concentrated. The concentrate was mixed with water and extracted with ethyl acetate. The extract was dried over MgSO₄, filtered and concentrated. The concentrate was recrystallized from ethyl acetate / hexane.

EXAMPLE 131D

4- (1-methylpiperidin-4-ylamino) -3- (trifluoromethylsulfonyl) benzenesulfonamide [0539] The title compound was prepared by substituting 1-methyl-4-aminopiperidine for 3- (Nmorpholinyl) -1-propylamine and EXAMPLE 131C for 4-fluoro -3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 131E

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide [0540] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.00 (d, 1H), 7.83 (dd, 1H), 7.61 (d, 1H), 7.36 (m, 2H), 7.19 (m, 1H), 7.07 (d, 2H), 7.01 (d, 1H), 6.93 (d, 1H), 6.72 (dd, 1H), 6.66 (m, 2H), 6.51 (d, 1H) , 6.39 (d, 1H), 3.79 (none, 1H), 3.11 (m, 6H), 2.90 (t, 2H), 2.78 (s, 2H), 2.65 ( s, 3H), 2.20 (m, 6H), 2.09 (m, 2H), 1.97 (m, 3H), 1.64 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 132

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2- (3-fluorophenoxy) benzamide [0541] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 65A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.43 (d, 1H), 8.23 ​​(d, 1H), 7.75 (dd, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 7.17 (m, 2H), 7.06 (d, 2H), 6.73 (m, 2H), 6.56 (dd, 1H), 6.51 (dd, 1H), 6.45 (d, 1H) , 3.74 (m, 1H), 3.18 (m, 4H),

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2.97 (m, 2H), 2.80 (s, 2H), 2.54 (m, 2H), 2.20 (m, 6H), 1.98 (m, 4H), 1.85 (m , 1H), 1.62 (m, 2H), 1.41 (t,

2H), 0.94 (s, 6H), 0.50 (m, 2H), 0.41 (m, 2H).

EXAMPLE 133

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopentylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2- (2,3-difluorophenoxy) benzamide [0542] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 117A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.05 (s, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.36 (d, 2H), 7.06 (m, 3H), 6.84 (m, 2H), 6.72 (dd, 1H), 6.43 (d, 1H), 6.31 (m, 1H), 3.89 (s, 1H) , 3.12 (m, 6H), 2.97 (m, 2H), 2.77 (s, 2H), 2.21 (m, 8H), 1.98 (m, 5H), 1.63 ( m, 8H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 134

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopentylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2- (2-fluorophenoxy) benzamide [0543] The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE 1F and EXAMPLE 117A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.39 (m, 1H), 8.07 (d, 1H), 7.76 (m, 1H), 7.61 (d, 1H), 7.34 (d, 2H), 7.18 (m, 2H), 7.07 (m, 3H), 6.91 (m, 2H), 6.68 (m, 1H), 6.28 (m, 1H), 3.26 (m, 8H) , 3.17 (m, 2H), 3.05 (m, 4H), 2.75 (s, 2H), 2.23 (m, 7H), 2.00 (m, 4H), 1.64 ( m, 6H), 1.40 (m, 2H), 0.94 (s, 6H).

EXAMPLE 135

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - ({ 4 - [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0544] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.77 (m, 1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.06 (m, 3H), 6.91 (m, 2H), 6.76 (dd, 1H), 6.45 (m, 2H), 3.62 (m, 4H), 3.49 (m, 2H) , 3.18 (m, 4H), 2.81 (s, 2H), 2.68 (t, 2H), 2.23 (m, 6H), 1.97 (m, 2H), 1.41 ( t, 2H), 0.94 (s, 6H).

EXAMPLE 136

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - [( 3-nitro-4 - {[1- (thien-3-ylmethyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 136A 4- (2-nitro-4-sulfamoyl-phenylamino) -piperidine-1-carboxylic acid tert-butyl ester [0545] Tert-butyl 4-amino-piperidine-1-carboxylate (8.63 g) was dissolved in 1.4 -dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added, followed by triethylamine (10.60 mL). The solution was heated at 90 ° C for 20 hours and then cooled. The solvent was removed under reduced pressure, and the material was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexane, increasing polarity to 100% ethyl acetate and further increasing to 20% methanol in dichloromethane.

EXAMPLE 136B

3-nitro-4- (piperidin-4-ylamino) -benzenesulfonamide [0546] The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE 1A in EXAMPLE 1B.

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EXAMPLE 136C

3-nitro-4- (1- (thiophen-3-ylmethyl) piperidin-4-ylamino) benzenesulfonamide [0547] The title compound was prepared by substituting thiophene-3-carboxaldehyde for 4'chlorobiphenyl-2-carboxaldehyde and EXAMPLE 136B for piperazine Tert-butyl 1-carboxylate in EXAMPLE 1A.

EXAMPLE 136D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - [( 3-nitro-4 - {[1- (thien-3-ylmethyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide [0548] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 136C for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.39 (d, 1H), 8.16 (d, 1H), 7.74 (dd, 1H), 7.54 (m, 3H), 7.35 (d, 2H), 7.10 (m, 4H), 6.87 (m, 2H), 6.74 (dd, 1H), 6.40 (m, 2H), 3.84 (m, 3H), 3.15 (m, 4H) , 3.03 (m, 2H), 2.79 (s, 2H), 2.62 (m, 2H), 2.23 (m, 6H), 2.02 (m, 4H), 1.73 ( m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 137

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2- (2-fluorophenoxy) benzamide [0549] EXAMPLE 122C (203 mg), EXAMPLE 11A (124 mg), 1-ethyl-3- [3- (dimethylamino) propyl hydrochloride ] -carbodiimide (142 mg), and 4-dimethylaminopyridine (90 mg) were stirred in CH₂cl₂(8 ml) overnight. The reaction was concentrated and the crude product was purified by preparative HPLC using a C18 column, 250 x 50 mm, 10 μ, and eluting using a gradient of 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. The salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.71 (br t, 1H), 8.38 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7, 18 (m, 1H), 7.06 (d, 2H), 6.98 (d, 1H), 6.92 (m, 2H), 6.66 (dd, 1H), 6.60 (m, 1H ), 6.26 (d, 1H), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.89 (br m, 2H), 2.75 (s, 2H), 2 , 60 (s, 6H), 2.20 (br m, 6H), 1.98 (s, 2H), 1.88 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 138

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2- (3-fluorophenoxy) benzamide [0550] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.70 (br t, 1H), 8.35 (d, 1H), 7.69 (dd, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7, 15 (dd, 1H), 7.06 (d, 2H), 6.95 (d, 1H), 6.70 (m, 2H), 6.50 (dd, 1H), 6.41 (m, 1H ), 6.38 (d, 1H), 3.47 (dd, 2H), 3.10 (br m, 4H), 2.94 (br m, 2H), 2.78 (s, 2H), 2 , 62 (s, 6H), 2.23 (br m, 6H), 1.99 (s, 2H), 1.90 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 139

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2- (4-fluorophenoxy) benzamide [0551] The title compound was prepared by substituting EXAMPLE 118C for EXAMPLE 122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.75 (br t, 1H), 8.39 (d, 1H), 7.75 (dd, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7, 06 (d, 2H), 7.00 (m, 3H), 6.75 (m, 2H), 6.66 (dd, 1H), 6.28 (d,

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1H), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.89 (br m, 2H), 2.75 (s, 2H), 2.60 (s, 6H), 2.20 (br m, 6H), 1.98 (s,

2H), 1.88 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 140

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - [( 4 - {[1- (2-fluoroethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide EXAMPLE 140A 4- (2-nitro-4-sulfamoyl-phenylamino) -piperidine- tert-butyl ester 1-carboxylic acid tert-butyl 4-amino-piperidine-1-carboxylate (8.63 g) was dissolved in 1,4-dioxane (250 ml), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added, followed by triethylamine (10.60 ml). The solution was heated at 90 ° C for 20 hours and then cooled. The solvent was removed under reduced pressure, and the material was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexane, increasing to 100% ethyl acetate and further increasing to 20% methanol in dichloromethane.

EXAMPLE 140B

3-Nitro-4- (piperidin-4-ylamino) -benzenesulfonamide [0553] The title compound was prepared by substituting EXAMPLE 140A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 140C

4- [1- (2-Fluoro-ethyl) -piperidin-4-ylamino] -3-nitro-benzenesulfonamide [0554] To EXAMPLE 140B (1000 mg) N, N-dimethylformamide (10 ml) was added. 1-Fluoro-2-iodoethane (462 mg) and triethylamine (1.18 mL) were added and the solution was heated at 70 ° C for 16 hours. The solvent was removed under reduced pressure, and the material was purified by flash column chromatography on silica gel using ethyl acetate, increasing to 10% methanol in dichloromethane.

EXAMPLE 140D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - [( 4 - {[1- (2-fluoroethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0555] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 140C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.41 (d, 1H), 8.21 (d, 1H), 7.76 (dd, 1H), 7.56 (d, 1H), 7.37 (d, 2H), 7.14 (d, 1H), 7.07 (d, 2H), 6.94-6.82 (m, 2H), 6.76 (dd, 1H), 6.48 (d, 1H), 6.41- 6.34 (m, 1H), 4.71 (t, 1H), 4.55 (t, 1H), 3.89-3.70 (m, 2H), 3.17 (br s, 4H), 3.09-2.90 (m, 4H), 2.91-2.77 (m, 3H), 2.26 (br s, 4H), 2.18 (m, 2H), 2.08-1 , 96 (m, 4H), 1.71 (q, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 141

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0556] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.81 (t, 1H), 8.44 (d, 1H), 7.73 (dd, 1H), 7.51 (d, 1H), 7.36 (d, 2H), 7.18 (t, 1H), 7.07 (d, 2H), 7.04 (d, 1H), 6.93 (dt, 1H), 6.78 (dd, 1H), 6.71 (dd, 1H) , 6.69 (d, 1H), 6.47 (d, 1H), 3.62 (t, 4H), 3.50 (q, 2H), 3.20 (br s, 4H), 2.81 (br s, 2H), 2.69 (t, 2H), 2.26 (m, 4H), 2.18 (t, 2H), 2.02-1.93 (m, 4H), 1.41 (t, 2H), 1.37-1.22 (m, 2H), 0.95 (s, 6H).

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EXAMPLE 142

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0557] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.71 (br t, 1H), 8.34 (d, 1H), 7.65 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7, 16 (dd, 1H), 7.07 (d, 2H), 6.93 (d, 1H), 6.89 (m, 1H), 6.73 (dd, 1H), 6.64 (dd, 1H ), 6.60 (dd, 1H), 6.38 (d, 1H), 3.45 (dd, 2H), 3.09 (br m, 4H), 2.93 (br m, 2H), 2 , 78 (s, 2H), 2.62 (s, 6H), 2.23 (br m, 6H), 1.98 (s, 2H), 1.90 (m, 2H) 1.41 (t, 2H), 0.93 (s, 6H).

EXAMPLE 143

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[3- (4-methylpiperazin-1-yl) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide EXAMPLE 143A

4- [3- (4-Methyl-piperazin-1-yl) -propylamino] -3-nitro-benzenesulfonamide [0558] The title compound was prepared by substituting 1- (3-aminopropyl) -4-methylpiperazine for 4-aminopiperidine-1 tert-butyl carboxylate in EXAMPLE 140A.

EXAMPLE 143B

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[3- (4-methylpiperazin-1-yl) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0559] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 143A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.55 (t, 1H), 8.39 (d, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 2H), 6.95 (d, 1H), 6.89 (dd, 1H), 6.73 (dd, 1H), 6.65 (d, 1H) , 6.60 (t, 1H), 6.40 (d, 1H), 3.43 (q, 2H), 3.12 (br s, 4H), 2.89 (br s, 2H), 2, 77 (s, 2H), 2.60-2.45 (m, 9H), 2.29-2.15 (m, 8H), 1.98 (br s, 2H), 1.81 (m, 2H ), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 144

2- (3-chlorophenoxy) -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 144A

Methyl 2- (3-chlorophenoxy) -4- (piperazin-1-yl) benzoate [0560] This EXAMPLE was performed by substituting piperazine instead of EXAMPLE 3F and EXAMPLE 36A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 144B

2- (3-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) benzoate methyl [0561] This EXAMPLE was performed by substituting EXAMPLE 144A for EXAMPLE 38F in EXAMPLE 38G.

EXAMPLE 144C 2- (3-chlorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazinic acid 1-yl) benzoic [0562] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 144B.

EXAMPLE 144D

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2- (3-chlorophenoxy) -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0563] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 144C and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.33 (d, 1H), 8.07 (d, 1H), 7.68 (dd, 1H), 7.62 (d, 1H), 7.40 (d, 2H), 7.15 (m, 3H), 7.01 (d, 1H), 6.86 (m, 1H), 6.72 (m, 1H), 6.64 (dd, 1H), 6.58 (m, 1H) , 6.39 (d, 1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.17 (m, 8H), 2.87 (s, 3H), 2.63 ( m, 5H), 2.26 (m, 4H), 2.13 (m, 3H), 1.79 (m, 1H), 1.20 (s, 6H).

EXAMPLE 145

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 145A

Methyl 2- (2,3-difluorophenoxy) -4- (piperazin-1-yl) benzoate [0564] This EXAMPLE was performed by substituting piperazine instead of EXAMPLE 3F and EXAMPLE 45A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 145B

2- (2,3-difluorophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1- methyl-benzoate [0565] This EXAMPLE was performed by substituting EXAMPLE 145A for EXAMPLE 38F in EXAMPLE 38G.

EXAMPLE 145C 4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2 (2 , 3-difluorophenoxy) benzoic [0566] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 145B.

EXAMPLE 145D

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0567] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 145C and EXAMPLE 3I. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆6) δ 8.32 (d, 1H), 8.06 (d, 1H), 7.71 (dd, 1H), 7.66 (d, 1H), 7.40 (d, 2H), 7, 15 (s, 2H), 7.03 (d, 1H), 6.81 (m, 2H), 6.73 (m, 1H), 6.43 (m, 1H), 6.27 (m, 1H ), 4.15 (m, 2H), 3.83 (m, 1H), 3.16 (m, 8H), 2.88 (s, 3H), 2.70 (m, 4H), 2.26 (s, 4H), 2.13 (m, 4H), 1.78 (m, 1H), 1.21 (s, 6H).

EXAMPLE 146

N - ({4 - [(1-allyl-4-yl) amino] -3-nitrophenyl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4dimetylocykloheks-1-en-1 yl] methyl} piperazin-1-yl) -2- (2,3-difluorophenoxy) benzamide

EXAMPLE 146A

4- (1-allylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0568] 3-nitro-4- (piperidin-4-ylamino) benzenesulfonamide hydrochloride (0.27 g), triethylamine (0.2 mL) and 3- bromoprop-1-ene (0.1 g) was dissolved in N, N-dimethylformamide (5 ml). The mixture was stirred at room temperature overnight. The solvent was dried under reduced pressure. The mixture was chromatographed on silica gel with 0-20% methanol in dichloromethane.

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EXAMPLE 146B

N - ({4 - [(1-allyl-4-yl) amino] -3-nitrophenylsulphonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4dimetylocykloheks-1-en-1-yl ] methyl} piperazin-1-yl) -2- (2,3-difluorophenoxy) benzamide [0569] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 146A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.39 (d, 1H), 8.14 (d, 1H), 7.75 (dd, 1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.08 (m, 3H), 6.86 (m, 2H), 6.74 (dd, 1H), 6.45 (d, 1H), 6.36 (m, 1H), 5.88 (m, 1H) , 5.37 (m, 2H), 3.83 (m, 1H), 3.13 (m, 8H), 2.74 (m, 4H), 2.17 (m, 8H), 1.98 ( s, 2H), 1.74 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 147

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 147A

Methyl 2- (3-chloro-2-fluorophenoxy) -4-fluorobenzoate [0570] The title compound was prepared by substituting 3-chloro-2-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 147B

Ethyl 2- (3-chloro-2-fluorophenoxy) -4- (piperazin-1-yl) benzoate [0571] The title compound was prepared by substituting piperazine for EXAMPLE 3F and EXAMPLE 147A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 147C

Ethyl 2- (3-chloro-2-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0572] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 147B for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 147D 2- (3-Chloro-2-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0573] The title compound was prepared by substituting EXAMPLE 147C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 147E

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0574] The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.33 (d, 1H), 8.05 (d, 1H), 7.68 (m, 2H), 7.35 (d, 2H), 7.02 (m, 4H), 6.84 (m, 1H), 6.72 (d, 1H), 6.43 (m, 2H), 3.83 (m, 1H), 3.12 (m, 6H), 2.84 (m, 4H) , 2.62 (s, 3H), 2.22 (m, 6H), 2.11 (m, 2H), 1.98 (s, 2H), 1.76 (m, 2H), 1.41 ( t, 2H), 0.94 (s, 6H).

EXAMPLE 148

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(3-morpholin-4-ylpropyl) amino] -3-nitrophenyl} sulfonyl) benzamide

111

[0575] The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE 1F and EXAMPLE 4A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.71 (m, 1H), 8.41 (d, 1H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.35 (d, 2H), 7.05 (m,

4H), 6.91 (m, 1H), 6.75 (dd, 1H), 6.56 (m, 1H), 6.47 (d, 1H), 3.64 (m, 4H), 3, 47 (q, 2H), 3.17 (m, 4H), 2.79 (s, 2H), 2.55 (m, 6H), 2.22 (m, 6H), 1.98 (s, 2H) ), 1.84 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 149

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(3-pyrrolidin-1-ylpropyl) amino] phenyl} sulfonyl) benzamide EXAMPLE 149A

3-nitro-4- (3- (pyrrolidin-1-yl) propylamino) benzenesulfonamide [0576] The title compound was prepared by substituting 3- (pyrrolidin-1-yl) propan-1-amine for 3 (N-morpholinyl) -1 -propylamine in EXAMPLE 4A.

EXAMPLE 149B

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(3-pyrrolidin-1-ylpropyl) amino] phenyl} sulfonyl) benzamide [0577] The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE 1F and EXAMPLE 149A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.43 (s, 1H), 8.32 (d, 1H), 7.70 (m, 2H), 7.35 (d, 2H), 7.07 (d, 2H), 6.97 (m, 2H), 6.85 (m, 1H), 6.71 (dd, 1H), 6.43 (m, 2H), 3.48 (q, 2H), 3.09 (m, 8H) , 2.77 (s, 2H), 2.21 (m, 8H), 1.92 (m, 8H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 150

2- (3-chloro-2-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(2-morpholin-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0578] The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.79 (m, 1H), 8.44 (d, 1H), 7.76 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.06 (m, 4H), 6.91 (m, 1H), 6.76 (dd, 1H), 6.58 (m, 1H), 6.48 (d, 1H), 3.62 (m, 4H) , 3.50 (q, 2H), 3.19 (m, 4H), 2.81 (s, 2H), 2.69 (m, 2H), 2.23 (m, 6H), 1.98 ( s, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 151

2- (2-chloro-6-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 151A

Methyl 2- (2-chloro-6-fluorophenoxy) -4-fluorobenzoate [0579] The title compound was prepared by substituting 2-chloro-6-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 151B

Methyl 2- (2-chloro-6-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0580] The title compound was prepared by substituting EXAMPLE 151A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 151C

112

2- (2-chloro-6-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0581] The title compound was prepared by substituting EXAMPLE 151B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 151D

2- (2-chloro-6-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0582] The title compound was prepared by substituting EXAMPLE 151C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.51 (d, 1H), 8.09 (d, 1H), 7.92 (dd, 1H), 7.60 (d, 1H), 7.32 (m, 5H), 7.17 (d, 1H), 7.05 (d, 2H), 6.56 (dd, 1H), 5.83 (d, 1H), 3.85 (m, 1H), 3.17 (m, 2H) , 2.95 (m, 4H), 2.81 (m, 2H), 2.73 (s, 2H), 2.59 (s, 3H), 2.15 (m, 8H), 1.97 ( m, 2H), 1.77 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 152

2- (2-chloro-6-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0583] The title compound was prepared by substituting EXAMPLE 151C for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.54 (d, 1H), 8.14 (d, 1H), 7.93 (dd, 1H), 7.58 (d, 1H), 7.34 (m, 5H), 7.20 (d, 1H), 7.04 (d, 2H), 6.59 (dd, 1H), 5.85 (d, 1H), 3.93 (dd, 2H), 3.85 (m, 1H) , 3.21 (s, 6H), 2.97 (m, 4H), 2.73 (m, 4H), 2.16 (m, 8H), 1.96 (s, 2H), 1.81 ( m, 2H), 1.69 (m, 2H), 1.54 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 154

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 154A

6-fluoro-1H-indol-5-ol [0584] The title compound was prepared from 2-fluoro-4-nitrophenol according to WO 02/12227 (page 78). EXAMPLE 154B

Methyl 4-fluoro-2- (6-fluoro-1H-indol-5-yloxy) benzoate [0585] The title compound was prepared as described in EXAMPLE 3A by replacing 2-methyl-5-indolol by EXAMPLE 154A.

EXAMPLE 154C

Methyl 2- (6-fluoro-1H-indol-5-yloxy) -4- (piperazin-1-yl) benzoate [0586] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 154B, respectively ,.

EXAMPLE 154D

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5-yloxy) benzoate [ 0587] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 154C and EXAMPLE 60D, respectively.

EXAMPLE 154E

113

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5-yloxy) ) benzoic [0588] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE

38G EXAMPLE 154D.

EXAMPLE 154F

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0589] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G, respectively EXAMPLE 154E and EXAMPLE 3I. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.12 (m, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (m, 3H), 7.28 (d, 1H), 7.11 (d, 1H), 7.05 (m, 2H), 6.59 (dd, 1H), 6.35 (m, 1H) , 6.08 (m, 1H), 3.76 (m, 1H), 3.06 (m, 8H), 2.72 (m, 6H), 2.17 (s, 6H), 1.98 ( m, 5H), 1.72 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 155

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(1-methylpiperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 155A

4 - ((1-methylpiperidin-4-yl) methylamino) -3-nitrobenzenesulfonamide [0590] The title compound was prepared by substituting 4-aminomethyl-N-methylpiperidine for 3 (N-morpholinyl-1-propylamine in EXAMPLE 4A).

EXAMPLE 155B

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(1-methylpiperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0591] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 155A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.45 (br t, 1H), 8.33 (d, 1H), 7.65 (m, 2H), 7.36 (d, 2H), 7.15 (t, 1H), 7, 06 (d, 2H), 6.97 (d, 1H), 6.89 (d, 1H), 6.60 (m, 2H), 6.38 (d, 1H), 3.02-3.12 (m, 8H), 2.77 (m, 4H), 2.65 (m, 2H), 2.24 (m, 4H), 2.19 (m, 2H), 1.91 (m, 1H) , 1.87 (m, 2H), 1.41 (m, 4H), 0.95 (s, 6H).

EXAMPLE 156

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy) -N - [( 4 - {[(1-methylpiperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0592] The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 1F and EXAMPLE 155A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.54 (br t, 1H), 8.37 (d, 1H), 7.72 (d, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7, 07 (d, 3H), 6.88 (dd, 2H), 6.75 (d, 1H), 6.46 (s, 1H), 6.36 (br s, 1H), 3.16 (m, 8H), 2.89 (m, 2H), 2.81 (m, 2H), 2.68 (s, 3H), 2.27 (m, 4H), 2.20 (m, 2H), 1, 99 (m, 2H), 1.91 (m, 3H), 1.55 (m, 2H), 1.41 (m, 2H), 0.95 (s, 6H).

EXAMPLE 157

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(4-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 157A

4-fluoro-1H-indol-5-ol [0593] The title compound was prepared from 2-fluoro-4-nitrophenol according to WO 02/12227 (page 78).

114

EP-2507211B1PL

EXAMPLE 157B

Methyl 4-fluoro-2- (4-fluoro-1H-indol-5-yloxy) benzoate [0594] The title compound was prepared as described in EXAMPLE 3A by replacing 2-methyl-5-indolol by EXAMPLE 157A.

EXAMPLE 157C

Methyl 2- (4-fluoro-1H-indol-5-yloxy) -4- (piperazin-1-yl) benzoate [0595] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 157B, respectively .

EXAMPLE 157D

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4-fluoro-1H-indol-5-yloxy) benzoate [ 0596] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 157C and EXAMPLE 60D, respectively.

EXAMPLE 157E 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4-fluoro-1H-indol-5-yloxy) acid benzoic [0597] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 157D.

EXAMPLE 157F

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(4-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0598] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G 157E and EXAMPLE 31. ¹1 H NMR (300 MHz, dimethyl sulfoxide d₆) δ 11.40 (m, 1H), 8.53 (d, 1H), 8.12 (d, 1H), 7.88 (d, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.33 (d, 2H), 7.16 (dd, 2H), 7.05 (d, 2H), 6.83 (m, 1H), 6.52 (m, 2H) , 6.02 (s, 1H), 3.77 (m, 2H), 3.03 (m, 6H), 2.70 (s, 3H), 2.04 (m, 12H), 1.71 ( m, 2H), 0.92 (s, 6H).

EXAMPLE 158

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- [3- (methoxymethoxy) -2-methylphenoxy] N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 158A

Ethyl 4-fluoro-2- (3-hydroxy-2-methylphenoxy) benzoate [0599] The title compound was prepared by substituting 2-methylbenzene-1,3-diol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 158B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-hydroxy-2-methylphenoxy) benzoate [0600] Title compound prepared by substituting EXAMPLE 158A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 158C

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (methoxymethoxy) -2-methylphenoxy) benzoate

115

[0601] A mixture of EXAMPLE 158B (0.6 g), chloro (methoxy) methane (0.18 g) and cesium carbonate (0.9 g) was suspended in N, N-dimethylformamide (15 ml). After 30 minutes of stirring at room temperature, the crude product was purified by preparative HPLC using a 250x50 mm C18 column and eluting with 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water.

EXAMPLE 158D 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (methoxymethoxy) -2-methylphenoxy) benzoic acid [0602] The title compound was prepared by substituting EXAMPLE 158C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 158E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- [3- (methoxymethoxy) -2-methylphenoxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0603] The title compound was prepared by substituting EXAMPLE 158D for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.43 (d, 1H), 8.10 (d, 1H), 7.73 (dd, 1H), 7.54 (d, 1H), 7.35 (d, 2H), 7.07 (m, 3H), 6.94 (t, 1H), 6.72 (d, 1H), 6.63 (dd, 1H), 6.19 (m, 2H), 5.21 (s, 2H) , 3.79 (m, 1H), 3.40 (s, 3H), 3.09 (m, 6H), 2.73 (m, 4H), 2.56 (s, 2H), 2.19 ( m, 6H), 2.07 (m, 6H), 1.96 (s, 2H), 1.74 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 159

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-hydroxy-2-methylphenoxy) -N- ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0604] EXAMPLE 158E (54 mg) and hydrogen chloride (1.25M in methanol) were added to the 10 ml vial into the microwave reactor. (0.5 ml) in tetrahydrofuran (4 ml) to give a solution. The mixture was stirred at 60 ° C in a CEM Discover microwave reactor for 20 minutes. The solvent was dried under reduced pressure and the crude product was purified by preparative HPLC using a 250 x 50 mm C18 column and eluting with 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water. The trifluoroacetic acid salt was dissolved in dichloromethane with ammonia and washed with saturated Na solution₂WHAT₃, dried over Na₂SO₄, filtered, and concentrated to give the product as the free base. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.38 (s, 1H), 8.46 (d, 1H), 8.13 (d, 1H), 7.77 (dd, 1H), 7.52 (d, 1H), 7.35 (d, 2H), 7.08 (m, 3H), 6.83 (t, 1H), 6.60 (dd, 1H), 6.51 (d, 1H), 6.08 (m, 2H) , 3.03 (m, 6H), 2.73 (m, 4H), 2.19 (m, 6H), 2.00 (m, 9H), 1.71 (m, 2H), 1.40 ( t, 2H), 0.94 (s, 6H).

EXAMPLE 160

2- (3-bromophenoxy) -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 160A

Methyl 2- (3-bromophenoxy) -4-fluorobenzoate [0605] The title compound was prepared as described in EXAMPLE 3A by replacing 2-methyl-5-indolol with 3-bromophenol.

EXAMPLE 160B

Methyl 2- (3-bromophenoxy) -4- (piperazin-1-yl) benzoate

116

EP-2507211B1EN [0606] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE

3F and EXAMPLE 3A with piperazine and EXAMPLE 160A, respectively.

EXAMPLE 160C

2- (3-bromophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl ) methyl benzoate [0607] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F with EXAMPLE 160B.

EXAMPLE 160D 2- (3-Bromophenoxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazinic acid 1-yl) benzoic [0608] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 160C.

EXAMPLE 160E

2- (3-bromophenoxy) -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0609] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 160D and EXAMPLE 3I. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.29 (d, 1H), 8.10 (m, 2H), 7.64 (d, 1H), 7.60 (dd, 1H), 7.40 (d, 2H), 7.15 (d, 2H), 7.06 (t, 1H), 6.96 (m, 2H), 6.94 (d, 1H), 6.68 (m, 3H), 6.37 (d, 1H) , 5.84 (m, 2H), 4.15 (m, 2H), 3.65 (m, 1H), 3.09 (m, 6H), 2.99 (m, 5H), 2.87 ( s, 2H), 2.75 (m, 2H), 2.26 (m, 4H), 1.98 (m, 1H), 1.21 (s, 6H).

EXAMPLE 161

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2- (3jodofenoksy) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 161A

Methyl 4-fluoro-2- (3-iodophenoxy) benzoate [0610] The title compound was prepared as described in EXAMPLE 3A by replacing 2-methyl-5-indolol with 3-iodophenol.

EXAMPLE 161B

Methyl 2- (3-iodophenoxy) -4- (piperazin-1-yl) benzoate [0611] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 161A, respectively.

EXAMPLE 161C

4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2- (3jodofenoksy) benzoate methyl [0612] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F with EXAMPLE 161B.

EXAMPLE 161D 4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2 (3 iodophenoxy) benzoic [0613] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 161C.

EXAMPLE 161E

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4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2- (3jodofenoksy) - N - ({4 - [(1-methylpiperidin- 4-yl) amino] -3-nitrophenyl sulfonyl} benzamide [0614] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 161D and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.34 (d, 1H), 8.08 (d, 1H), 7.64 (m, 2H), 7.40 (d, 2H), 7.17 (m, 3H), 6.95 (m, 3H), 6.71 (m, 2H), 6.37 (d, 1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.15 (m, 8H) , 2.87 (s, 3H), 2.60 (m, 4H), 2.17 (m, 8H), 1.76 (m, 1H), 1.20 (s, 6H).

EXAMPLE 162

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (2-hydroxyethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 162A

Tert-butyl 4- (2-nitro-4-sulfamoylphenylamino) piperidine-1-carboxylate [0615] The title compound was prepared by substituting tert-butyl 4-aminopiperidine-1-carboxylate for instead of 3- (N-morpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 162B [0616] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 162A instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 162C

2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3-nitro-4- ( piperidin-4-ylamino) phenylsulfonyl) benzamide [0617] The title compound was prepared by substituting EXAMPLE 162B for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 162D

N- (4- (1- (2- (tert-butyldimethylsilyloxy) ethyl) piperidin-4-ylamino) -3-nitrophenylsulfonyl) -2- (3chlorofenoksy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzamide [0618] The title compound was prepared by substituting EXAMPLE 162C for tert-butyl piperazine-1-carboxylate and 2- (tert-butyldimethylsilyloxy) acetaldehyde for 4'-chlorobiphenyl 2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 162E

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (2-hydroxyethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0619] A mixture of EXAMPLE 162D (270 mg) in anhydrous tetrahydrofuran (5 ml) and tetrabutylammonium fluoride (5 ml 1M in tetrahydrofuran) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was purified by reverse phase HPLC on a C18 column using a 40-70% acetonitrile / 0.1% trifluoroacetic acid in water gradient to afford the title compound as the trifluoroacetic salt. The trifluoroacetate salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄ and concentrated to give the title compound. ¹H NMR (400

MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.09 (d, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.14 (m, 1H), 7.05 (m, 3H), 6.88 (dd, 1H), 6.73 (dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H) , 6.40 (d, 1H), 3.85 (m,

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1H), 3.68 (m, 2H), 3.28 (m, 4H), 3.12 (m, 4H), 2.99 (m, 4H), 2.77 (s, 2H), 2, 16 (m, 8H), 1.98 (s, 2H), 1.83 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 163

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(3- nitro-4 - {[1- (2-phenylethyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide [0620] The title compound was prepared by substituting EXAMPLE 162C for tert-butyl piperazine-1-carboxylate and 2-phenylacetaldehyde for 4 ' -chlorobiphenyl-2-carboxaldehyde

EXAMPLE 1A. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.37 (d, 1H), 8.16 (d, 1H), 7.70 (dd, 1H), 7.59 (d, 1H), 7.30 (m, 8H), 7.16 (m, 1H), 7.07 (m, 3H), 6.89 (d, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.62 (d, 1H) , 6.42 (d, 1H), 3.84 (m, 1H), 3.27 (m, 6H), 2.98 (m, 8H), 2.78 (s, 2H), 2.17 ( m, 8H), 1.98 (s, 2H), 1.78 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 164

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3,4dichlorofenoksy) -N - ({ 4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 164A

Ethyl 2- (3,4-dichlorophenoxy) -4-fluorobenzoate [0621] The title compound was prepared by substituting 2,3-dichlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 164B

Ethyl 2- (3,4-dichlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0622] The title compound was prepared by substitution of EXAMPLE 164A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 164C 2- (3,4-dichlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [0623] The title compound was prepared by substituting EXAMPLE 164B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 164D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3,4dichlorofenoksy) -N - ({ 4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0624] The title compound was prepared by substituting EXAMPLE 164C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (s, 1H), 7.62 (d, 2H), 7.31 - 7.40 (m, 3H), 7.04 - 7.10 ( m, 2H), 6.98 (d, 1H), 6.98 (d, 1H), 6.70 - 6.81 (m, 2H), 6.64 (dd, 1H), 6.42 (d , 1H), 3.79 (s, 1H), 3.19 - 3.27 (m, 2H), 3.12 (s, 5H), 2.69 - 2.81 (m, 4H), 2, 63 (s, 2H), 2.15 - 2.28 (m, 8H), 2.08 (s, 2H), 1.98 (s, 3H), 1.77 (s, 1H), 1.36 - 1.45 (m, 2H), 1.24 (s, 1H), 0.95 (s, 6H).

EXAMPLE 165

2- (2-chloro-3,5-difluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 165A

Ethyl 2- (2-chloro-3,5-difluorophenoxy) -4-fluorobenzoate

119

[0625] The title compound was prepared by substituting 2-chloro-3,5-difluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 165B

Ethyl 2- (2-chloro-3,5-difluorophenoxy) -4- (piperazin-1-yl) benzoate [0626] The title compound was prepared by substituting piperazine instead of EXAMPLE 3F and EXAMPLE 165A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 165C

Ethyl 2- (2-chloro-3,5-difluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [ 0627] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 165B for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 165D 2- (2-chloro-3,5-difluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) acid benzoic [0628] The title compound was prepared by substituting EXAMPLE 165C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 165E

2- (2-chloro-3,5-difluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl ) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0629] The title compound was prepared by substituting EXAMPLE 165D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H . ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.30 (m, 1H), 8.06 (m, 1H), 7.68 (m, 2H), 7.36 (d, 2H), 7.07 (d, 2H), 7.00 (d, 1H), 6.78 (m, 2H), 6.45 (d, 1H), 5.93 (d, 1H), 3.77 (m, 1H), 3.12 (m, 4H) , 2.76 (s, 3H), 2.21 (m, 6H), 2.07 (m, 2H), 1.98 (s, 2H), 1.72 (m, 2H), 1.41 ( t, 2H), 0.94 (s, 6H).

EXAMPLE 166

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-Methoxyphenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 166A

Ethyl 4-fluoro-2- (3-methoxyphenoxy) benzoate [0630] The title compound was prepared by substituting 3-methoxyphenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 166B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methoxyphenoxy) benzoate [0631] The title compound was prepared by substitution of EXAMPLE 166A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 166C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methoxyphenoxy) benzoic acid [0632] The title compound was prepared by substitution of EXAMPLE 166B for EXAMPLE 1E in EXAMPLE 1F.

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EXAMPLE 166D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-Methoxyphenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0633] The title compound was prepared by substituting EXAMPLE 166C for EXAMPLE

122C and EXAMPLE 3I instead of EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.39 (d, 1H), 8.10 (br d, 1H), 7.73 (dd, 1H), 7.57 (d, 1H), 7.37 (d, 2H), 7, 05 (m, 4H), 6.68 (dd, 1H), 6.45 (dd, 1H), 6.30 (m, 3H), 3.80 (br m, 1H), 3.64 (s, 3H), 3.18 (br m, 1H), 3.07 (br m, 4H), 2.80 (br m, 1H), 2.78 (s, 2H), 2.60 (s, 2H) , 2.50 (s, 3H), 2.20 (br m, 6H), 2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1 , 40 (br t, 2H), 0.93 (s, 6H).

EXAMPLE 167

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- [3- (hydroxymethyl) phenoxy] -N- ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 167A

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methylphenoxy) benzoate [0634] The title compound was prepared by substitution 3 -hydroxybenzaldehyde instead of EXAMPLE 1D and EXAMPLE 214A instead of EXAMPLE 1C in EXAMPLE 1E.

EXAMPLE 167B 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methylphenoxy) benzoic acid [0635] The title compound was prepared by substitution of EXAMPLE 167A instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 167C

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3formylofenoksy) -N- (4- (1-methylpiperidin 4-ylamino) -3-nitrophenylsulfonyl) benzamide [0636] The title compound was prepared by substituting EXAMPLE 167B for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 167D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- [3- (hydroxymethyl) phenoxy] -N- ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0637] EXAMPLE 167C (107 mg) was dissolved in ethanol (3 mL) and tetrahydrofuran (9 mL) was added, and

NaBH₄ (13 mg) and the mixture was stirred at room temperature for 10 minutes. After careful addition of 2N aqueous HCl (0.67 mL), the reaction was concentrated and the crude material was purified by preparative HPLC using a C18 column, 250 x 50 mm, 10μ, and eluting using a 20-100% CH gradient₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. The salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound. ¹1 H NMR (500 MHz, CDCl₃/ MeOH-d₄) δ 8.80 (d, 1H), 8.45 (br d, 1H), 8.03 (dd, 1H), 7.86 (d, 1H), 7.39 (m, 1H), 7, 27 (m, 3H), 7.09 (s, 1H), 6.95 (d, 4H), 6.60 (dd, 1H), 6.12 (d, 1H), 4.67 (s, 2H ), 3.63 (br s, 1H),

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3.15 (br t, 4H), 2.82 (br s, 1H), 2.80 (s, 3H), 2.35 (m, 5H), 2.28 (br t, 4H), 2, 20 (br t, 2H), 2.10 (br m, 2H),

1.99 (s, 2H), 1.73 (m, 2H), 1.43 (t, 2H), 0.94 (s, 6H).

EXAMPLE 168

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1,4-dimethyl-piperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 168A

Tert-butyl 4- (benzyloxycarbonylamino) -4-methylpiperidine-1-carboxylate [0638] 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (5.0 g), diphenylphosphoryl azide (DPPA, 4.58 ml), triethylamine (2.86 ml), and benzyl alcohol (4.26 ml) were stirred in toluene (45 ml) at 110 ° C for 24 hours. The mixture was cooled, concentrated, and chromatographed on silica gel using 10% ethyl acetate / hexane as the eluent to give pure product.

EXAMPLE 168B

Tert-butyl 4-amino-4-methylpiperidine-1-carboxylate [0639] EXAMPLE 168A (4.5 g) and ethanol (100 ml) were added to wet 20% Pd (OH)₂-C (0.900 g) in a 250 ml stainless steel pressure vessel and stirred for 3 hours at 30 psi (207 kPa) at room temperature. The mixture was filtered through a nylon membrane and concentrated to give the product.

EXAMPLE 168C

Tert-butyl 4-methyl-4- (2-nitro-4-sulfamoylphenylamino) piperidine-1-carboxylate [0640] The title compound was prepared by substituting EXAMPLE 168B for 3- (N-morpholinyl) 1-propylamine in EXAMPLE 4A.

EXAMPLE 168D

4- (4-methylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0641] The title compound was prepared by substituting EXAMPLE 168C for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 168E

4- (1,4-dimethylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide [0642] EXAMPLE 168D (1.33 g), iodomethane (0.29 mL), and triethylamine (0.65 mL) in acetonitrile (20 mL ) was stirred for 1 hour. The mixture was concentrated and chromatographed on silica gel using 10% methanol / dichloromethane as the eluent to give the product.

EXAMPLE 168F

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1,4-dimethylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0643] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 168E for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.55 (m, 1H), 8.43 (d, 1H), 7.82 (d, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 7.38 (d, 2H), 7.18 (dd, 1H), 7.09 (d, 2H), 7.05 (m, 1H), 6.76 (d, 2H), 6.34 (d, 1H) , 2.94-3.12 (m, 11H), 2.70 (m, 4H), 2.27 (m, 4H), 2.00 (s, 3H), 1.55 (s, 3H), 1.41 (m, 2H), 0.95 (s, 6H).

EXAMPLE 169

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1,4-dimethyl-piperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

122

[0644] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 168E instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.49 (m, 1H), 8.40 (d, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.27 (m, 1H), 7.22 (t, 1H), 7.07 (d, 2H), 7.00 (d, 1H), 6.77 (d, 1H), 6.72 (d, 1H) , 6.45 (d, 1H), 3.20 (m, 4H), 3.05 (m, 6H), 2.88 (m, 2H), 2.73 (m, 4H), 2.27 ( m, 4H), 2.20 (m, 2H), 1.99 (s, 3H), 1.55 (s, 3H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 170

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- ({1- [2- (2-methoxyethoxy) ethyl] piperidin-4-yl} amino) -3-nitrophenyl] sulfonyl} benzamide [0645] A mixture of EXAMPLE 162C (100 mg), 1-bromo-2- (2- methoxyethoxy) ethane (52 mg), cesium carbonate (70 mg) in N, N-dimethylformamide was heated at 60 ° C overnight. The solvent was removed under reduced pressure. The residue was purified by reverse phase HPLC on a C18 column using a 40-70% acetonitrile / 0.1% TFA in water gradient to afford the title compound as the trifluoroacetate salt. The TFA salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄ and concentrated to give the title compound. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.36 (d, 1H), 8.12 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.14 (m, 1H), 7.05 (m, 3H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.60 (m, 1H) , 6.40 (d, 1H), 3.81 (s, 1H), 3.65 (t, 2H), 3.56 (m, 2H), 3.47 (m, 2H), 3.31 ( m, 2H), 3.26 (m, 3H), 3.18 (m, 2H), 3.13 (m, 2H), 2.97 (m, 2H), 2.77 (m, 4H), 2.21 (m, 7H), 2.07 (m, 2H), 1.98 (s, 2H), 1.76 (m, 2H), 1.41 (t, 2H), 0.94 (s , 6H).

EXAMPLE 171

2- (2-chloro-3-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N- ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 171 A

2-chloro-3- (methoxymethoxy) phenol [0646] The title compound was prepared by substituting 2-chlorobenzene-1,3-diol for EXAMPLE 158B in EXAMPLE 158C.

EXAMPLE 171B

Methyl 2- (2-chloro-3- (methoxymethoxy) phenoxy) -4-fluorobenzoate [0647] The title compound was prepared by substituting EXAMPLE 171A for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 171C

Methyl 2- (2-chloro-3- (methoxymethoxy) phenoxy) -4- (piperazin-1-yl) benzoate [0648] The title compound was prepared by substituting piperazine for EXAMPLE 3F and EXAMPLE 171B instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 171D

Methyl 2- (2-chloro-3- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate

123

[0649] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 171C for tert-butyl piperazine-1-carboxylate in

EXAMPLE 1A.

EXAMPLE 171E 2- (2-chloro-3- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoic acid [0650] The title compound was prepared by substituting 171D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 171F

2- (2-chloro-3- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- ( 4- (1-methylpiperidin-4-ylamino) -3-nitrophenylsulfonyl) benzamide [0651] The title compound was prepared by substituting EXAMPLE 171E for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 171G

2- (2-chloro-3-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0652] The title compound was prepared by substituting EXAMPLE 171F for EXAMPLE 158 in EXAMPLE 159. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 10.13 (s, 1H), 8.41 (d, 1H), 8.08 (d, 1H), 7.77 (dd, 1H), 7.60 (d, 1H), 7.35 (d, 2H), 7.07 (m, 3H), 6.89 (t, 1H), 6.67 (dd, 1H), 6.59 (m, 1H), 6.19 (d, 1H) , 6.08 (d, 1H), 3.80 (m, 1H), 3.09 (m, 6H), 2.79 (m, 4H), 2.57 (s, 3H), 2.21 ( m, 6H), 2.08 (m, 2H), 1.97 (s, 2H), 1.74 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 172

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(3- nitro-4 - {[1- (3-phenylpropyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide [0653] The title compound was prepared by substituting EXAMPLE 162C for tert-butyl piperazine-1-carboxylate and 3 'phenylpropanal for 4' -chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.36 (d, 1H), 8.10 (m, 1H), 7.69 (m, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.31 (m, 2H), 7.22 (m, 3H), 7.14 (m, 1H), 7.07 (d, 2H), 7.02 (d, 1H), 6.88 (d, 1H) , 6.74 (dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H), 6.41 (d, 1H), 3.84 (m, 1H), 3.29 ( m, 4H), 3.12 (m, 4H), 2.81 (m, 5H), 2.64 (m, 2H), 2.22 (m, 6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 173

2- (3-chlorophenoxy) -4- (4 - {[- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- { [1- (2-methoxyethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0654] The title compound was prepared by substituting 1-bromo-2-methoxyethane for 1-bromo-2 (2-methoxyethoxy) ethane in EXAMPLE 170. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.36 (d, 1H), 8.13 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.15 (m, 1H), 7.06 (m, 3H), 6.89 (dd, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.61 (d, 1H) , 6.41 (d, 1H), 3.82 (m, 1H), 3.57 (t, 2H), 3.38 (m, 4H), 3.13 (m, 6H), 2.99 ( m, 2H), 2.89 (m, 1H), 2.78 (s, 3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.98 (s, 2H), 1.78 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 174

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2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-ethylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0655] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 47A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.34 (d, 1H), 8.07 (s, 1H), 7.58 - 7.71 (m, 2H), 7.36 (d, 2H), 7.00-7.14 ( m, 4H), 6.85 - 6.94 (m, 1H), 6.73 (dd, 1H), 6.64 (dd, 1H), 6.59 (d, 1H), 6.39 (d , 1H), 3.86 (s, 1H), 3.11 (s, 5H), 2.94 (d, 2H), 2.72 - 2.81 (m, 3H), 2.12 - 2, 27 (m, 8H), 1.98 (s, 2H), 1.77 (s, 2H), 1.41 (t, 2H), 1.18 (t, 3H), 0.94 (s, 6H ).

EXAMPLE 175

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(1-Isopropylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0656] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 41A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.98 (bs, 1H), 8.34 (d, 1H), 8.04 (s, 1H), 7.59 - 7.73 (m, 2H), 7.36 (d, 2H) , 7.14 (t, 1H), 7.04 - 7.09 (m, 2H), 7.01 (d, 1H), 6.87 (d, 1H), 6.72 (dd, 1H), 6.61 - 6.66 (m, 1H), 6.58 (s, 1H), 6.39 (d, 1H), 3.90 (s, 1H), 3.11 (s, 6H), 2 , 73 - 2.83 (m, 2H), 2.14 - 2.28 (m, 9H), 1.98 (s, 3H), 1.76 (s, 2H), 1.41 (t, 3H ), 1.14-1.29 (m, 6H), 0.94 (s, 6H).

EXAMPLE 176

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-hydroxyphenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 176A

Ethyl 2- (3-hydroxyphenoxy) -4-fluorobenzoate [0657] The title compound was prepared by substituting resorcinol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 176B

Ethyl 2- (3-hydroxyphenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0658] The title compound was prepared by substituting EXAMPLE 176A instead of EXAMPLE 3 A in EXAMPLE 3 G.

EXAMPLE 176C

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (methoxymethoxy) phenoxy) benzoate [0659] EXAMPLE suspension 176B (0.295 g), methoxymethyl chloride (0.117 ml) and cesium carbonate (0.334 g) in N, N-dimethylformamide (3 ml) was stirred at 60 ° C for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water (2 x), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 5% 20% ethyl acetate / hexane) to give the product.

EXAMPLE 176D 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (methoxymethoxy) phenoxy) benzoic acid

125

[0660] The title compound was prepared by substituting EXAMPLE 176C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 176E

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (methoxymethoxy) phenoxy) -N- (4- (1-methylpiperidin-4-ylamino) -3-nitrophenylsulfonyl) benzamide [0661] The title compound was prepared by substituting EXAMPLE 176D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 176F

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-hydroxyphenoxy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0662] Suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3 mL) and HCl (1.25M in methanol, 2 mL) stirred for 1 hour at 60 ° C. The product was concentrated. The crude product was purified by RP HPLC (C8, 30% - 100% CH₃CN / water / 0.1% TFA) to give the product. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.31 (s, 1H), 8.10 (s, 1H), 7.66 - 7.73 (m, 2H), 7.56 (d, 1H), 7.34 - 7.38 ( m, 2H), 7.02 - 7.09 (m, 2H), 6.95 - 7.02 (m, 1H), 6.65 (dd, 1H), 6.34 (s, 1H), 6 , 29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H), 4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68 - 2.80 (m, 3H), 2.20 (d, 6H), 2.08 (d, 2H), 1.97 (s, 2H), 1.69 - 1.79 (m, 2H), 1.63 (s, 1H), 1.39 (d, 2H), 1.21 - 1.36 (m, 9H), 0.94 (s, 6H).

EXAMPLE 177

2- (2-chloro-3-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 177A 2-chloro-3-fluorophenol [0663] For 2-chloro-3-fluorophenylboronic acid solution (5 , 0 g) in tetrahydrofuran (50 mL) and 1M aqueous NaOH (30 mL) at 0 ° C, a 30% hydrogen peroxide solution (4 mL) was added, and the reaction was stirred for 2 hours. The reaction was quenched with saturated aqueous Na solution₂S₂ABOUT₃, acidified with concentrated aqueous HCl, and extracted twice with ethyl acetate. The combined extracts were washed with brine, concentrated, and chromatographed on silica gel using 10% ethyl acetate / hexane as the eluent to give the product.

EXAMPLE 177B

Methyl 2- (2-chloro-3-fluorophenoxy) -4-fluorobenzoate [0664] The title compound was prepared by substituting EXAMPLE 177A for 2-methyl-5-indolol and methyl 2,4-difluorobenzoate instead of ethyl 2,4-difluorobenzoate in EXAMPLE 3A.

EXAMPLE 177C

Methyl 2- (2-chloro-3-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0665] The title compound was prepared by substituting EXAMPLE 177B for methyl 2-bromo-4-fluoro benzoate and EXAMPLE 3F instead of EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 177D 2- (2-Chloro-3-fluorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0666] The title compound was prepared by substituting EXAMPLE 177C for EXAMPLE 1E in EXAMPLE 1F.

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EXAMPLE 177E

2- (2-chloro-3-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0667] The title compound was prepared by substituting EXAMPLE 177D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.39 (d, 1H), 8.15 (m, 1H), 7.76 (d, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.15 (d, 1H), 7.07 (d, 2H), 7.02 (m, 1H), 6.88 (t, 1H), 6.77 (d, 1H), 6.44 (s, 1H) , 6.33 (d, 1H), 3.91 (m, 1H), 3.18 (m, 4H), 3.07 (m, 2H), 2.77 (m, 6H), 2.27 ( m, 4H), 2.19 (m, 4H), 1.99 (s, 3H), 1.77 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 178

2- (2-chloro-3-fluorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0668] The title compound was prepared by substituting EXAMPLE 177D for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.28 (d, 1H), 8.10 (m, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.08 (d, 2H), 6.98 (m, 2H), 6.80 (t, 1H), 6.74 (d, 1H), 6.37 (d, 1H), 6.22 (d, 1H) , 3.89 (m, 1H), 3.28 (m, 4H), 3.09 (m, 6H), 2.84 (m, 4H), 2.73 (m, 3H), 2.40 ( m, 2H), 2.23 (m, 6H), 2.01 (m, 1H), 1.99 (s, 3H), 1.68 (m, 2H), 1.55 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 179

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0669] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.50 (br t, 1H), 8.38 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (m, 3H), 7, 06 (m, 3H), 6.98 (d, 1H), 6.92 (ddd, 1H), 6.70 (dd, 1H), 6.56 (dd, 1H), 6.24 (d, 1H ), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.90 (br m, 2H), 2.75 (s, 2H), 2.60 (s, 6H), 2 , 20 (br m, 6H), 1.98 (s, 2H), 1.90 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 180

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2metoksyfenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 180A

Ethyl 4-fluoro-2- (2-methoxyphenoxy) benzoate [0670] The title compound was prepared by substituting 2-methoxyphenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 180B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methoxyphenoxy) benzoate [0671] The title compound was prepared by substituting EXAMPLE 180A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 180C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methoxyphenoxy) benzoic acid

127

[0672] The title compound was prepared by substituting EXAMPLE 180B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 180D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2metoksyfenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0673] The title compound was prepared by substituting EXAMPLE 180C for EXAMPLE 122C and EXAMPLE 3I instead of EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.47 (d, 1H), 8.15 (br d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.37 (d, 2H), 7, 13 (d, 1H), 7.05 (m, 4H), 6.80 (m, 2H), 6.60 (dd, 1H), 6.07 (d, 1H), 3.80 (br m, 1H), 3.73 (s, 3H), 3.22 (br m, 1H), 3.05 (br m, 1H), 3.00 (br m, 4H), 2.75 (s, 2H) , 2.62 (br s, 2H), 2.50 (s, 3H), 2.20 (br m, 6H), 2.04 (br m, 2H), 1.98 (s, 2H), 1 , 73 (br m, 2H), 1.40 (br t, 2H), 0.93 (s, 6H).

EXAMPLE 181

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2metylofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 181A

Ethyl 4-fluoro-2- (2-methylphenoxy) benzoate [0674] The title compound was prepared by substituting 2-methylphenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 181B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methylphenoxy) benzoate [0675] The title compound was prepared by substitution of EXAMPLE 181A instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 181C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-methylphenoxy) benzoic acid [0676] The title compound was prepared by substitution of EXAMPLE 181B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 181D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (2metylofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0677] The title compound was prepared by substituting EXAMPLE 181C for EXAMPLE 122C and EXAMPLE 3I instead of EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.40 (d, 1H), 8.12 (br d, 1H), 7.73 (dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7, 10 (m, 2H), 7.05 (d, 2H), 6.96 (m, 1H), 6.84 (m, 1H), 6.64 (dd, 1H), 6.46 (d, 1H ), 6.20 (d, 1H), 3.80 (br m, 1H), 3.10 (br m, 3H), 3.05 (br m, 4H), 2.77 (s, 2H), 2.76 (br m, 2H), 2.58 (s, 2H), 2.20 (br m, 6H), 2.16 (s, 3H), 2.09 (br m, 2H), 1, 98 (s, 2H), 1.78 (br m, 2H), 1.40 (br t, 2H), 0.93 (s, 6H).

EXAMPLE 182

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3metylofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 182A

Ethyl 4-fluoro-2- (3-methylphenoxy) benzoate

128

[0678] The title compound was prepared by substituting 3-methylphenol for 2-methyl-5-indolol in

EXAMPLE 3A.

EXAMPLE 182B

Ethyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methylphenoxy) benzoate [0679] The title compound was prepared by substitution of EXAMPLE 182A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 182C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-methylphenoxy) benzoic acid [0680] The title compound was prepared by substitution of EXAMPLE 182B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 182D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3metylofenoksy) -N - ({4- [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0681] The title compound was prepared by substituting EXAMPLE 182C for EXAMPLE 122C and EXAMPLE 3I instead of EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.40 (d, 1H), 8.10 (br d, 1H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.36 (d, 2H), 7, 05 (m, 4H), 6.73 (d, 1H), 6.67 (dd, 1H), 6.52 (m, 2H), 6.29 (d, 1H), 3.80 (br m, 1H), 3.10 (br m, 3H), 3.05 (br m, 4H), 2.77 (s, 2H), 2.76 (br m, 2H), 2.58 (s, 2H) , 2.20 (br m, 6H), 2.16 (s, 3H), 2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1 , 40 (br t, 2H), 0.93 (s, 6H).

EXAMPLE 183

2- (2-chlorophenoxy) -4- (4 - {[6- (4-chlorophenyl) -1,3-benzodioxol-5-yl] methyl} piperazin-1-yl) -N - ({4- [(1 methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 183A

6- (4-chlorophenyl) benzo [d] [1,3] dioxole-6-carboxaldehyde [0682] To a solution of 6-bromobenzo [d] [1,3] dioxole-6-carboxaldehyde (4.6 g), acid 4-chlorophenylboronic (3.78 g) and tetrakis (triphenylphosphine) palladium (0) (0.232 g) in toluene (80 ml) and methanol (30 ml) 2N aqueous Na solution₂WHAT₃ (30 ml). The mixture was stirred at reflux overnight. The mixture was diluted with ether (400 mL) and washed with water, brine and dried over Na₂SO₄. After filtration and concentration of the solvent, the residue was applied to a column and eluted with 3% ethyl acetate in hexane to give the product.

EXAMPLE 183B

Methyl 2- (2-chlorophenoxy) -4- (4 - ((6- (4-chlorophenyl) benzo [d] [1,3] dioxol-5-yl) methyl) piperazin-1-yl) benzoate [0683] Title compound prepared as described in EXAMPLE 38G by replacing EXAMPLE 38E with EXAMPLE 183A.

EXAMPLE 183C 2- (2-chlorophenoxy) -4- (4 - ((6- (4-chlorophenyl) benzo [d] [1,3] dioxol-5-yl) methyl) piperazin-1-yl) benzoic acid [0684] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 183B.

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EXAMPLE 183D

2- (2-chlorophenoxy) -4- (4 - {[6- (4-chlorophenyl) -1,3-benzodioxol-5-yl] methyl} piperazin-1-yl) -N - ({4- [(1 -methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0685] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 183C and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (d, 1H), 8.07 (d, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.38 (m, 6H), 7.02 (m, 3H), 6.86 (m, 1H), 6.79 (s, 1H), 6.72 (dd, 1H), 6.51 (d, 1H), 6.28 (d, 1H) , 6.04 (s, 2H), 3.81 (m, 1H), 3.25 (s, 3H), 3.08 (m, 6H), 2.72 (m, 5H), 2.33 ( m, 4H), 2.07 (m, 2H), 1.74 (m, 1H).

EXAMPLE 184

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 184A

4- (4-methylpiperazin-1-ylamino) -3-nitrobenzenesulfonamide [0686] The title compound was prepared by substituting 4-methylpiperazine-1-amine for 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 184B

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0687] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 184A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.14 (s, 1H), 8.38 (d, 1H), 7.77 (dd, 1H), 7.55 (m, 2H), 7.37 (m, 3H), 7.08 (m, 3H), 6.95 (m, 1H), 6.72 (dd, 1H), 6.62 (d, 1H), 6.27 (d, 1H), 3.10 (m, 4H) , 2.97 (m, 4H), 2.77 (s, 2H), 2.45 (s, 3H), 2.20 (m, 6H), 1.97 (s, 2H), 1.40 ( t, 2H), 0.94 (m, 6H).

EXAMPLE 185

2- (3-chlorophenoxy) -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl ) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0688] The title compound was prepared by substituting EXAMPLE 38H for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H . ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.15 (s, 1H), 8.34 (d, 1H), 7.68 (dd, 1H), 7.57 (d, 1H), 7.51 (d, 1H), 7.39 (d, 2H), 7.16 (m, 3H), 6.92 (m, 1H), 6.75 (dd, 1H), 6.68 (dd, 1H), 6.64 (m, 1H) , 6.43 (d, 1H), 4.15 (s, 2H), 3.15 (m, 6H), 2.99 (m, 6H), 2.88 (s, 2H), 2.49 ( s, 3H), 2.26 (m, 4H), 2.17 (s, 2H), 1.20 (s, 6H).

EXAMPLE 186

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2- (2,3difluorofenoksy ) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0689] The title compound was prepared by substituting EXAMPLE 145B for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H . ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.15 (s, 1H), 8.34 (d, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 7.16 (d, 2H), 6.87 (m, 2H), 6.74 (dd, 1H), 6.46 (d, 1H), 6.34 (m, 1H) , 4.15 (s, 2H), 3.14 (m, 6H), 3.00 (m, 4H), 2.88 (s, 2H), 2.52 (s, 3H), 2.26 ( m, 4H), 2.17 (s, 2H), 1.21 (s, 6H).

EXAMPLE 187

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

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EXAMPLE 187A

4- (4- (N- (2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) tert-butyl benzoyl) sulfamoyl) -2-nitrophenylamino) piperidine-1-carboxylate [0690] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 187B

2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3-nitro-4- ( piperidin-4-ylamino) phenylsulfonyl) benzamide [0691] EXAMPLE 187A was treated with TFA (0.5 mL) and stirred for 6 hours. The product was concentrated and purified by RP HPLC (C8, 30% - 100% CH₃CN / water / 0.1% TFA).

EXAMPLE 187C

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0692] Suspension of EXAMPLE 187B (50 mg), cyclopropanecarboxaldehyde (100 mg) and MPCNBH resin₃ (0.2 g, 2.43 mmol / g) in dichloromethane (4 mL) / methanol (3 mL) was shaken for 16 hours at room temperature. The product was filtered, washed with a dichloromethane / methanol mixture and concentrated. The crude product was purified by RP HPLC (C8, 30% - 100% CH₃CN / water / 0.1% TFA) to give the product. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67 - 7.75 (m, 1H), 7.60 (d, 1H), 7.36 (d, 2H) , 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.63 (s, 1H), 6.60 ( s, 1H), 6.40 (s, 1H), 3.86 (s, 1H), 3.12 (s, 5H), 2.71 - 2.80 (m, 3H), 2.13 - 2 , 28 (m, 9H), 1.98 (s, 3H), 1.79 (s, 1H), 1.41 (t, 2H), 0.99 - 1.11 (m, 2H), 0, 94 (s, 6H), 0.84 (d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).

EXAMPLE 188

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide EXAMPLE 188A

4- (4- (N- (2- (2-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) tert-butyl benzoyl) sulfamoyl) -2-nitrophenylamino) piperidine-1-carboxylate [0693] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 188B

2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3-nitro-4- ( piperidin-4-ylamino) phenylsulfonyl) benzamide [0694] The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE 187A in EXAMPLE 187B.

EXAMPLE 188C

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0695] The title compound was prepared by substituting EXAMPLE 188B for EXAMPLE 187B in EXAMPLE 187C. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.41 (d, 1H), 8.13 (s, 1H), 7.79 (dd, 1H), 7.58 (d, 1H), 7.33 - 7.40 (m, 3H) , 7.04 - 7:16 (m, 4H), 6.94 (t, 1H), 6.72 (dd, 1H), 6.61 (s, 1H), 6.27 (d, 1H), 3.91 (s, 1H), 3.44 (s, 2H), 3.02 - 3.15 (m, 5H), 2.95 (s, 2H), 2.69 - 2.82 (m, 3H), 2.13 131

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2.28 (m, 8H), 1.97 (s, 3H), 1.83 (s, 2H), 1.32 - 1.46 (m, 3H), 0.99 - 1.10 (m, 1H), 0.94 (s, 6H), 0.76 - 0.90 (m, 1H), 0.59 - 0.71 (m, 2H), 0.34 (d, 2H).

EXAMPLE 189

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- ({1- [2- (dimethylamino) -2-oxoethyl] piperidin-4-yl} amino) -3-nitrophenyl] sulfonyl} benzamide [0696] The title compound was prepared by substituting 2-chloro-N, N-dimethylacetamide for 1-bromo -2- (2-methoxyethoxy) ethane in EXAMPLE 170. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 9.63 (s, 1H), 8.46 (s, 1H), 8.21 (m, 1H), 7.78 (m, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.22 (m, 2H), 7.11 (d, 2H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.72 (m, 2H) , 6.57 (s, 1H), 4.28 (m, 2H), 3.85 (m, 8H), 3.16 (m, 4H), 2.96 (m, 7H), 2.82 ( m, 2H), 2.11 (m, 8H), 1.47 (s, 2H), 0.96 (s, 6H).

EXAMPLE 190

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[1- (2-morpholin-4-ethylethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0697] The title compound was prepared by substituting EXAMPLE 162C for tert-butyl piperazine-1-carboxylate and 2-morpholineacetaldehyde instead of 4'-chlorobiphenyl-2-carboxaldehyde in

EXAMPLE 1A. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.46 (d, 1H), 8.29 (d, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 7.21 (m, 2H), 7.11 (d, 2H), 6.96 (dd, 1H), 6.83 (dd, 1H), 6.73 (dd, 1.83Hz, 1H), 6.69 ( m, 1H), 6.58 (s, 1H), 3.82 (m, 10H), 3.27 (m, 4H), 3.09 (m, 6H), 2.81 (m, 7H), 2.23 (m, 2H), 2.15 (m, 2H), 2.04 (s, 2H), 1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s , 6H).

EXAMPLE 191

N - [(4 - {[(4-Aminotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] -2- (2chlorofenoksy) -4- (4 - {[2- (4 chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) benzamide

EXAMPLE 191A

4 - ((4-aminotetrahydro-2H-pyran-4-yl) methylamino) -3-nitrobenzenesulfonamide [0698] The title compound was prepared by substituting 4- (aminomethyl) tetrahydro-2H-pyran-4-amine for (tetrahydropyran-4- yl) methylamine in EXAMPLE 1G.

EXAMPLE 191B

N - [(4 - {[(4-Aminotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] -2- (2chlorofenoksy) -4- (4 - {[2- (4 -chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) benzamide [0699] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 191A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.57 (t, 1H), 8.47 (d, 1H), 8.18 (s, 3H), 7.79 (dd, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 7.34 (d, 1H), 7.24 (t, 1H), 7.11 (d, 2H), 7.01-7.03 (m, 2H), 6.82 ( dd, 1H), 6.73-6.76 (m, 2H), 6.56 (s, 1H), 3.85 (d, 2H), 3.71-3.73 (m, 4H), 3 , 14 (br s, 2H), 2.23 (s, 2H), 2.04 (m, 2H), 1.82-1.87 (m, 2H), 1.70-1.75 (m, 2H), 1.47 (t, 2H), 0.96 (s, 6H).

EXAMPLE 192

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(4-hydroxy-1-methyl-piperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

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EXAMPLE 192A [0700] The title compound was prepared by substituting 4- (aminomethyl) -1-methylpiperidin-4-ol for (tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 192B

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(4-hydroxy-1-methylpiperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0701] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.38 (s, 1H), δ 8.65 (t, 1H), 8.46 (d, 1H), 7.74 (dd, 1H), 7.53 (d, 1H), 7, 40 (d, 2H), 7.19-7.22 (m, 2H), 7.11 (d, 2H), 6.97 (dd, 1H), 6.82 (dd, 1H), 6.70 -6.74 (m, 2H), 6.57 (s, 1H), 3.60 (d, 2H), 3.47 (d, 2H), 3.10-3.17 (m, 4H), 2.80-2.81 (m, 4H), 2.23 (s, 2H), 2.04 (s, 2H), 1.76-1.85 (m, 4H), 1.47 (t, 2H), 0.96 (s, 6H).

EXAMPLE 193

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0702] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 49C, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.15 (s, 1H), 8.51 (d, 1H), 8.16 (d, 1H), 7.82 (dd, 1H), 7.54 (d, 1H), 7.31 (m, 4H), 7.08 (m, 4H), 6.60 (dd, 1H), 6.36 (s, 1H), 6.08 (d, 1H), 3.92 (m, 2H) , 3.74 (m, 1H), 3.04 (m, 7H), 2.71 (m, 3H), 2.16 (m, 6H), 1.99 (m, 4H), 1.49 ( m, 10H), 0.92 (s, 6H).

EXAMPLE 194

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(3S) -1-methylpyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 194A (tert-butyl) (S) -3- (2-nitro-4-sulfamoylphenylamino) pyrrolidine-1-carboxylate Tert-butyl 1-carboxylate in EXAMPLE 140A.

EXAMPLE 194B (S) -3- (4- (N- (2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoyl) sulfamoyl) -2-nitrophenylamino) pyrrolidine-1-tert-butyl carboxylate [0704] The title compound was prepared by substituting EXAMPLE 194A for EXAMPLE 1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 194C (S) -2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3 -nitro-4- (pyrrolidin-3-ylamino) phenylsulfonyl) benzamide [0705] The title compound was prepared by substituting EXAMPLE 194B for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 194D

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2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(3S) -1-methylpyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0706] To a solution of EXAMPLE 194C (470 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added 37 % formaldehyde solution in water (0.42 ml) and MP-CNBH resin₃ (947 mg, 2.38 mmol / g)). The reaction mixture was stirred overnight at room temperature. The resin was filtered off and then the reaction mixture was concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate followed by a 3-10% methanol / dichloromethane gradient.¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.42 (d, 1H), 8.34 (m, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.08 (m, 3H), 6.95 (m, 1H), 6.76 (dd, 1H), 6.67 (m, 2H), 6.45 (d, 1H) , 3.53 (m, 2H), 3.16 (m, 7H), 2.83 (m, 4H), 2.61 (br m, 1H), 2.27 (m, 4H), 2.18 (m, 3H), 1.98 (m, 3H), 1.41 (m, 2H), 0.94 (s, 6H).

EXAMPLE 195

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(3R) -1-methylpyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 195A tert-butyl (r) -3- (2-nitro-4-sulfamoylphenylamino) pyrrolidine-1-carboxylate [0707] The title compound was prepared by substituting tert-butyl (R) -3-aminopyrrolidine-1-carboxylate for 4-aminopiperidine Tert-butyl 1-carboxylate in EXAMPLE 140A.

EXAMPLE 195B (R) -3- (4- (N- (2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoyl) sulfamoyl) -2-nitrophenylamino) tert-butyl pyrrolidine-1-carboxylate [0708] The title compound was prepared by substituting EXAMPLE 195A for EXAMPLE 1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 195C (R) -2- (3-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3 -nitro-4- (pyrrolidin-3-ylamino) phenylsulfonyl) benzamide [0709] The title compound was prepared by substituting EXAMPLE 195B for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 195D

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[(3R) -1-methylpyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0710] The title compound was prepared by substituting EXAMPLE 195C for EXAMPLE

194C in EXAMPLE 194D. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.36 (d, 1H), 8.23 ​​(m, 1H), 7.72 (dd, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.16 (t, 1H), 7.06 (m, 2H), 6.98 (m, 1H), 6.90 (dd, 1H), 6.73 (dd, 1H), 6.64 (m, 2H) , 6.41 (d, 1H), 4.01 (s, 1H), 3.28 (m, 2H), 3.24 (m, 1H), 3.13 (m, 5H), 2.76 ( m, 2H), 2.69 (m, 3H), 2.56 (m, 1H), 2.24 (m, 7H), 1.90 (br s, 2H), 1.41 (m, 2H) , 0.94 (s, 6H).

EXAMPLE 197

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4- yl) amino] -3-nitrophenyl} sulfonyl) -2- [3- (1H-pyrrol-2-yl) phenoxy] benzamide [0711] A mixture of EXAMPLE 161 (0.095 g), 1- (tert-butoxycarbonyl) -1H acid pyrrole-2-ylboronic acid (0.025 g), tetrakis (triphenylphosphine) palladium (0) (0.012 g), and CsF (0.046 g) in dimethoxyethane (2 ml) and methanol (1 ml) were heated in a CEM Discover microwave reactor (80 ° C) , Twenty minutes).

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The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was then treated with 4 N HCl in dioxane. The solvent was removed and the residue was purified by reverse phase preparative HPLC to afford the title compound.¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 1H), 8.39 (s, 1H), 8.04 (d, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 7.34 (d, 2H), 7.11-7.25 (m, 5H), 7.04 (d, 2H), 6.96 (d, 1H), 6.80 (s, 1H), 6.66 ( d, 2H), 6.48 (d, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 6.08 (d, 1H), 3.05 (s, 6H), 2.73 (s, 2H), 2.18-2.24 (m, 6H), 1.74 (s, 3H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 198

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (3-fluorophenoxy) -N - [(4- {[(4-hydroxy-1-methylpiperidin-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0712] The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE 1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.44 (s, 1H), 8.31 (d, 1H), 7.92 (s, 1H), 7.63-7.66 (m, 2H), 7.36 (d, 2H) , 7.07 (d, 2H), 6.99 (d, 1H), 6.71 (dd, 1H), 6.62-6.65 (m, 1H), 6.47 (dd, 1H), 6.36-6.40 (m, 2H), 5.16 (s, 1H), 3.09 (s, 6H), 2.92 (br s, 2H), 2.76 (a, 2H), 2.62-2.64 (m, 2H), 2.18-2.23 (m, 6H), 1.93 (d, J = 5.49 Hz, 2H), 1.721,76 (m, 4H) , 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 199

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0713] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 9.12 (s, 1H), 8.33 (d, 1H), 7.66 (dd, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.36 (d, 2H),

7.17 (t, 1H), 7.07 (d, 2H), 6.91 (m, 1H), 6.75 (dd, 1H), 6.68 (dd, 1H), 6.63 (m , 1H), 6.42 (d, 1H), 3.14 (m,

4H), 2.96 (m, 6H), 2.78 (s, 2H), 2.45 (s, 3H), 2.21 (m, 6H), 1.98 (s, 2H), 1, 41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 200

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 200A

2,3-difluoro-4-nitrophenol [0714] A solution of 2,3-difluoro-4-nitroanisole (10 g) in 48% HBr (60 ml) and 30% HBr in acetic acid (30 ml) was stirred at 120 ° C through the night. The mixture was cooled to room temperature and extracted with ethyl acetate (3x 200 mL) and the combined extracts were washed with brine and dried over Na₂SO₄. Filtration and evaporation of the solvent gave the product.

EXAMPLE 200B

6,7-difluoro-1H-indol-5-ol [0715] The title compound was prepared as in EXAMPLE 154A by replacing 2-fluoro-4-nitrophenol with EXAMPLE 200A.

EXAMPLE 200C

Methyl 2- (6,7-difluoro-1H-indol-5-yloxy) -4-fluorobenzoate

135

[0716] The title compound was prepared as described in EXAMPLE 3A by replacing 2-methyl-5-indolol with EXAMPLE 200B.

EXAMPLE 200D

Methyl 2- (6,7-difluoro-1H-indol-5-yloxy) -4- (piperazin-1-yl) benzoate [0717] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 200C.

EXAMPLE 200E

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6,7-difluoro-1H-indol-5-yloxy) benzoate methyl [0718] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 200D and EXAMPLE 60D.

EXAMPLE 200F 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6.7-difluoro-1H-indol-5- iloxy) benzoic [0719] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 200E.

EXAMPLE 200G

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0720] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 200F and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.63 (s, 1H), 8.40 (d, 1H), 8.06 (d, 1H), 7.72 (dd, 1H), 7.59 (d, 1H), 7.35 (m, 3H), 7.05 (d, 2H), 6.96 (d, 1H), 6.72 (d, 1H), 6.64 (dd, 1H), 6.36 (d, 1H) , 6.24 (d, 1H), 3.74 (m, 1H), 3.12 (m, 8H), 2.73 (s, 3H), 2.55 (m, 2H), 2.14 ( m, 10H), 1.74 (m, 3H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 201

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0721] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and EXAMPLE 49C, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.64 (s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.35 (m, 4H), 7.05 (d, 2H), 6.92 (d, 1H), 6.64 (m, 2H), 6.36 (d, 1H), 6.23 (s, 1H) , 3.92 (m, 2H), 3.67 (m, 1H), 3.01 (m, 8H), 2.73 (s, 2H), 2.25 (m, 8H), 1.97 ( m, 5H), 1.53 (m, 8H), 0.94 (m, 6H).

EXAMPLE 202

4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({4- [ Tert-butyl (1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) amino] carbonyl} phenoxy) -1H-indole-1-carboxylate

EXAMPLE 202A

Ethyl 2- (1H-indol-4-yloxy) -4-fluorobenzoate [0722] The title compound was prepared by substituting 4-hydroxyindole for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 202B

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Ethyl 2- (1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0723] The title compound prepared by substituting EXAMPLE 202A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 202C 2- (1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0724] The title compound was prepared by substituting EXAMPLE 202B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 202D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- (1H-indol-4-yloxy) -N- ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0725] The title compound was prepared by substituting EXAMPLE 202C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H, except that 2-10% methanol in CH was used for the chromatography₂cl₂.

EXAMPLE 202E bis (2,2,2-trifluoroacetate) 4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1- yl) -2 - {[({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) amino] carbonyl} phenoxy) -1H-tert-butyl indole-1-carboxylate [0726] EXAMPLE 202D (0.58 g) was dissolved in CH₂cl₂ (30 ml), then di-tert-butyl dicarbonate (0.14 g) and 4-dimethylaminopyridine (0.02 g) were added and the reaction was stirred at room temperature for 60 hours. The reaction was then filtered through celite, concentrated, and the crude product was purified by preparative HPLC using a 250 x 50 mm C18 column, eluting with 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.80 (v br s, 1H), 9.65, 9.45 (both v br s, together 2H), 8.55 (d, 1H), 8.12 (br d, 1H), 7 , 80 (dd, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H), 7.40 (d, 2H), 7.19 (d, 1H), 7.10 (m, 3H), 6.80 (dd, 1H), 6.59 (d, 1H), 6.43 (s, 1H), 6.41 (d, 1H), 4, 05 (v br s, 1H), 3.85 (v br s, 1H), 3.60, 3.50, 3.40 (all v br m, together 10H), 3.10 (v br m, 2H ), 2.95, 2.90 (both br m, 5H together), 2.20 br m, 4H), 2.05 (br s, 2H), 1.80 (br m, 1H), 1.67 (s, 9H), 1.45 (br t, 2H), 0.95 (s, 6H).

EXAMPLE 203

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[4- (dimethylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] benzamide EXAMPLE 203A

4- (4- (dimethylamino) cyclohexylamino) -3-nitrobenzenesulfonamide [0727] The title compound was prepared by substitution N¹N¹-dimethylcyclohexane-1,4-diamine instead of 1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 203B

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[4- (dimethylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0728] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 203A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 9.16 (d, 1H), 8.31 - 8.39 (m, 2H), 8.03 - 8.07 (m, 1H), 7.46 (d, 2H), 7.08 - 7.17 (m, 4H), 7.00 - 7.04

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EP-2507211B1PL (m, 1H), 6.91 - 6.99 (m, 2H), 6.82 (dd, 1H), 6.69 (d, 1H), 3.44 - 3.52 (m, 1H), 3.14 - 3.20 (m, 4H), 2.84 (s,

2H), 2.64 (s, 1H), 2.49 (s, 6H), 2.31 (t, 2H), 2.22 - 2.28 (m, 4H), 2.09 - 2.15 (m, 2H), 2.05 (s, 2H), 1.97 2.02 (m, 2H), 1.47 - 1.56 (m, 2H), 1.42 (t, 2H), 1 , 27 - 1.37 (m, 2H), 1.25 (s, 1H), 0.93 - 0.98 (m, 6H).

EXAMPLE 204

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[4- (diethylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 204A

4- (4- (diethylamino) cyclohexylamino) -3-nitrobenzenesulfonamide [0729] The title compound was prepared by substitution N¹N¹-diethylcyclohexane-1,4-diamine instead of 1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 204B

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-diethyl-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4- {[4- (diethylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0730] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 204A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 9.18 (d, 1H), 8.32 - 8.39 (m, 2H), 8.05 - 8.09 (m, 1H), 7.46 (d, 2H), 7.15 ( t, 1H), 7.08 - 7.13 (m, 3H), 6.98 - 7.05 (m, 2H), 6.94 (dd, 1H), 6.82 (dd, 1H), 6 , 69 (d, 1H), 3.43 - 3.50 (m, 1H), 3.13 - 3.19 (m, 4H), 2.84 (s, 2H), 2.72 (t, 1H ), 2.63 (q, 4H), 2.31 (t, 2H), 2.22 - 2.28 (m, 4H), 2.11 (d, 2H), 2.00 (s, 2H) , 1.91 (d, 2H), 1.40 - 1.48 (m, 4H), 1.24 - 1.34 (m, 2H), 1.10 (t, 6H), 0.93 - 0 , 99 (m, 6H).

EXAMPLE 205 trans-2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(4-morpholin-4-yl-cyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 205A trans-4- (4-morpholinocyclohexylamino ) -3-nitrobenzenesulfonamide [0731] The title compound was prepared by substituting trans-4-morpholinocyclohexanamine for 1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 205B trans-2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0732] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 9.17 (d, 1H), 8.42 (d, 1H), 8.32 (dd, 1H), 8.00 (d, 1H), 7.46 (d, 2H), 7.15 (t, 1H), 7.11 (d, 2H), 7.07 (d, 1H), 7.03 (d, 1H), 6.99 (d, 1H), 6.93 (dd, 1H) , 6.81 (dd, 1H), 6.69 (d, 1H), 3.73 - 3.78 (m, 4H), 3.43 3.50 (m, 1H), 3.15 - 3, 21 (m, 4H), 2.84 (s, 2H), 2.50 - 2.54 (m, 4H), 2.31 (t, 2H), 2.21 - 2.27 (m, 5H) , 2.11 (d, 2H), 2.00 (s, 2H), 1.91 (d, 2H), 1.36 - 1.43 (m, 4H), 1.28 - 1.34 (m , 2H), 0.96 (s, 6H).

EXAMPLE 206

4- {4- [1- (4'-chloro-1,1'-biphenyl-2-yl) ethyl] piperazine-1-yl} -2- (2-chlorophenoxy) -N - ({4 - [( 1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0733] ​​The title compound was prepared as described in EXAMPLE 137 by replacing EXAMPLE

122C EXAMPLE and EXAMPLE 111A EXAMPLE 3I. ¹H NMR (400 MHz, CH₂CD₂) δ 8.80 (s, 1H), 8.41 (d, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.55 (t, 2H), 7.29 - 7.37 (m, 4H), 7.17 - 7.28 (m, 4H), 7.10 138

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7.15 (m, 2H), 6.94 (d, 1H), 6.58 (d, 1H), 5.95 (s, 1H), 3.53 - 3.64 (m, 1H), 3 , 39 (q, 1H), 3.01 - 3.12 (m,

4H), 2.77 (t, 2H), 2.38 - 2.46 (m, 2H), 2.15 - 2.31 (m, 7H), 2.05 (d, 2H), 1.63 - 1.74 (m, 2H), 1.22 (d, 3H).

EXAMPLE 207

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 207A

2-chloro-4- (methoxymethoxy) phenol [0734] The title compound was prepared by substituting 2-chlorobenzene-1,4-diol for EXAMPLE 158B in EXAMPLE 158C.

EXAMPLE 207B

Ethyl 2- (2-chloro-4- (methoxymethoxy) phenoxy) -4-fluorobenzoate [0735] The title compound was prepared by substituting EXAMPLE 207A for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 207C

Ethyl 2- (2-chloro-4- (methoxymethoxy) phenoxy) -4-fluorobenzoate [0736] The title compound was prepared by substituting piperazine instead of EXAMPLE 3F and EXAMPLE 207B instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 207D

Ethyl 2- (2-chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [0737 ] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 207C for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 207E 2- (2-Chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoic acid [0738] The title compound was prepared by substituting EXAMPLE 207D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 207F

2- (2-chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- ( 4- (1-methylpiperidin-4-ylamino) -3-nitrophenylsulfonyl) benzamide [0739] The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 207G

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0740] The title compound was prepared by substituting EXAMPLE 207F for EXAMPLE 158 in EXAMPLE 159. ¹H NMR (500 MHz, pyridine-d₅) δ 12.30 (br. s, 1H), 9.29 (d, 1H), 8.49 (d, 1H), 8.40 (dd, 1H), 8.08 (d, 1H), 7 , 45 (d, 2H), 7.09 (m, 3H), 7.01 (d, 1H), 6.93 (dd, 1H), 6.75 (dd, 1H), 6.58 (d, 1H), 3.54 (m, 1H), 3.13 (m, 4H), 2.81 (s, 2H), 2.65 (m, 2H), 2.29 (m, 2H), 2, 21 (m, 4H), 2.16 (s, 3H), 2.07 (m, 2H), 1.96 (m, 4H), 1.66 (m, 2H), 1.41 (t, 2H ), 0.95 (s, 6H).

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EXAMPLE 208

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 208A

2- (2-chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- ( 4- (4-methylpiperazin-1-ylamino) -3-nitrophenylsulfonyl) benzamide [0741] The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE 1F and EXAMPLE 184A instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 208B

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0742] The title compound was prepared by substituting EXAMPLE 208A for EXAMPLE

158E in EXAMPLE 159. ¹H NMR (500 MHz, pyridine-d₅) δ 12.33 (br. s, 1H), 9.28 (m, 2H), 8.44 (dd, 1H), 8.07 (d, 1H), 7.76 (d, 1H), 7 , 45 (d, 2H), 7.09 (m, 3H), 6.94 (dd, 1H), 6.75 (dd, 1H), 6.57 (d, 1H), 3.13 (m, 4H), 2.94 (m, 4H), 2.81 (m, 4H), 2.29 (m, 2H), 2.19 (m, 10H), 1.99 (s, 2H), 1, 41 (t, 2H), 0.95 (m, 6H).

EXAMPLE 209

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-4- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 209A 6-Fluoro-4-methoxy-1H-indole-2- methyl acid ester carboxylic [0743] A solution of sodium methoxide (25% by weight in methanol, 22.25 mL) and methanol (52 mL) was added to the flask and cooled to -20 ° C using an acetonitrile / dry ice bath. Ethyl 2-azidoacetate (25% by weight in ethanol, 50.3 g) and 4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolved in ethyl 2-azidoacetate solution) were added dropwise to a stirred solution of sodium methoxide at -20 ° C. The solution was then stirred at -20 ° C for 3.5 hours and then at 0 ° C for one hour. The solution was poured onto ice, filtered under reduced pressure, and washed with water. The filtered solid was dissolved in xylene (100 mL), washed twice with brine, and dried using anhydrous sodium sulfate and filtered. In a separate flask, xylene (50 ml) was brought to the boil. The xylene solution containing the filtered material was added dropwise to boiling xylene. The solution was then refluxed for five hours, cooled, and kept in the freezer for 16 hours. The precipitate was filtered off. The volume of the filtrate was reduced under reduced pressure to give a second crop of precipitate, which was washed with hexane, then 5% ethyl acetate in hexane and combined with the material from the first filtration.

EXAMPLE 209B 6-fluoro-4-methoxy-1H-indole-2-carboxylic acid [0744] The title compound was prepared by substituting EXAMPLE 209A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 209C

6-Fluoro-4-methoxy-1H-indoles. EXAMPLE 209B (1775 mg) was dissolved in N-methylpyrrolidinone (75 ml), and copper powder (2157 mg) was added. The solution was mixed to keep the copper powder in suspension and solution

140

EP-2507211B1EN was divided into nine microwave reactor vials, each containing a magnetic stirring element. Each vial was heated in a CEM Discover microwave reactor at 260 ° C for 25 minutes with stirring. The vial contents were combined, added to water, and extracted with ethyl ether. The ether was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexane.

EXAMPLE 209D

6-Fluoro-1H-indol-4-ol [0746] Aluminum chloride (727 mg) was added to dichloromethane (20 mL), the mixture was cooled to 0 ° C, and benzyl mercaptan (4512 mg) was added. EXAMPLE 209C (600 mg) dissolved in dichloromethane (5 mL) was added dropwise. The solution was stirred for 30 minutes at 0 ° C. Benzyl mercaptan (451 mg) and aluminum chloride (727 mg) were added, and the solution was stirred for 75 minutes at 0 ° C. The reaction was stopped by adding 1M aqueous HCl. The solution was extracted with ethyl acetate, which was subsequently washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by flash column chromatography on silica gel using 5% ethyl acetate in hexane, increasing to 20% ethyl acetate in hexane, and increasing again to 50% ethyl acetate in hexane.

EXAMPLE 209E 4-Fluoro-2- (6-fluoro-1H-indol-4-yloxy) benzoic acid ethyl ester [0747] The title compound was prepared by substituting EXAMPLE 209D for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 209F 4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (6-fluoro-1H-indol- acid ethyl ester 4-yloxy) benzoic [0748] The title compound was prepared by substituting EXAMPLE 209E for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 209G

4- {4- [2- (4-Chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (6-fluoro-1H-indol-4-yloxy) acid benzoic [0749] The title compound was prepared by substituting EXAMPLE 209F for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 209H

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-4- yl) oxy] -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0750] The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.14 (br s, 1H), 8.37 (d, 1H), 8.08 (d, 1H), 7.68 (dd, 1H), 7.59 (d, 1H), 7, 35 (d, 2H), 7.19 (t, 1H), 7.05 (d, 2H), 6.97 (d, 1H), 6.78 (dd, 1H), 6.71 (dd, 1H ), 6.34 (d, 1H), 6.26 (t, 1H), 5.97 (dd, 1H), 3.74 (m, 1H), 3.18-3.09 (m, 2H) , 3.05 (br s, 4H), 2.83-2.70 (m, 2H), 2.74 (br s, 2H), 2.57 (s, 3H), 2.25-2.12 (m, 6H), 2.09-2.01 (m, 2H), 1.96 (s, 2H), 1.72 (q, 2H), 1.39 (t, 2H), 0.93 ( s, 6H).

EXAMPLE 210

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4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-4- yl) oxy] -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0751] The title compound was prepared by substituting EXAMPLE 209G instead of EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.16 (br s, 1H), 8.39 (d, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 7.38-7.32 (d, 2H ), 7.21 (t, 1H), 7.05 (d, 2H), 6.99 (d, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 6.26 (t, 2H), 6.00 (d, 1H), 3.993.89 (m, 3H), 3.76 (m, 1H), 3.26 (m, 2H) , 3.07 (m, 4H), 2.72 (br s, 2H), 2.27-2.12 (m, 8H), 2.09-1.95 (m, 4H), 1.86- 1.48 (m, 8H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 211

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({4 - [(4-methylpiperazin-1-yl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

EXAMPLE 211A

4- (4-methylpiperazin-1-ylamino) -3- (trifluoromethylsulfonyl) benzenesulfonamide [0752] The title compound was prepared by substituting 4-methylpiperazine-1-amine for 3- (Nmorpholinyl) -1-propylamine and EXAMPLE 131C instead of 4-fluoro -3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 211B

2- (2-chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- ( 4- (4-methylpiperazin-1-ylamino) -3- (trifluoromethylsulfonyl) phenylsulfonyl) benzamide [0753] The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE 1F and EXAMPLE 211 A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 211C

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (4 - (4-methylpiperazin-1-ylamino) -3- (trifluoromethylsulfonyl) phenylsulfonyl) benzamide [0754] The title compound was prepared by substituting EXAMPLE 211B for EXAMPLE

158E in EXAMPLE 159. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.87 (s, 1H), 8.08 (d, 1H), 7.96 (s, 1H), 7.90 (dd, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H), 6.89 (d, 1H), 6.83 (d, 1H), 6.73 (dd, 1H) , 6.65 (dd, 1H), 6.21 (d, 1H), 3.07 (m, 4H), 2.90 (m, 6H), 2.76 (s, 2H), 2.41 ( s, 3H), 2.21 (m, 6H), 1.97 (s, 2H), 1.40 (t, 3H), 0.94 (s, 6H).

EXAMPLE 212

2 - ({1,3-bis [(4-methylpiperazin-1-yl) methyl] -1H-indol-4-yl} oxy) -4- (4 - {[2- (4-chlorophenyl) -4, 4dimetylocykloheks-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 212A

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2- (1H-indol-4-yloxy) benzamide [0755] The title compound was prepared by substituting EXAMPLE 202C for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H.

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EXAMPLE 212B

2 - ({1,3-bis [(4-methylpiperazin-1-yl) methyl] -1H-indol-4-yl} oxy) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] benzamide [0756] EXAMPLE 212A (0, 25 g) was dissolved in methanol (0.60 ml), to which 37% (w / w) formaldehyde in water (0.22 ml) and 1-methylpiperazine (0.33 ml) were added. The reaction was heated at 60 ° C for two hours, then cooled and concentrated. The crude product was purified by preparative HPLC using a C18 column, 250 x 50 mm, 10μ, and eluting using a gradient of 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. The salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.68 (br t, 1H), 8.00 (s, 1H), 7.82 (d, 1H), 7.38 (m, 3H), 7.25 (d, 1H), 7, 08 (d, 2H), 6.87 (d, 1H), 6.75 (d, 1H), 6.67 (m, 2H), 6.58 (s, 1H), 5.58 (d, 1H ), 4.85 (s, 2H), 3.40 (m, 4H), 3.20 (v br s, 4H), 3.05 (v br s, 4H), 2.79 (s, 2H) , 2.60 (v br s, 2H), 2.40 (br m, 6H), 2.20 (m, 21H), 2.09 (s, 3H), 1.98 (s, 2H), 1 , 80 (m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 213

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2 - ({3 - [(4-methylpiperazin-1-yl) methyl] 1H-indol-4-yl} oxy) benzamide [0757] EXAMPLE 212A (0, 13 g) in methanol (0.30 ml) was added 37% (wt) formaldehyde in water (0.022 ml) and 1-methylpiperazine (0.035 ml). The reaction was heated at 60 ° C for 50 minutes, then cooled and concentrated. The crude product was purified by preparative HPLC using a C18 column, 250 x 50 mm, 10μ, and eluting using a gradient of 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. The salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.23 (s, 1H), 8.68 (br t, 1H), 7.96 (s, 1H), 7.79 (d, 1H), 7.38 (d, 2H), 7, 31 (s, 1H), 7.17 (br d, 1H), 7.08 (d, 2H), 6.75 (d, 2H), 6.66 (d, 1H), 6.60 (m, 2H), 5.65 (d, 1H), 4.33 (br s, 2H), 3.40 (m, 4H), 3.20 (v br s, 4H), 3.03 (v br s, 4H), 2.79 (s, 2H), 2.60 (v br s, 2H), 2.42 (br m, 2H), 2.20 (m, 15H), 1.98 (s, 2H) , 1.83 (m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 214

2- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4- (1-methylpiperidin-4-ylamino) - 3-nitrophenylsulfonylcarbamoyl) phenoxy) -N, N-dimethylbenzamide EXAMPLE 214A

Methyl 2-bromo-4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0758] The title compound was prepared by substituting EXAMPLE 3F for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 214B

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin) -2- (2- (dimethylcarbamoyl) phenoxy) benzoate

143

[0759] The title compound was prepared by substituting EXAMPLE 214A for EXAMPLE 1C and 2-hydroxy-N, N-dimethylbenzamide instead of EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 214C 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2- (dimethylcarbamoyl) phenoxy) benzoic acid [0760] The title compound was prepared by substituting EXAMPLE 214B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 214D

2- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4- (1-methylpiperidin-4-ylamino) - 3-nitrophenylsulfonylcarbamoyl) phenoxy) -N, N-dimethylbenzamide [0761] The title compound was prepared by substituting EXAMPLE 214C for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.35 (s, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.12 (m, 2H), 7.06 (d, 2H), 7.02 (d, 1H), 6.93 (t, 1H), 6.68 (dd, 1H), 6.47 (d, 1H) , 6.18 (d, 1H), 3.72 (m, 1H), 3.04 (m, 4H), 2.95 (m, 2H), 2.86 (s, 3H), 2.75 ( s, 2H), 2.70 (s, 3H), 2.42 (m, 2H), 2.19 (m, 6H), 2.01 (m, 4H), 1.67 (m, 2H), 1.40 (t, 2H), 1.24 (s, 3H), 0.94 (s, 6H).

EXAMPLE 215

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 [(1 tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenylsulfonyl) -2 - {[2- (trifluoromethyl) -1H-indol-4-yl] oxy} benzamide

EXAMPLE 215A

Methyl 2- (3-amino-2-methylphenoxy) -4-fluorobenzoate [0762] The title compound was prepared by substituting 3-amino-2-methylphenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 215B (E) -2- (3- (1-chloro-2,2,2-trifluoroethylideneamino) -2-methylphenoxy) -4-fluorobenzoate [0763] To a mixture of triethylamine (0.476 g) and triphenylphosphine (3.05 g) in CCl₄ (10 ml) trifluoroacetic acid (0.477 g) was added dropwise at 0 ° C. The solution was stirred for 10 minutes. EXAMPLE 215A (1.08 g) in CCl was added to this solution₄ (5 ml). The solution was heated to reflux for 3 hours. After cooling, the reaction mixture was concentrated, and diluted with 3: 7 ethyl acetate / hexane. The solid was filtered off, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel eluting with 1:10 ethyl acetate / hexane to give the title compound.

EXAMPLE 215C (E) -2- (2- (bromomethyl) -3- (1-chloro-2,2,2-trifluoroethylideneamino) phenoxy) -4-fluorobenzoate [0764] A mixture of EXAMPLE 215B (1.4 g), N-bromosuccinimide (0.671 g), and benzoyl peroxide (0.044 g) in CCl₄ (20 ml) was refluxed for 4 hours. After cooling, the solid was filtered off. Then the filtrate was concentrated. The residue was purified by flash chromatography on silica gel eluting with 1:20 ethyl acetate / hexane to give the title compound.

EXAMPLE 215D

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Methyl 4-fluoro-2- (2- (trifluoromethyl) -1H-indol-4-yloxy) benzoate [0765] Magnesium (0.081 g) in tetrahydrofuran (10 mL) was treated with EXAMPLE 215C (1.3 g) in tetrahydrofuran (5 ml) dropwise at 0 ° C. After the addition was complete, a pair of I crystals were added to the reaction₂. After 2 hours of stirring, magnesium began to disappear. The reaction was stirred for another 6 hours at room temperature. The reaction was quenched with saturated aqueous NH solution₄Cl, and extracted with ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with a 1: 4 mixture of ethyl acetate / hexane to afford the title compound.

EXAMPLE 215E

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2- (trifluoromethyl) -1H-indol-4-yloxy) methyl benzoate [0766] The title compound was prepared by substituting EXAMPLE 215D for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 215F [0767] A mixture of EXAMPLE 215E (0.13 g) and lithium iodide (0.534 g) in pyridine (2 mL) was heated in a CEM Discover microwave reactor (130 ° C, 30 minutes). Pyridine was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was then purified by reverse phase preparative HPLC to give the desired product.

EXAMPLE 215G

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 [(1 -tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) -2 - {[2- (trifluoromethyl) -1H-indol-4-yl] oxy} benzamide [0768] The title compound was prepared by substituting EXAMPLE 215F instead of EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.29 (s, 1H), 8.39 (d, 1H), 8.12 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.00-7.12 (m, 5H), 6.85 (s, 1H), 6.71 (dd, 1H), 6.34 (d, 1H), 6.29 ( d, 1H), 3.93 (dd, 1H), 3.06-3.09 (m, 6H), 2.76 (s, 2H), 2.62-2.64 (m, 2H), 2 , 16-2.19 (m, 6H), 2.03-2.05 (m, 2H), 1.96 (s, 2H), 1.79-1.82 (m, 2H), 1.66 -1.68 (m, 2H), 1.49-1.57 (m, 2H), 1.96 (t, 2H), 0.93 (s, 6H).

EXAMPLE 216

2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl-piperazin-1-yl) -N- ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 216A

2- (2-chloro-4- (methoxymethoxy) phenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- ( 3-nitro-4- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonyl) benzamide [0769] The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 216B

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2- (2-chloro-4-hydroxy-phenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0770] The title compound was prepared by substituting EXAMPLE 216A for EXAMPLE

158E in EXAMPLE 159. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.83 (br. s, 1H), 8.47 (s, 1H), 8.17 (br. s, 1H), 7.76 (d, 1H), 7.50 (d, 1H) , 7.35 (d, 2H), 7.08 (m, 3H), 6.83 (m, 2H), 6.67 (m, 2H), 6.22 (d, 1H), 3.93 ( m, 2H), 3.81 (m, 1H), 3.07 (m, 6H), 2.75 (s, 2H), 2.19 (m, 8H), 1.97 (s, 2H), 1.68 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 217

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

EXAMPLE 217A

4-nitro-2- (trifluoromethyl) phenol [0771] The title compound was prepared as described in EXAMPLE 200A by replacing 2,3-difluoro4-nitroanisole with 2-trifluoromethyl-4-nitroanisole.

EXAMPLE 217B

6- (trifluoromethyl) -1H-indol-5-ol [0772] The title compound was prepared analogously to the preparation of 2-fluoro-4-nitrophenol in WO 02/12227 (page 78).

EXAMPLE 217C

Methyl 4-fluoro-2- (6- (trifluoromethyl) -1H-indol-5-yloxy) benzoate [0773] The title compound was prepared as described in EXAMPLE 3 A by replacing 2-methyl-5-indolol by EXAMPLE 217B.

EXAMPLE 217D

Methyl 4- (piperazin-1-yl) -2- (6- (trifluoromethyl) -1H-indol-5-yloxy) benzoate [0774] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 217C.

EXAMPLE 217E

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6- (trifluoromethyl) -1H-indol-5-yloxy ) methyl benzoate [0775] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 217D and EXAMPLE 60D, respectively.

EXAMPLE 217F 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6 (trifluoromethyl) -1H-indol-5 acid -yloxy) benzoic [0776] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 217E.

EXAMPLE 217G

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

146

EP-2507211B1EN [0777] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 217F and EXAMPLE 3I, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.38 (s, 1H), 8.43 (d, 1H), 8.09 (d, 1H), 7.77 (dd, 1H), 7.67 (s, 1H), 7.55 (m,

2H), 7.33 (d, 2H), 7.02 (m, 4H), 6.67 (dd, 1H), 6.38 (s, 1H), 3.71 (m, 1H), 3, 05 (m, 7H), 2.72 (s, 3H), 2.25 (m, 7H), 1.98 (m, 5H), 1.72 (m, 3H), 1.38 (t, 3H ), 0.92 (s, 6H).

EXAMPLE 218

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 [(1 -tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) -2 - {[6- (trifluoromethyl) -1H-indol-5-yl] oxy} benzamide [0778] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 217F and EXAMPLE 49C, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.42 (s, 1H), 8.46 (d, 1H), 8.16 (d, 1H), 7.77 (dd, 1H), 7.70 (s, 1H), 7.56 (m, 2H), 7.33 (m, 3H), 7.03 (m, 5H), 6.69 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H) , 3.91 (m, 3H), 3.72 (m, 1H), 3.02 (m, 8H), 2.72 (s, 2H), 2.25 (m, 10H), 1.95 ( m, 4H), 1.48 (m, 5H), 0.92 (s, 6H).

EXAMPLE 219

2 - [(2-amino-1,3-thiazol-4-yl) methoxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 219A

Methyl 2 - ((2-aminothiazol-4-yl) methoxy) -4-fluorobenzoate A mixture of methyl 4-fluoro-2-hydroxybenzoate (552 mg), 4- (chloromethyl) thiazol-2-amine hydrochloride (600 mg ) and Cs₂WHAT₃ (2.64 g) in 15 ml of N, N-dimethylformamide was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with ethyl acetate (2x), washed with water (2x) and brine, dried over MgSO₄, filtered and concentrated. The residue was chromatographed on silica gel using 10-50% ethyl acetate in hexane as the eluent. EXAMPLE 219B

Methyl 2 - ((2-aminothiazol-4-yl) methoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0780] The title compound was prepared by substituting EXAMPLE 219A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 219C

2 - ((2- (tert-butoxycarbonylamino) thiazol-4-yl) methoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1- Methyl-yl) benzoate [0781] To a solution of EXAMPLE 219B (280 mg), 4- (dimethylamino) pyridine (2.94 mg), triethylamine (81 μ0) in 10 ml tetrahydrofuran, a solution of di-butri-butyl dicarbonate was added at room temperature. (134 μ0) in 3 ml tetrahydrofuran through a flexible needle. The mixture was stirred at room temperature overnight, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine and dried over MgSO₄, filtered and concentrated. The oily residue was chromatographed on silica gel using 25-60% ethyl acetate in hexane.

EXAMPLE 219D 2 - ((2- (tert-butoxycarbonylamino) thiazol-4-yl) methoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazinic acid 1-yl) benzoic acid

147

[0782] The title compound was prepared by substituting EXAMPLE 219C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 219E

4 - ((5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-nitro-4- (1 ( tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonylcarbamoyl) phenoxy) methyl) tert-butyl-2-ylcarbamate [0783] The title compound was prepared by substituting EXAMPLE 219D instead of EXAMPLE 1F and EXAMPLE 49C, respectively in EXAMPLE 1H.

EXAMPLE 219F

2 - ((2-aminothiazol-4-yl) methoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N - (3-nitro-4- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonyl) benzamide [0784] This EXAMPLE was performed by substituting EXAMPLE 219E for EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 0.96 (s, 6H) 1.36 - 1.78 (m, 8H) 1.99 (m, 2H) 2.14 - 2.31 (m, 7H) 2.40 - 2.64 ( m, 3H) 2.78 (m, 2H) 2.92 (d, 2H) 3.16 - 3.43 (m, 10H) 3.75 (m, 1H) 3.84 - 3.96 (m, 2H) 5.01 (s, 2H) 6.51 (d, 1H) 6.57 (s, 1H) 6.63 (s, 1H) 6.93 (s, 2H) 7.06 (d, 2H) 7.28 (d, 1H) 7.37 (d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.28 (d, 1H) 8.62 (d, 1H).

EXAMPLE 220

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0785] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 200F and EXAMPLE 184A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.72 (s, 1H), 9.14 (s, 1H), 8.47 (d, 1H), 7.82 (m, 1H), 7.54 (dd, 2H), 7.41 (t, 1H), 7.34 (d, 2H), 7.04 (d, 1H), 6.92 (d, 1H), 6.66 (d, 1H), 6.42 (d, 1H) , 6.21 (s, 1H), 2.98 (m, 11H), 2.73 (s, 2H), 2.40 (s, 4H), 2.17 (m, 7H), 1.95 ( s, 3H), 1.38 (t, 2H), 0.93 (s, 6H).

EXAMPLE 221

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0786] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.19 (s, 1H), 9.17 (s, 1H), 8.52 (d, 1H), 7.89 (dd, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.34 (m, 4H), 7.23 (d, 1H), 7.04 (d, 2H), 6.62 (dd, 1H), 6.39 (m, 1H) , 6.07 (m, 1H), 2.94 (m, 10H), 2.71 (s, 2H), 2.36 (s, 3H), 2.15 (m, 6H), 1.95 ( s, 2H), 1.38 (t, 2H), 0.92 (m, 6H).

EXAMPLE 222

4 - [(5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({4- [Tert-Butyl [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) amino] carbonyl} phenoxy) methyl] -1,3-thiazol-2-ylcarbamate [0787] The title compound was prepared by substituting EXAMPLE 219D for EXAMPLE 1F, respectively and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300

MHz, dimethyl sulfoxide-d₆) δ 0.96 (s, 6H) 1.37 - 1.54 (m, 12H) 1.60 - 1.79 (m, 2H) 1.97 - 2.08 (m, 3H) 2.15 - 2.30 (m, 7H) 2.38 (s, 3H) 2.78 (s, 2H) 2.91 (d, 2H) 3.17 - 3.26 (m, 5H) 3.69 - 3, 84 (m, 1H) 5.08 (s,

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2H) 6.48 (d, 1H) 6.53 (s, 1H) 7.07 (d, 2H) 7.17 (s, 1H) 7.23 (d, 1H) 7.37 (d, 2H) 7.43 (d, 1H) 7.90 (dd, 1H)

8.22 (d, 1H) 8.58 (d, 1H) 10.39 (s, 1H) 11.35 (s, 1H).

EXAMPLE 223

2 - [(2-amino-1,3-thiazol-4-yl) methoxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0788] The title compound was prepared by substituting EXAMPLE 222 for EXAMPLE 1A in

EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 0.96 (s, 6H) 1.42 (t, 2H) 1.59 - 1.76 (m, 2H) 1.92 - 2.06 (m, 3H) 2.16 - 2.42 ( m, 11H) 2.78 (s, 4H) 3.20 - 3.26 (m, 5H) 3.67 - 3.82 (m, 1H) 4.99 (s, 2H) 6.50 (d, 1H) 6.55 (s, 1H) 6.62 (s, 1H) 6.91 (s, 2H) 7.08 (d, 2H) 7.26 (d, 1H) 7.37 (d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.24 (d, 1H) 8.60 (d, 1H).

EXAMPLE 224

2- [3- (acetylamino) phenoxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 224A

Methyl 2- (3-acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoate [0789] The title compound was prepared by substituting 3-acetamidophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 224B 2- (3-Acetamidophenoxy) -4- (4 - ((4'-chlorobiphenyl-2-yl) methyl) piperazin-1-yl) benzoic acid [0790] The title compound was prepared by substituting EXAMPLE 224A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 224C

2- [3- (acetylamino) phenoxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0791] The title compound was prepared by substituting EXAMPLE 224B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.48 (s, 1H), 9.89 (s, 1H), 8.59 (m, 1H), 8.50 (d, 1H), 7.71 (dd, 1H), 7.47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd, 1H), 6.50 (dd, 1H) , 6.39 (d, 1H), 3.86 (dd, 2H), 3.37 (m, 2H), 3.30 (m, 6H), 3.16 (m, 4H), 2.35 ( s, 4H), 2.00 (s, 3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 225

2- [3- (acetylamino) phenoxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0792] The title compound was prepared by substituting EXAMPLE 224B for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.86 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.70 (dd, 1H), 7.54 (d, 1H), 7.36 (d, 2H), 7.29 (d, 1H), 7.09 (m, 4H), 6.98 (m, 1H), 6.70 (dd, 1H), 6.45 (dd, 1H) , 6.33 (d, 1H), 3.95 (dd, 2H), 3.83 (m, 1H), 3.36 (m, 3H), 3.24 (m, 2H), 3.11 ( m, 4H), 2.77 (m, 4H), 2.17 (m, 8H), 1.98 (m, 5H), 1.66 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 226

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2 - [(2-chlorophenyl) amino] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 226A

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-chlorophenylamino) benzoate [0793] Solution of EXAMPLE 214A ( 500 mg), cesium carbonate (429 mg), palladium (II) acetate (21 mg), racBINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) (58.5 mg) and toluene (6 , 4 ml) was degassed using N₂. The solution was stirred at 115 ° C for 5 minutes. After cooling to room temperature, 2-chloroaniline (144 mg) was added and the reaction mixture was degassed again with N₂ and stirred at 115 ° C for 45 minutes. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water and brine, dried (MgSO₄), filtered and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with dichloromethane / 1% methanol.

EXAMPLE 226B 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-chlorophenylamino) benzoic acid [0794] The title compound was prepared by substitution of EXAMPLE 226A instead of EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 226C

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (2-Chloro-phenylamino) -N- (3-nitro-4 - (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonyl) benzamide [0795] The title compound was prepared by substituting EXAMPLE 226B for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.11 (br s, 1H), 9.15 (br s, 1H), 8.53 (d, 1H), 7.97 - 8.20 (m, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.47 (d, 1H), 7.42 (dd, 1H), 7.36 (d, 2H), 7.22 (t, 1H), 7, 15 (d, 1H), 7.07 (d, 2H), 6.89 (t, 1H),

6.52 (d, 1H), 6.34 (dd, 1H), 3.96 (d, 2H), 3.46 - 3.78 (m, 2H), 3.33 - 3.40 (m, 2H), 3.23 - 3.28 (m, 2H), 2.96 - 3.14 (m, 6H), 2.13 - 2.31 (m, 8H), 1.98 (br s, 6H ), 1.65 (br s, 4H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 227

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-metoksy1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 227A

6-Methoxy-1H-indol-5-ol [0796] 5- (Benzyloxy) -6-methoxy-1H-indole (3.00 g) was added to methanol (100 ml) and ethyl acetate (100 ml) in a pressure vessel . Palladium hydroxide on carbon (0.832 g) was added and the solution was shaken under 30 psi (207 kPa) hydrogen pressure at room temperature for 40 minutes. The mixture was filtered through a nylon membrane, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, the solution was filtered through a pad of silica gel, and the solvent was removed from the filtrate under reduced pressure.

EXAMPLE 227B 4-Fluoro-2- (6-methoxy-1H-indol-5-yloxy) benzoic acid methyl ester

150

[0797] The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE 227A for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 227C 2- (6-methoxy-1H-indol-5-yloxy) -4-piperazin-1-yl-benzoic acid methyl ester [0798] The title compound was prepared by substituting piperazine for EXAMPLE 3F and EXAMPLE 227B instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 227D 4- {4- [2- (4-Chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (6-methoxy-1H-indol- acid methyl ester) 5-yloxy) benzoic [0799] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 227C for tert-butyl piperazine-1-carboxylate in

EXAMPLE 1A.

EXAMPLE 227E 4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (6-methoxy-1H-indol-5- iloxy) benzoic [0800] The title compound was prepared by substituting EXAMPLE 227D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 227F

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-metoksy1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0801] The title compound was prepared by substituting EXAMPLE 227E instead of EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.02 (br s, 1H), 8.60 (d, 1H), 8.25 (d, 1H), 7.89 (dd, 1H), 7.54 (d, 1H), 7, 33 (d, 2H), 7.29-7.26 (m, 2H), 7.21 (d, 1H), 7.09 (s, 1H), 7.04 (d, 2H), 6.59 (dd, 1H), 6.36 (t, 1H), 6.03 (d, 1H), 3.96-3.87 (m, 3H), 3.74 (s, 3H), 3.73 ( m, 1H), 2.97 (m, 8H), 2.70 (br s, 2H), 2.13 (br s, 8H), 2.05-1.92 (m, 4H), 1.74 (m, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).

EXAMPLE 229

2 - [(2-amino-1,3-benzothiazol-6-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 229A

Methyl 2- (2-aminobenzo [d] thiazol-6-yloxy) -4-fluorobenzoate [0802] The title compound was prepared by substituting 2-aminobenzo [d] thiazol-6-ol for 2-methyl-indolol in EXAMPLE 3A.

EXAMPLE 229B

2- (2-amino-benzo [d] thiazol-6-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate methyl [0803] The title compound was prepared by substituting EXAMPLE 229A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 229C

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2- (2- (tert-butoxycarbonylamino) Benzo [d] thiazol-6-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin- Methyl 1-yl) benzoate [0804] The title compound was prepared by substituting EXAMPLE 229B for EXAMPLE

219B in EXAMPLE 219C.

EXAMPLE 229D 2- (2- (tert-butoxycarbonylamino) benzo [d] thiazol-6-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazine acid -1-yl) benzoic [0805] The title compound was prepared by substituting EXAMPLE 229C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 229E

6- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4- (1-methylpiperidin-4-ylamino) - Tert-butyl 3-nitrophenylsulfonylcarbamoyl) phenoxy) benzo [d] thiazol-2ylcarbamate [0806] The title compound was prepared by substituting EXAMPLE 229D instead of EXAMPLE 1F and EXAMPLE 3I, respectively, in EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 229F

2 - [(2-amino-1,3-benzothiazol-6-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0807] The title compound was prepared by substituting EXAMPLE 229E for EXAMPLE 1A in EXAMPLE 1B, 1 H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 0.93 (s, 6H) 1.39 (t, 2H) 1.62 - 1.80 (m, 2H) 1.91 - 2.24 (m, 10H) 2.50 - 2.62 ( m, 4H) 2.74 (s, 4H) 2.97 - 3.18 (m, 5H) 3.66 - 3.82 (m, 1H) 6.24 (d, 1H) 6.64 (dd, 1H) 6.75 (dd, 1H) 6.92 (d, 1H) 7.01 - 7.12 (m, 3H) 7.20 (d, 1H) 7.31 (s, 2H) 7.35 ( d, 2H)

7.52 (d, 1H) 7.61 - 7.71 (m, 1H) 8.09 (d, 1H) 8.44 (d, 1H).

EXAMPLE 230

2 - [(2-chlorophenyl) amino] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0808] The title compound was prepared by substituting EXAMPLE 226B for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.11 (br s, 1H), 8.53 (d, 1H), 7.02 (br s, 1H), 7.94 (dd, 1H), 7.81 (d, 1H), 7 , 46 (dd, 1H), 7.42 (dd, 1H), 7.36 (d, 2H), 7.18 - 7.25 (m, 1H), 7.14 (d, 1H), 7, 07 (d, 2H), 6.85 - 6.92 (m, 1H),

6.52 (d, 1H), 6.33 (dd, 1H), 3.88 (br s, 1H), 3.01 - 3.09 (m, 7H), 2.66 - 2.83 (m, 6H ), 2.07 - 2.32 (m, 8H), 1.97 (br s, 3H), 1.78 (br s, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 231

5- [5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({[(4- { Tert-butyl [3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] amino} carbonyl) phenoxy] -1H-indole-1-carboxylate

EXAMPLE 231A

Ethyl 2- (1H-indol-5-yloxy) -4-fluorobenzoate [0809] The title compound was prepared by substituting 5-hydroxyindole for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 231B

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Ethyl 2- (1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0810] Title compound prepared by substituting EXAMPLE 231A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 231C 2- (1H-Indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0811] The title compound was prepared by substituting EXAMPLE 231B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 231D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] -2- (1H-indol-5-yloxy) benzamide [0812] The title compound was prepared by substituting EXAMPLE 231C for EXAMPLE 1F and EXAMPLE 11A instead of EXAMPLE 1G in EXAMPLE 1H, except that 2-10% methanol in CH was used for the chromatography₂cl₂.

EXAMPLE 231E bis (2,2,2-trifluoroacetate) 5- [5- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1- yl) -2 - ({[(4 - {[3- (dimethylamino) propyl] amino} -3-nitrophenyl) sulfonyl] amino} carbonyl) phenoxy] -1H-tert-butyl indole-1-carboxylate [0813] Compound the title was made by substituting EXAMPLE 231D for EXAMPLE 202D in EXAMPLE 202E. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.63 (v br s, 1H), 9.40 (v br s, 2H), 8.61 (br t, 1H), 8.53 (d, 1H), 8.00 (d, 1H) ), 7.85 (dd, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 7.10 (m, 4H), 6.97 (dd, 1H), 6.76 (dd, 1H), 6.43 (d, 1H), 6.33 (d, 1H), 3.60, 3.50, 3.30 (all v br m, total 10H), 3.10 (br m, 4H), 2.79 2.77 (both s, together 6H), 2.20 (br m, 2H), 2.04 (s, 2H), 1.85 (br m, 2H), 1.66 (s, 9H), 1.45 (br t, 2H), 0.95 (s, 6H).

EXAMPLE 232

2 - [(2-amino-1,3-benzothiazol-6-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] piperazin- 1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 232A

6- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-nitro-4- (1- (tetrahydro -2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonylcarbamoyl) phenoxy) benzo [d] thiazol-2-ylcarbamate tert-butyl [0814] The title compound was prepared by substituting EXAMPLE 229D instead of EXAMPLE 1F and EXAMPLE 49C respectively 1G in EXAMPLE 1H.

EXAMPLE 232B

2 - [(2-amino-1,3-benzothiazol-6-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0815] The title compound was prepared by substitution EXAMPLE 232A instead of EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 0.95 (s, 6H) 1.44 (br. s, 2H) 1.61 1.89 (m, 3H) 1.90 - 2.12 (m, 5H) 2.13 - 2.32 (m, 4H) 2.36 - 2.63 (m, 2H) 2.97 - 3.78 (m, 16H) 4.01 (dd,

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2H) 6.30 (s, 1H) 6.72 (d, 1H) 6.84 (d, 1H) 7.11 (m, 3H) 7.18 - 7.32 (m, 2H) 7.33 - 7.55 (m, 5H) 7.68 - 7.89 (m, 1H) 8.17 (d, 1H) 8.57 (d, 1H) 9.25 (br. S, 1H) 11.62 ( br. s, 1H).

EXAMPLE 233

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[3- (3-oxopiperazin-1-yl) propyl] amino} phenyl) sulfonyl] benzamide [0816] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and EXAMPLE 254A instead of EXAMPLE 11A in EXAMPLE 137, ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (br s, 1H), 8.62 (br t, 1H), 8.57 (d, 1H), 7.83 (dd, 1H), 7.75 (s, 1H), 7 , 51 (d, 1H), 7.37 (dd, 1H), 7.34 (m, 3H), 7.26 (d, 1H), 7.08 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.43 (dd, 2H), 3.18 (br m, 2H), 3 , 04 (br m, 4H), 2.95 (s, 2H), 2.70 (s, 2H), 2.55 (t, 2H), 2.45 (t, 2H), 2.17 (br m, 6H), 1.95 (s, 2H), 1.79 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 234 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0817] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and EXAMPLE 205A instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.54 (s, 1H), 8.17 (br d, 1H), 7.84 (d, 1H), 7.52 (d, 1H), 7, 34 (m, 4H), 7.24 (br d, 1H), 7.11 (br d, 1H), 7.04 (d, 2H), 6.64 (d, 1H), 6.40 (s , 1H), 6.09 (s, 1H), 3.62 (br m, 4H), 3.58 (v br s, 1H), 3.00 (br m, 4H), 2.73 (s, 2H), 2.65 (br m, 4H), 2.47 (v br s, 1H), 2.18 (br m, 6H), 2.06 (br m, 2H), 1.93 (br m , 4H), 1.40 (m, 6H), 0.92 (s, 6H).

EXAMPLE 235 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7difluoro- 1H-indol-5-yl) oxy] -N- (14 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0818] The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE 122C and EXAMPLE 205A instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.72 (s, 1H), 8.46 (s, 1H), 8.15 (br d, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7, 40 (dd, 1H), 7.34 (d, 2H), 7.06 (br d, 1H), 7.05 (d, 2H), 6.91 (br d, 1H), 6.66 (br d, 1H), 6.40 (s, 1H), 6.25 (d, 1H), 3.62 (br m, 4H), 3.58 (v br s, 1H), 3.00 (br m , 4H), 2.73 (s, 2H), 2.65 (br m, 4H), 2.47 (v br s, 1H), 2.18 (br m, 6H), 2.06 (br m , 2H), 1.93 (br m, 4H), 1.40 (m, 6H), 0.92 (s, 6H).

EXAMPLE 236

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 236A

Tert-butyl 1- (cyclopropylmethyl) piperidin-4-ylcarbamate [0819] The title compound was prepared by substituting cyclopropanecarboxaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and piperidin-4-ylcarbamate of tert-butyl instead of piperazine-1-carboxylate.

EXAMPLE 236B

154

Bis (2,2,2-trifluoroacetate) 1- (cyclopropylmethyl) piperidin-4-amine [0820] The title compound was prepared by substituting EXAMPLE 236A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 236C

4- (1- (cyclopropylmethyl) piperidin-4-ylamino) -3-nitrobenzenesulfonamide [0821] The title compound was prepared by substituting EXAMPLE 236B for 4- (1-isopropylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide in EXAMPLE 41A.

EXAMPLE 236D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0822] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 236C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 12.39 (s, 1H), 9.31 (d, 1H), 8.49 (d, 1H), 8.45 (dd, 1H), 8.15 (d, 1H), 7.47 - 7.52 (m, 3H), 7.41 - 7.45 (m, 3H), 7.04 (d, 2H), 6.98 (d, 1H), 6.71 (dd, 1H), 6.57 (dd, 2H), 3.48 - 3.55 (m, 1H), 3.01 - 3.07 (m, 4H), 2.86 (d, 2H), 2.74 (s, 2H), 2.21 - 2.26 (m, 2H), 2.19 (d, 4H), 2.07 - 2.13 (m, 4H), 1.93 - 2.00 (m, 4H) , 1.63 - 1.71 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H), 0.84 - 0.91 (m, 1H), 0.45 - 0 , 49 (m, 2H), 0.11 (q, 2H).

EXAMPLE 237

4- (4- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl}} piperazin-1-yl) -N - [(4 - {[1- (cyclopropylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] -2 - [(6,7-difluoro-1H-indol-5-yl) oxy] benzamide [0823] The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE 1F and EXAMPLE 236C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 13.12 (s, 1H), 9.29 (d, 1H), 8.49 (d, 1H), 8.46 (dd, 1H), 8.11 (d, 1H), 7.42 (d, 2H), 7.19 (s, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.75 (dd, 1H), 6.66 (d, 1H) , 6.51 - 6.54 (m, 1H), 3.50 - 3.55 (m, 1H), 3.07 - 3.13 (m, 4H), 2.83 - 2.87 (m, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.11 - 2.23 (s, 8H), 1.93 - 2.00 (m, 4H), 1.63 - 1.71 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H), 0.84 - 0.90 (m, 1H), 0.44 - 0.49 (m , 2H), 0.08 - 0.12 (m, 2H).

EXAMPLE 238

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0824] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F in EXAMPLE 1H . ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.23 (s, 1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.30-7.34 (m, 4H), 7.17 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 ( s, 1H), 6.09 (s, 1H), 3.85 (dd, 2H), 3.26 (t, 2H), 3.03 (s, 4H), 2.74 (s, 2H), 2.12-2.19 (m, 6H), 1.94 (s, 2H), 1.87-1.90 (m, 1H), 1.62 (d, 2H), 1.38 (t, 2H), 1.22-1.30 (m, 2H), 0.92 (s, 6H).

EXAMPLE 239

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - [(3-nitro-4 - {[3- (3-oxopiperazin-1-yl) propyl] amino} phenyl) sulfonyl] benzamide [0825] The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE 122C and EXAMPLE 254A instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.68 (br s, 1H), 8.70 (v br s, 1H), 8.46 (s, 1H), 7.74 (s, 1H), 7.73 (br s, 1H) .

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7.52 (d, 1H), 7.37 (dd, 1H), 7.34 (d, 2H), 7.05 (d, 2H), 7.95 (v br s, 1H), 6.83 (v br s, 1H), 6.67 (dd, 1H),

6.39 (s, 1H), 6.25 (d, 1H), 3.44 (q, 2H), 3.18 (br m, 2H), 3.04 (br m, 4H), 2.97 (s, 2H), 2.73 (s, 2H), 2.57 (t,

2H), 2.47 (t, 2H), 2.18 (br m, 6H), 1.95 (s, 2H), 1.88 (m, 2H), 1.37 (t, 2H), 0 , 91 (s, 6H).

EXAMPLE 240

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 240A

N- (4-chloro-3-nitrophenylsulphonyl) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6 -fluoro-1H-indol-5-yloxy) benzamide [0826] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and 4-chloro-3-nitrobenzenesulfonamide instead of EXAMPLE 11A in EXAMPLE 137.

EXAMPLE 240B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(2-hydroxy-1-tetrahydro-2H-pyran-4-ethylethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0827] EXAMPLE 240A (150 mg) was dissolved in dioxane ( 1.8 ml), then 2-amino-2- (tetrahydro-2H-pyran-4-yl) ethanol (35 mg) and triethylamine (0.078 ml) were added. The reaction was heated at 110 ° C for 20 hours. The reaction was concentrated and the crude product was purified by preparative HPLC using a C18 column, 250 x 50 mm, 10μ, and eluting using a gradient of 20-100% CH₃CN versus 0.1% trifluoroacetic acid in water to give the product as the trifluoroacetic salt. The salt was dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.23 (s, 1H), 8.60 (d, 1H), 8.58 (d, 1H), 7.84 (dd, 1H), 7.52 (d, 1H), 7.39 (dd, 1H), 7.33 (m, 4H), 7.29 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.42 (s, 1H) , 6.08 (s, 1H), 5.03 (t, 1H), 3.85 (m, 2H), 3.74 (m, 1H), 3.63 (m, 1H), 3.57 ( m, 1H), 3.26 (dd, 2H), 3.02 (br m, 4H), 2.73 (s, 2H), 2.18 (br m, 6H), 1.95 (s, 2H) ), 1.94 (m, 1H), 1.61 (br m, 2H), 1.38 (m, 3H), 1.30 (m, 1H), 0.92 (s, 6H).

EXAMPLE 241

4- (4- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl ) oxy] -N - {[4 - ({[4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide

EXAMPLE 24 1 A

4 - ((4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) methylamino) -3-nitrobenzenesulfonamide [0828] The title compound was prepared by substituting (4- (aminomethyl) tetrahydro-2H-pyran-4-yl) methanol for ( tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 241B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[4 - ({[4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide [0829] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 241A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.22 (s, 2H), 9.10 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 1H), 7.30 -7.39

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EP-2507211B1PL (m, 5H), 7.24 (d, 1H), 7.02-7.05 (m, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6 , 08 (s, 1H), 5.22 (t, 1H), 3.51-3.62 (m, 6H), 3.41 (d, 2H), 3.03 (s, 4H), 2, 73 (s, 2H), 2.09-2.18 (m, 6H), 1.95 (s, 2H), 1.45-1.51 (m, 4H), 1.38 (t, 2H) , 0.92 (s, 6H).

EXAMPLE 242

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 242A

Ethyl 2- (4-amino-2-chlorophenoxy) -4-fluorobenzoate [0830] To a solution of ethyl 2,4-difluorobenzoate (6.48 g) and 4-amino-2-chlorophenol (5.0 g) in diglyme ( 40 ml) K was added₃AFTER₄ (7.39 g). The mixture was stirred at 110 ° C overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na₂SO₄. The mixture was filtered, and the solvent was evaporated and the residue was applied to a column and eluted with 10% ethyl acetate in hexane to give the product.

EXAMPLE 242B

Ethyl 2- (4-amino-2-chloro-5-iodophenoxy) -4-fluorobenzoate [0831] To a solution of EXAMPLE 242A (8.15 g) in dichloromethane (60 ml) was added bis (pyridine) iodonium tetrafluoroborate (9.79) g). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with an aqueous Na solution₂S₂ABOUT₃, water, brine and dried over Na₂SO₄. The mixture was filtered, and the solvent was evaporated and the residue was applied to a column and eluted with 10% ethyl acetate in hexane to give pure product.

EXAMPLE 242C

Ethyl 2- (4-amino-2-chloro-5 - ((trimethylsilyl) ethynyl) phenoxy) -4-fluorobenzoate [0832] For the mixture of EXAMPLE 242B (3.0 g), bis (triphenylphosphine) palladium (II) dichloride ( 242 mg), CuI (66 mg) in triethylamine (30 mL) was added trimethylsilylacetylene (2.2 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NH₄Cl, water, brine and dried over Na₂SO₄. The mixture was filtered, and the solvent was evaporated and the residue was applied to a column and eluted with 10% ethyl acetate in hexane to give pure product.

EXAMPLE 242D

Ethyl 2- (4-amino-2-chloro-5-ethynylphenoxy) -4-fluorobenzoate [0833] To a solution of EXAMPLE 242C (2.69 g) in methanol (20 ml) was added CsF (5 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (200 ml) and washed with water, brine and dried over Na₂SO₄. The mixture was filtered, and the solvent was evaporated.

EXAMPLE 242E

Ethyl 2- (6-chloro-1H-indol-5-yloxy) -4-fluorobenzoate [0834] To a solution of EXAMPLE 242D (1.0 g) in ethanol (20 ml) was added NaAuCl₄ 2H₂O (60 mg). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na₂SO₄. The mixture was filtered, and

157

The solvent was evaporated and the residue was applied to a column and eluted with 10% ethyl acetate in hexane to give pure product.

EXAMPLE 242F

Ethyl 2- (6-chloro-1H-indol-5-yloxy) -4- (piperazin-1-yl) benzoate [0835] The title compound was prepared as described in EXAMPLE 3G by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 242E, respectively .

EXAMPLE 242G

2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate ethyl [0836] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 242F and EXAMPLE 60D.

EXAMPLE 242H 2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1- acid yl) benzoic [0837] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 242G.

EXAMPLE 242I

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0838] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 49C, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.52 (m, 1H), 8.18 (d, 1H), 7.83 (dd, 1H), 7.53 (m, 2H), 7.40 (m, 1H), 7.33 (d, 3H), 7.18 (m, 1H), 7.04 (m, 4H), 6.62 (m, 1H), 6.38 (s, 1H) , 6.01 (d, 1H), 3.92 (m, 2H), 3.77 (m, 1H), 3.13 (m, 8H), 2.71 (s, 2H), 2.24 ( m, 8H), 1.95 (m, 6H), 1.52 (m, 6H), 0.94 (s, 6H).

EXAMPLE 243

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6,7-difluoro1H-indol- 5-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0839] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F EXAMPLE 200F. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.75 (s, 1H), 8.59 (t, 1H), 8.53 (d, 1H), 7.82 (dd, 1H), 7.49 (d, 1H), 7.41 (m, 1H), 7.34 (d, 3H), 7.12 (d, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.69 (dd, 1H) , 6.43 (d, 1H), 6.24 (d, 1H), 3.85 (m, 2H), 3.07 (m, 5H), 2.74 (m, 2H), 2.23 ( m, 6H), 1.92 (m, 5H), 1.60 (m, 3H), 1.30 (m, 4H), 0.94 (s, 6H).

EXAMPLE 244

2 - [(6-chloro-1H-in- dol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl } piperazin-1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0840] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 242H and EXAMPLE 184A, respectively.¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.24 (s, 1H), 9.19 (s, 1H), 8.52 (d, 1H), 7.88 (dd, 1H), 7.56 (m, 3H), 7.42 (t, 1H), 7.31 (m, 3H), 7.03 (d, 2H), 6.63 (dd, 1H), 6.41 (s, 1H), 5.98 (d, 1H) , 2.94 (m, 10H), 2.70 (s, 3H), 2.37 (m, 3H), 2.14 (m, 6H), 1.94 (s, 2H), 1.37 ( t, 2H), 0.91 (s, 6H).

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EXAMPLE 245

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[1- (1,3-thiazol-4-ylmethyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 245A

Tert-butyl 1- (thiazol-4-ylmethyl) piperidin-4-ylcarbamate [0841] The title compound was prepared by substituting thiazole-4-carboxaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and tert-butyl piperidin-4-ylcarbamate for piperazine. Tert-butyl carboxylate in EXAMPLE 1A

EXAMPLE 245B [0842] The title compound was prepared by substituting EXAMPLE 245A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 245C

3-nitro-4- (1- (thiazol-4-ylmethyl) piperidin-4-ylamino) benzenesulfonamide [0843] The title compound was prepared by substituting EXAMPLE 245B instead of (tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 245D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[1- (1,3-thiazol-4-ylmethyl) piperidin-4-yl] amino} phenyl) sulfonyl] benzamide [0844] The title compound was prepared by substitution of EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 245C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.16 (s, 1H), 9.08 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.29 -7.34 (m, 4H), 7.18 (d, 1H), 7.15 (m, 1H), 7.04 (d, 2H), 6.60 (dd, 1H), 6.37 ( s, 1H), 6.08 (s, 1H), 4.28 (s, 2H), 2.902.98 (m, 8H), 2.72 (s, 2H), 2.14-2.17 (m , 6H), 2.01 (m, 2H), 1.95 (s, 2H), 1.53-1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 246

2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3- nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0845] The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.60 (t, 1H), 8.42 (d, 1H), 7.71 (dd, 1H), 7.51 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.10 (d, 1H), 7.07 (d, 2H), 6.93 (dd, 1H), 6.79 (dd, 1H), 6.72 (dd, 1H) , 6.69 (t, 1H), 6.47 (d, 1H), 3.87 (dd, 2H), 3.21-3.32 (m, 4H), 3.20 (s, 4H), 2.81 (s, 2H), 2.27 (s, 4H), 2.16 (br s, 2H), 1.90-1.98 (m, 3H), 1.63-1.66 (m , 2H), 1.41 (t, 2H), 1.27-1.30 (m, 2H), 0.94 (s, 6H).

EXAMPLE 247

2- (4-amino-3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0846] The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE 1F in

EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.12 (s, 1H), 8.50 (d, 2H), 7.84 (dd, 1H), 7.58 (d, 1H), 7.32-7.34 (m, 2H) , 7.28 (d, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 7.04 (d, 2H), 6.58 (dd, 1H),

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6.34 (s, 1H), 6.07 (d, 1H), 3.63-3.70 (m, 6H), 2.96 (s, 4H), 2.71 (s, 2H), 2 ., 12-2.16 (m, 6H), 1.95 (s, 2H),

1.72-1.76 (m, 2H), 1.55-1.60 (m, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

EXAMPLE 248

N - [(4 - {[(4-Aminotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] -4- (4 - {[2- (4-chlorophenyl) -4,4- dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0847] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 191A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.12 (s, 1H), 8.50 (d, 1H), 7.84 (dd, 1H), 7.32-7.34 (m, 3H), 7.28 (d, 1H) , 7.15 (d, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 6.58 (dd, 1H), 6.34 (s, 1H), 6.07 ( d, 1H), 3.85-3.89 (m, 4H), 3.61-3.63 (m, 2H), 3.66-3.69 (m, 4H), 3.48-3, 51 (m, 2H), 2.96 (s, 4H), 2.71 (s, 2H), 2.14-2.18 (m, 6H), 1.95 (s, 2H), 1.72 -1.76 (m, 2H), 1.57-1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 249

4- (4- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl}} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(4 - {[(3S, 4R) -3-hydroxy-1- (1,3-thiazol-4-ylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 249A [0848] A mixture of tert-butyl (3S, 4R) -1-benzyl-3-hydroxypiperidin-4-ylcarbamate (0.42 g) and palladium hydroxide on carbon (0.095 g) in ethanol (15 ml) was hydrogenated with balloon with H₂. The reaction mixture was stirred for 16 hours. The solid was filtered off, and the filtrate was concentrated to give the title compound.

EXAMPLE 249B (3R, 4S) -3-hydroxy-1- (thiazol-4-ylmethyl) piperidin-4-ylcarbamate tert-butyl [0849] The title compound was prepared by substituting thiazole-4-carboxaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 249A instead of tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 249C (3R, 4S) -4-amino-1- (thiazol-4-ylmethyl) piperidin-3-ol [0850] The title compound was prepared by substituting EXAMPLE 249B for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 249D

4 - ((3S, 4R) -3-hydroxy-1- (thiazol-4-ylmethyl) piperidin-4-ylamino) -3-nitrobenzenesulfonamide [0851] The title compound was prepared by substituting EXAMPLE 249C for (tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 249E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl}} piperazin-1-yl) -2 - [(6-fluoro1H-indol-5 yl) oxy] -N - [(4 - {[(3S, 4R) -3-hydroxy-1- (1,3-thiazol-4-ylmethyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [0852] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 249D instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.64 (t, 1H), 9.07-9.09 (m, 1H), 8.60 (s, 1H), 8.57 (s, 1H) , 7.82 (d,

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EP-2507211B1PL

1H), 7.80 (s, 1H), 7.51 (d, 2H), 7.19-7.32 (m, 6H), 7.04 (d, 2H), 6.62-6.64 (m, 2H), 6.39 (s, 1H), 6.08 (s,

1H), 3.82 (m, 2H), 3.01 (s, 4H), 2.77 (s, 2H), 2.12-2.16 (m, 6H), 1.81 (m, 2H) ), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 250

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- ({[4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide

EXAMPLE 250A

4 - ((4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) methylamino) -3-nitrobenzenesulfonamide [0853] The title compound was prepared by substituting (4- (aminomethyl) tetrahydro-2H-pyran-4-yl) methanol for ( tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 250B

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- ({[4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl] methyl} amino) -3-nitrophenyl] sulfonyl} benzamide [0854] The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE 1F and EXAMPLE 250A for EXAMPLE 1G in EXAMPLE 1H . ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 9.11 (s, 1H), 8.44 (d, 1H), 7.72 (dd, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 7.17 -7.20 (m, 2H), 7.07 (d, 2H), 6.95 (dd, 2H), 6.78 (dd, 1H), 6.72 (dd, 1H), 6.69 ( t, 1H), 6.48 (d, 1H), 5.24 (t, 1H), 3.54-3.65 (m, 6H), 3.42 (d, 2H), 3.21 (s , 4H), 2.84 (s, 2H), 2.26-2.34 (m, 4H), 2.17-2.19 (m, 2H), 1.481.55 (m, 4H), 0, 95 (s, 6H).

EXAMPLE 251

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[3-nitro-4- (tetrahydro-2H-pyran-4-ylamino) phenyl] sulfonyl} benzamide [0855] The title compound was prepared by substituting tetrahydro-2H-pyran-4-amine for 2 -amino2- (tetrahydro-2H-pyran-4-yl) ethanol in EXAMPLE 240B. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 1H), 8.58 (d, 1H), 8.24 (d, 1H), 7.84 (dd, 1H), 7.52 (d, 1H), 7.38 (dd, 1H), 7.33 (m, 3H), 7.29 (d, 1H), 7.23 (d, 1H), 7.03 (d, 2H), 6.64 (dd, 1H) , 6.40 (s, 1H), 6.08 (s, 1H), 3.90 (m, 3H), 3.47 (m, 2H), 3.03 (br m, 4H), 2.73 (s, 2H), 2.19 (br m, 6H), 1.95 (s, 2H), 1.91 (br m, 2H), 1.60 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 252

4- (4- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl}} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[4- (morpholin-4-ylamino) -3-nitrophenyl] sulfonyl} benzamide

EXAMPLE 252A

4- (morpholinoamino) -3-nitrobenzenesulfonamide [0856] The title compound was prepared by substituting morpholin-4-amine for 4- (1-isopropylpiperidin-4-ylamino) -3-nitrobenzenesulfonamide in EXAMPLE 41A.

EXAMPLE 252B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[4- (morpholin-4-ylamino) -3-nitrophenyl] sulfonyl} benzamide [0857] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 252A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 12.38 (s, 1H), 9.26 - 9.30 (m, 2H), 8.48 (dd, 1H), 8.14 (d, 1H), 7.71 (d, 1H) , 7.51 (t, 1H), 7.46 - 7.50

161

EP-2507211B1PL (m, 2H), 7.41 - 7.45 (m, 3H), 7.04 (d, 2H), 6.71 (dd, 1H), 6.54 - 6.58 (m, 2H), 3.86 (s, 2H), 3.71 (s, 2H),

3.01 - 3.07 (m, 4H), 2.89 (d, 4H), 2.74 (s, 2H), 2.23 (t, 2H), 2.07 - 2.13 (m, 4H), 1.96 (s, 2H), 1.38 (t, 2H),

0.92 (s, 6H).

EXAMPLE 253 2- (3-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- (morpholin-4-ylamino) -3-nitrophenyl] sulfonyl} benzamide The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE 1F and EXAMPLE 252A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 9.26 (s, 1H), 9.13 (d, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 7.67 (d, 1H), 7.46 (d, 2H), 7.10-7.16 (m, 3H), 7.08 (t, 1H), 7.02 (d, 1H), 6.93 (dd, 1H), 6.82 ( dd, 1H), 6.69 (d, 1H), 3.88 (s, 2H), 3.77 (s, 2H), 3.27 (s, 2H), 3.13 - 3.19 (m , 4H), 2.93 (s, 4H), 2.84 (s, 2H), 2.31 (t, 2H), 2.23 - 2.28 (m, 4H), 2.00 (s, 2H), 1.42 (t, 2H), 0.97 (s, 6H).

EXAMPLE 254

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(3- nitro-4 - {[3- (3-oxopiperazin-1-yl) propyl] amino} phenyl) sulfonyl] benzamide EXAMPLE 254A

3-nitro-4- [3- (3-oxo-piperazin-1-yl) -propylamino] -benzenesulfonamide [0859] The title compound was prepared by substituting 4- (3-aminopropyl) piperazin-2-one for 4 aminopiperidine-1 tert-butyl carboxylate in EXAMPLE 140A.

EXAMPLE 254B

2- (2-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(3- nitro-4 - {[3- (3-oxopiperazin-1-yl) propyl] amino} phenyl) sulfonyl] benzamide [0860] The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE 1F and EXAMPLE 254A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.85 (t, 1H), 8.47 (d, 1H), 7.80-7.72 (m, 2H), 7.51 (d, 1H), 7.41 (dd, 1H) , 7.36 (d, 2H), 7.18-7.03 (m, 4H), 7.00 (td, 1H), 6.75 (dd, 1H), 6.71 (d, 1H), 6.30 (d, 1H), 3.46 (q, 2H), 3.22-3.11 (m, 6H), 2.97 (s, 2H), 2.79 (br s, 2H), 2.59 (t, 2H), 2.47 (t, 2H), 2.31-2.12 (m, 6H), 1.97 (br s, 2H), 1.82 (m, 2H), 1.46 9t, 2H), 0.94 (s, 6H).

EXAMPLE 255

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

EXAMPLE 255A

Methyl 2- (6-aminopyridin-3-yloxy) -4-fluorobenzoate [0861] A mixture of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (1.039 g), CsF (1.956 g), bis (triphenylphosphine) palladium (II) dichloride (0.301 g), and methyl 2-bromo-4-fluorobenzoate (1.0 g) in 50 ml of dimethoxyethane-methanol (1: 1) heated at 80 ° C for 2.5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was chromatographed on silica gel with 25-80% ethyl acetate in hexane.

EXAMPLE 255B

Methyl 2- (6-aminopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate

162

[0862] The title compound was prepared by substituting EXAMPLE 255A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 255C

2- (6- (tert-butoxycarbonylamino) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) methyl benzoate [0863] The title compound was prepared by substituting EXAMPLE 255B for EXAMPLE 219B in EXAMPLE 219C.

EXAMPLE 255D 2- (6- (tert-butoxycarbonylamino) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl acid ) benzoic [0864] The title compound was prepared by substituting EXAMPLE 255C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 255E

5- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-nitro-4- (1- (tetrahydro -2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonylcarbamoyl) phenoxy) pyridin-2-ylcarbamate tert-butyl [0865] The title compound was prepared by substituting EXAMPLE 255D instead of EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G, respectively.

EXAMPLE 255F

2- (6-aminopyridin-3-yl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0866] The title compound was prepared by substituting EXAMPLE 255E for EXAMPLE 1A in EXAMPLE 1B. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 0.96 (s, 6H) 1.42 (t, 2H) 1.61 - 1.75 (m, 2H) 1.92 - 2.05 (m, 6H) 2.21 (s, 5H) 2.28 - 2.42 (m, 3H) 2.80 - 3.57 (m, 14H) 3.95 - 4.00 (m, 2H) 6.31 (d, 1H) 6.68 (d, 1H) 6.82 (dd, 1H) 7.08 (d, 2H) 7.15 (s, 1H) 7.28-7.41 (m, 4H) 7.68 (d, 1H) 7.85 ( dd, 1H)

8.22 (s, 1H) 8.50 (d, 1H).

EXAMPLE 256

4- (4- {1- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] ethyl} piperazin-1-yl) -2 - [(6-fluoro-1Hindol- 5-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide EXAMPLE 256A

4- (4- (1- (2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) ethyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5-yloxy) benzoate methyl [0867] The title compound was prepared as described in EXAMPLE 110D by replacing EXAMPLE 34A with EXAMPLE 154B.

EXAMPLE 256B 4- (4- (1- (2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) ethyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5- iloxy) benzoic [0868] The title compound was prepared as described in EXAMPLE 110E by replacing EXAMPLE 110D with EXAMPLE 256A.

163

EP-2507211B1PL

EXAMPLE 256C

4- (4- {1- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] ethyl} piperazin-1-yl) -2 - [(6-fluoro-1Hindol- 5-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0869] The title compound was prepared as described in EXAMPLE 110F by replacing

EXAMPLE 110E EXAMPLE 256B. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.29 (s, 1H),

11.22 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 7.86 (d, 1H), 7.52 (d, 1H), 7.27 - 7 , 40 (m, 5H), 7.15 (d, 1H), 7.02 (d, 2H), 6.60 - 6.68 (m, 1H), 6.40 (s, 1H), 6, 08 (d, 1H), 3.84 (dd, 2H), 3.20 - 3.32 (m, 4H), 3.01 (s, 4H), 2.59 - 2.72 (m, 1H) , 2.16 - 2.31 (m, 4H), 1.75 - 2.12 (m, 5H), 1.58 - 1.65 (m, 2H), 1.31 - 1.41 (m, 2H), 1.20 - 1.29 (m, 2H), 1.01 (d, 3H), 0.91 (s, 3H), 0.90 (s, 3H).

EXAMPLE 257

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-4- yl) oxy] -N - [(3-nitro-4 - {[3- (3-oxopiperazin-1-yl) propyl] amino} phenyl) sulfonyl] benzamide [0870] The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE 1F and EXAMPLE 254A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.23 (br s, 1H), 8.75 (t, 1H), 8.43 (d, 1H), 7.74 (br s, 1H), 7.61 (dd, 1H), 7 , 51 (d, 1H), 7.35 (d, 2H), 7.24 (t, 1H), 7.05 (d, 2H), 6.95 (d, 1H), 6.85 (dd, 1H), 6.76 (dd, 1H), 6.42 (d, 1H), 6.26 (t, 1H), 6.06 (dd, 1H), 3.43 (q, 2H), 3, 20-3.08 (m, 6H), 2.97 (br s, 2H), 2.76 (br s, 2H), 2.57 9t, 2H), 2.47 (t, 2H), 2, 27-2.12 (m, 6H), 1.97 (br s, 2H), 1.80 (m, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 258

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[(3S) tetrahydro-2H-pyran-3-ylmethyl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 258A [0871] The title compound was prepared by substituting (tetrahydro-2H-pyran-3-yl) methanamine for 1- (tetrahydropyran-4-yl) methylamine in EXAMPLE 1G.

EXAMPLE 258B (S) -3-nitro-4 - ((tetrahydro-2H-pyran-3-yl) methylamino) benzenesulfonamide [0872] The racemic mixture of EXAMPLE 258A was separated by chiral SFC on an AD column (21 mm ID x 250) mm long), using a gradient of 10-30% 0.1% diethylaminomethanol in CO₂for 15 minutes (oven temperature: 40 ° C; flow rate: 40 ml / minute) to afford the title compound.

EXAMPLE 258C (R) -3-nitro-4 - ((tetrahydro-2H-pyran-3-yl) methylamino) benzenesulfonamide [0873] The racemic mixture of EXAMPLE 258A was separated by chiral SFC on an AD column (21 mm ID x 250) mm long), using a gradient of 10-30% 0.1% diethylaminomethanol in CO₂for 15 minutes (oven temperature: 40 ° C; flow rate: 40 ml / minute) to afford the title compound.

EXAMPLE 258D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[(3S) tetrahydro-2H-pyran-3-ylmethyl] amino} phenyl) sulfonyl] benzamide

164

EP-2507211B1EN [0874] The title compound was prepared as described in EXAMPLE 110F by replacing

EXAMPLE 110E and EXAMPLE 1G EXAMPLE 154E and EXAMPLE 258B, respectively. ¹H

NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.22 (s, 2H), 8.50 - 8.65 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H) , 7.28 - 7.35 (m, 4H), 7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 3.79 (dd, 1H), 3.68 - 3.74 (m, 1H), 3.14 - 3.32 (m, 4H), 3.03 (s, 4H), 2.73 (s, 2H), 2.08 - 2.25 (m, 6H), 1.78 1.97 (m, 4H), 1.55 - 1.66 (m, 1H), 1.41 - 1.52 (m, 1H), 1.23 - 1.40 (m, 3H), 0.92 (s, 6H).

EXAMPLE 259

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[(3R) -tetrahydro-2H-pyran-3-ylmethyl] amino} phenyl) sulfonyl] benzamide [0875] The title compound was prepared as described in EXAMPLE 110F by replacement of EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 258C, respectively. ¹H

NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.22 (s, 2H), 8.50 - 8.65 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H) , 7.28 - 7.35 (m, 4H), 7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 3.79 (dd, 1H), 3.68 - 3.74 (m, 1H), 3.14 - 3.32 (m, 4H), 3.03 (s, 4H), 2.73 (s, 2H), 2.08 - 2.25 (m, 6H), 1.78 1.97 (m, 4H), 1.55 - 1.66 (m, 1H), 1.41 - 1.52 (m, 1H), 1.23 - 1.40 (m, 3H), 0.92 (s, 6H).

EXAMPLE 260

5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) -3,4-dihydroisoquinoline-2 (1H) tert-butyl carboxylate

EXAMPLE 260A

Tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2 (1H) carboxylate [0876] Mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol hydrochloride (1.0 g), di-tert-butyl dicarbonate (1.27 g) and 1.0 N aqueous NaOH (14.5 mL) in dioxane (20 mL) were stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with a 5% aqueous HCl solution. The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.

EXAMPLE 260B

Tert-butyl 5- (2- (ethoxycarbonyl) -5-fluorophenoxy) -3,4-dihydroisoquinoline-2 (1H) -carboxylate [0877] The title compound was prepared by substituting EXAMPLE 260A for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 260C

5- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (ethoxycarbonyl) phenoxy) -3,4-dihydroizochinolino- Tert-butyl 2 (1H) -carboxylate [0878] The title compound was prepared by substituting EXAMPLE 260B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 260D 2- (2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) 4,4-dimethylcyclohex-1 acid -enyl) methyl) piperazin-1-yl) benzoic [0879] The title compound was prepared by substituting EXAMPLE 260C for EXAMPLE 1E in EXAMPLE 1F.

165

EP-2507211B1PL

EXAMPLE 260E 2- (2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1- anhydride 3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonic acid enyl) methyl) piperazin-1-yl) benzoic [0880] The title compound was prepared by substituting EXAMPLE 260D for EXAMPLE 1F in EXAMPLE 1F. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.63 (s, 1H), 8.45 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.15 (d, 1H), 7.06 (d, 2H), 6.97 (t, 1H), 6.80 (d, 1H), 6.73 (dd, 1H), 6.37 (d, 1H) , 6.31 (d, 1H), 4.48 (s, 2H), 3.86 (dd, 2H), 3.53 (t, 2H), 3.14 (s, 4H), 2.67- 2.75 (m, 2H), 2.16-2.30 (m, 6H), 1.63 (d, 2H), 1.43 (s, 9H), 0.94 (s, 6H).

EXAMPLE 261

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

EXAMPLE 261A 4-Fluoro-2- (6-nitro-pyridin-3-yloxy) benzoic acid methyl ester [0881] Methyl 4-Fluoro-2-hydroxybenzoate (3.00 g), 5-chloro-2-nitropyridine (3 , 08 g), and potassium carbonate (4.87 g) were added to dimethyl sulfoxide (50 mL), heated to 110 ° C for one hour, cooled, added to water, and extracted with ethyl ether. The ether was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexane, increasing to 20% ethyl acetate in hexane and increasing again to 30% ethyl acetate in hexane.

EXAMPLE 261B 2- (6-Amino-pyridin-3-yloxy) -4-fluoro-benzoic acid methyl ester EXAMPLE 261A (1015 mg), cyclohexene (3.52 mL, 2853 mg), and 10% palladium on carbon ( 100 mg) was added to ethanol (12 ml) and ethyl acetate (4 ml) and heated at 75 ° C for three hours. The solution was cooled and filtered under reduced pressure through diatomaceous earth. The solvent was removed under reduced pressure.

EXAMPLE 261C 2- (6-Amino-pyridin-3-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1- acid methyl ester yl} benzoic [0883] The title compound was prepared by substituting EXAMPLE 261B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 261D 2- (6-Amino-pyridin-3-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazine-1- acid yl} benzoic [0884] The title compound was prepared by substituting EXAMPLE 261C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 261E

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

166

[0885] The title compound was prepared by substituting EXAMPLE 261D for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.53 (br s, 1H), 8.19 (br s, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.47 (d, 1H), 7.36 (d, 2H), 7.25-7.14 (m, 1H), 7.10 (m, 1H), 7.07 (d, 2H), 6.58 (dd, 1H), 6 , 43 (d, 1H), 6.10 (br s, 1H), 5.81 (m, 2H), 3.94 (d, 2H), 3.03 (br s, 6H), 2.73 ( m, 2H), 2.24-2.12 (m, 8H), 2.09-2.00 (m, 2H), 1.97 (br s, 2H), 2.09-2.00 (m , 2H), 1.84-1.74 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.47 (m, 4H), 1.40 (t, 2H ), 0.94 (s, 6H).

EXAMPLE 262

4- (4 - {[2- (4-chlorophenyl) -5,5-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide EXAMPLE 262A

Methyl 5,5-dimethyl-2- (trifluoromethylsulfonyloxy) cyclohex-1-enocarboxylate [0886] The title compound was prepared by substituting 4,4-dimethyl-2-methoxycarbonylcyclohexanone for 5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 3B.

EXAMPLE 262B

Methyl 2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enocarboxylate [0887] The title compound was prepared by substituting EXAMPLE 262A for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 262C (2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enyl) methanol [0888] The title compound was prepared by substituting EXAMPLE 262B for EXAMPLE 3C in EXAMPLE 3D.

EXAMPLE 262D

2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enocarboxaldehyde [0889] The title compound was prepared as described in EXAMPLE 53F by replacing EXAMPLE 53E with EXAMPLE 262C.

EXAMPLE 262E

Tert-butyl 4 - ((2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enyl) methyl) piperazine-1-carboxylate [0890] The title compound was prepared as described in EXAMPLE 1A by replacing 4'-chlorobiphenyl-2 -carboxaldehyde EXAMPLE 262D.

EXAMPLE 262F

1- ((2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enyl) methyl) piperazine [0891] The title compound was prepared as described in EXAMPLE 110C by replacing EXAMPLE 110B with EXAMPLE 262E.

EXAMPLE 262G

Methyl 4- (4 - ((2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5-yloxy) benzoate [ 0892] The title compound was prepared as described in EXAMPLE 110D by replacing EXAMPLE 34A and EXAMPLE 110C with EXAMPLE 154B and EXAMPLE 262F, respectively.

EXAMPLE 262H 4- (4 - ((2- (4-chlorophenyl) -5,5-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6-fluoro-1H-indol-5-yloxy) acid benzoic acid

167

EP-2507211B1EN [0893] The title compound was prepared as described in EXAMPLE 110E by replacing

EXAMPLE 110D EXAMPLE 262G.

EXAMPLE 262I

4- (4 - {[2- (4-chlorophenyl) -5,5-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0894] The title compound was prepared as described in EXAMPLE 110F by replacing

EXAMPLE 110E EXAMPLE 262H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.27 (s, 1H),

11.22 (s, 1H), 8.61 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t , 1H), 7.31 - 7.36 (m, 3H), 7.30 (d, 1H), 7.16 (d, 1H), 7.07 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.08 (d, 1H), 3.84 (dd, 2H), 3.22 - 3.32 (m, 4H), 3.02 (s, 4H ), 2.68 (s, 2H), 2.17 (s, 6H), 1.84 - 1.96 (m, 3H), 1.57 - 1.65 (m, 2H), 1.39 ( t, 2H), 1.20 1.31 (m, 2H), 0.92 (s, 6H).

EXAMPLE 263

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(2-methoxyethyl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 263A

4- (2-methoxyethylamino) -3-nitrobenzenesulfonamide [0895] The title compound was prepared by substituting 2-methoxyethanamine for 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 263B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(2-methoxyethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0896] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.28 (s, 1H), 11.21 (s, 1H), 8.58 (m, 2H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.32 (m, 5H), 7.15 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.10 (m, 1H) , 3.58 (m, 4H), 3.30 (s, 3H), 3.04 (m, 4H), 2.73 (s, 2H), 2.17 (m, 6H), 1.95 ( s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 264

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[3-nitro-4- (tetrahydro-2H-pyran-4-ylmethoxy) phenyl] sulfonyl} benzamide EXAMPLE 264A

3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzenesulfonamide [0897] (Tetrahydro-2H-pyran-4-yl) methanol (2.0 g) in tetrahydrofuran (20 ml) was treated with 60% NaH (1.377 g). The solution was stirred for 20 minutes at room temperature. To this solution, 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) was added in portions. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% HCl, and extracted with ethyl acetate three times.

The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 20% -60% ethyl acetate in hexane.

EXAMPLE 264B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - {[3-nitro-4- (tetrahydro-2H-pyran-4-ylmethoxy) -phenyl] sulfonyl} benzamide

168

[0898] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 264A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.12 (s, 1H), 8.10 (d, 1H), 7.52 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 7.33 -7.35 (m, 3H), 7.28 (d, 1H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.10 ( s, 1H), 4.09 (d, 2H), 3.88 (dd, 2H),

3.05 (s, 4H), 2.80 (br s, 2H), 2.03-2.20 (m, 6H), 1.63-1.65 (m, 2H), 1.33-1 , 40 (m, 4H), 0.92 (s, 6H).

EXAMPLE 265

2 - [(3-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 265A

Ethyl 2- (1H-indol-5-yloxy) -4-fluorobenzoate [0899] The title compound was prepared by substituting 5-indolol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 265B

Ethyl 2- (3-chloro-1H-indol-5-yloxy) -4-fluorobenzoate [0900] N-Chloro-succinimide (160 mg) was added portionwise to a solution of EXAMPLE 265A (300 mg) in toluene (10 mL) and the mixture stirred at room temperature for about two hours. The mixture was chromatographed on a silica gel column using 30% ethyl acetate in hexane to afford the title compound.

EXAMPLE 265C

2- (3-chloro-1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate ethyl [0901] The title compound was prepared by substituting EXAMPLE 265B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 265D 2- (3-chloro-1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1- acid yl) benzoic [0902] The title compound was prepared by substituting EXAMPLE 265C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 265E

2- (3-chloro-1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide [0903] The title compound was prepared by substituting EXAMPLE 265D for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.42 (s, 1H), 11.30 (br s, 1H), 8.60 (t, 1H), 8.54 (d, 1H), 7.78 (dd, 1H), 7, 55 (d, 1H), 7.50 (d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H ), 7.00 (d, 1H), 6.92 (dd, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 3.85 (dd, 2H), 3.28 (dd, 2H), 3.07 (m, 4H), 2.75 (m, 2H), 2.25-2.15 (m, 6H), 1.95 (br.s, 2H), 1, 90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).

EXAMPLE 266

2 - [(3-chloro-1H-indol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

169

EP-2507211B1PL

EXAMPLE 266A

Ethyl 2- (1H-indol-4-yloxy) -4-fluorobenzoate [0904] The title compound was prepared by substituting 4-indolol for 2-methyl-5-indolol in

EXAMPLE 3A.

EXAMPLE 266B

Ethyl 2- (3-chloro-1H-indol-4-yloxy) -4-fluorobenzoate [0905] The title compound was prepared by substituting EXAMPLE 266A for EXAMPLE 265A in EXAMPLE 265B.

EXAMPLE 266C

2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate ethyl [0906] The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 266D 2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1- acid yl) benzoic [0907] The title compound was prepared by substituting EXAMPLE 266C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 266E

2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide [0908] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.56 (s, 1H), 11.00 (br s, 1H), 8.64 (t, 1H), 8.54 (d, 1H), 7.81 (dd, 1H), 7, 58 (d, 1H), 7.45 (d, 1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.16 (d, 2H), 7.10 (t, 1H ), 7.03 (d, 2H), 6.68 (dd, 1H), 6.62 (d, 1H), 6.10 (d, 1H), 3.85 (dd, 2H), 3.26 (t, 2H), 3.02 (br.s, 4H), 2.73 (br.s, 2H), 2.20-2.10 (m, 6H), 1.95 (br.s, 2H) ), 1.90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).

EXAMPLE 267

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4- [(tetrahydro -2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-5-yl) oxy] benzamide [0909] Solution of EXAMPLE 265E (38 mg) in ethanol (5 mL) and 1 N aq. HCl (5 mL) were stirred at 85 ° C for 7 hours. The mixture was cooled to ambient temperature and concentrated. The residue was purified by reverse phase HPLC on a C18 column using a water-acetonitrile gradient with ammonium acetate buffer to afford the title compound. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.30 (br s, 1H), 10.33 (s, 1H), 8.61 (t, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7, 47 (d, 1H), 7.35 (d, 2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.84 (s, 1H), 6.80 (d, 1H ), 6.74 (d, 1H), 6.67 (dd, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.43 (s, 2H), 3.27 (t, 2H), 3.10 (br.s, 4H), 2.77 (br.s, 2H), 2.25-2.10 (m, 6H), 1.97 (br.s, 2H) ), 1.90 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).

170

EP-2507211B1PL

EXAMPLE 268

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4- [(tetrahydro -2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide [0910] The title compound was prepared by substituting EXAMPLE 266E for EXAMPLE

265E in EXAMPLE 267. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.50 (br s, 1H), 10.40 (s, 1H), 8.59 (t, 1H), 8.54 (d, 1H), 7.72 (d, 1H), 7, 47 (d, 1H), 7.35 (d, 2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.96 (t, 1H), 6.75 (dd, 1H ), 6.46 (d, 1H), 6.44 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.28 (t, 2H), 3.25 (s, 2H), 3.19 (br.s, 4H), 2.82 (br.s, 2H), 2.28 (br.s, 4H), 2.18 (m, 2H), 1, 98 (br.s, 2H), 1.90 (m, 1H), 1.63 (d, 2H), 1.41 (t, 2H), 1.27 (m, 2H), 0.94 (s , 6H).

EXAMPLE 269

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-4- yl) oxy] -N - ({4 - [(2-methoxyethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0911] The title compound was prepared by substituting EXAMPLE 209G instead of EXAMPLE 1F and EXAMPLE 263A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.22 (br s, 1H), 8.55 (t, 1H), 8.43 (d, 1H), 7.61 (dd, 1H), 7.51 (d, 1H), 7, 35 (d, 2H), 7.24 (t, 1H), 7.05 (d, 2H), 7.00 (d, 1H), 6.89 (dd, 1H), 6.77 (dd, 1H ), 6.43 (d, 1H), 6.26 (t, 1H), 6.06 (t, 1H), 3.63-3.51 (m, 4H), 3.32 (s, 3H) , 3.13 (br s, 4H), 2.78 (br s, 2H), 2.31-2.12 (m, 6H), 1.97 (br s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 270

5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate

EXAMPLE 270A

2- (6- (bis (tert-butoxycarbonyl) amino) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4dimetylocykloheks-1-enyl) methyl) piperazin-1- methyl) benzoate [0912] EXAMPLE 261C (1080 mg) was dissolved in acetonitrile (12 ml) and 4-dimethylaminopyridine (47 mg) and di-tert-butyl dicarbonate (462 mg) were added. The solution was stirred at room temperature for 16 hours, the solvent volume was reduced, and the material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane.

EXAMPLE 270B 2- (6-tert-butoxycarbonylamino-pyridin-3-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazine-1- acid yl} benzoic [0913] The title compound was prepared by substituting EXAMPLE 270A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 270C

5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [tetrrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate [0914] The title compound was prepared by substituting EXAMPLE 270B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.72 (s, 1H), 8.61 (t, 1H), 8.55 (d, 1H), 7.95 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 1H), 7.47 (d, 1H), 7.36 (d, 2H), 7.32 (dd, 1H), 7.19 (d, 1H), 7.06

171

EP-2507211B1PL (d, 2H), 6.70 (dd, 1H), 6.27 (d, 1H), 3.86 (dd, 2H), 3.13 (br s, 4H), 2.78 ( br s, 2H), 2.54 (m, 1H), 2.45 (m,

1H), 2.29-2.13 (m, 6H), 1.97 (br s, 2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.48 (s, 9H), 1.40 (t, 2H), 1.34-1.20 (m,

4H), 0.94 (s, 6H).

EXAMPLE 271

4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [(1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate

EXAMPLE 271A 2- (2-Amino-pyridin-4-yloxy) -4-fluoro-benzoic acid methyl ester [0915] The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and 2-aminopyridin-4-ol instead 2-methyl-5-indolol in EXAMPLE 3A, except that the heating took place at 130 ° C.

EXAMPLE 271B 2- (2-Amino-pyridin-4-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethylcyclohex-1-enylmethyl] -piperazin-1- acid methyl ester yl} benzoic [0916] The title compound was prepared by substituting EXAMPLE 271A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 271C

2- (2- (bis (tert-butoxycarbonyl) amino) pyridin-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4dimetylocykloheks-1-enyl) methyl) piperazin-1- methyl) benzoate [0917] The title compound was prepared by substituting EXAMPLE 271B for EXAMPLE 261C in EXAMPLE 270A.

EXAMPLE 27 1 D 2- (2-tert-butoxycarbonylamino-pyridin-4-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethylcyclohex-1-enylmethyl] piperazinic acid 1-yl} benzoic [0918] The title compound was prepared by substituting EXAMPLE 271C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 271E

4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [(1-tetrahydro-2H-pyran-4-yl-piperidin-4-yl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate [0919] The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.32 (br s, 1H), 8.42 (m, 1H), 8.21 (d, 1H), 8.02 (m, 1H), 7.76 (m, 1H), 7, 58 (d, 1H), 7.40-7.34 (m, 2H), 7.26 (m, 1H), 7.20-6.95 (m, 4H), 6.67 (d, 1H) , 6.30 (br s, 1H), 3.99-3.90 (m, 3H), 3.89 (m, 1H), 3.07 (br s, 4H), 2.76 (br s, 2H), 2.42-2.32 (m, 1H), 2.30-2.14 (m, 8H), 2.13-2.03 (m, 2H),

20.2-1.95 (m, 3H), 1.90-1.65 (m, 6H), 1.60-1.49 (m, 2H), 1.40 (t, 2H), 1, 31 (t, 9H), 0.94 (s, 6H).

EXAMPLE 272

2 - [(6-aminopyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

172

[0920] The title compound was prepared by substituting EXAMPLE 270C for EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.64 (t, 1H), 8.60 (d, 1H), 7.89 (dd,

1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.24 (d, 1H), 7.18 (dd, 1H), 7, 06 (d, 2H), 6.61 (dd, 1H), 6.47 (d, 1H), 6.07 (d, 1H), 5.90 (br s, 2H), 3.85 (dd, 2H), 3.07 (br s, 4H), 2.75 (br s, 2H), 2.28-2.11 (m, 10H),

1.97 (br s, 2H), 1.92 (m, 1H), 1.63 (dd, 2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 ( s, 6H).

EXAMPLE 273

2 - [(2-aminopyridin-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0921] The title compound was prepared by substituting EXAMPLE 271E for EXAMPLE 1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.49 (br s, 1H), 8.16-8.06 (m, 1H), 7.86 (dd, 1H), 7.70 (dd, 1H), 7.44 (d, 1H ), 7.40-7.35 (m, 2H), 7.16-7.09 (m, 2H), 7.07 (d, 2H), 6.59 (d, 1H), 6.45 ( dd, 1H), 6.19 (d, 1H), 3.96-3.89 (m, 3H), 3.81 (m, 1H), 3.00 (br s, 4H), 2.93- 2.77 (m, 2H), 2.74 (br s, 2H), 2.29-2.11 (m, 8H), 2.09-1.95 (m, 4H), 1.90-1 , 46 (m, 8H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 274

2 - [(5-bromopyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 274A

Methyl 2- (5-bromopyridin-3-yloxy) -4-fluorobenzoate [0922] To a solution of 5-bromopyridin-3-ol (1.060 g) in 2-methyltetrahydrofuran (15 ml), potassium tert-butoxide (6.09) was added dropwise. ml, 1.0M in tetrahydrofuran). After stirring for 5 minutes, methyl 2,4-difluorobenzoate (1.049 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) and the reaction was heated to 75 ° C. N, N-dimethylformamide (2 mL) was added to the reaction and the reaction stirred overnight. The reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel (SF40-80) using a 5% to 35% ethyl acetate / hexane gradient as eluent gave the product.

EXAMPLE 274B

Methyl 2- (5-bromopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0923] The title compound was prepared by substituting EXAMPLE 274A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 274C 2- (5-Bromopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 0924] The title compound was prepared by substituting EXAMPLE 274B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 274D

2 - [(5-bromopyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

173

[0925] The title compound was prepared by substituting EXAMPLE 274C for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.99 - 11.42 (m, 1H), 8.62 (s, 1H),

8.42 (d, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 7.71 (dd, 1H), 7.54 (d, 1H), 7.37 (d , 2H), 7.19 (t, 1H), 7.09 (t, 3H),

6.81 (dd, 1H), 6.59 (d, 1H), 3.87 (dd, 2H), 3.44 - 3.15 (m, 8H), 2.88 (s, 2H), 2 , 33 (s, 4H), 2.19 (s, 2H),

1.97 (d, 3H), 1.66 (d, 2H), 1.50 - 1.20 (m, 4H), 0.97 (d, 6H).

EXAMPLE 275

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-piran- 3-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 275A

2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl ) ethyl piperazin-1-yl) benzoate [0926] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 38F with EXAMPLE 242F.

EXAMPLE 275B 2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran- 3yl) methyl) piperazin-1-yl) benzoic [0927] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 275A.

EXAMPLE 275C

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-piran- 3yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0928] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and EXAMPLE 1G, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.27 (s, 1H), 11.19 (m, 1H), 8.62 (t, 1H), 8.58 (d, 1H), 7.84 (dd, 1H), 7.54 (m, 3H), 7.43 (m, 1H), 7.36 (m, 3H), 7.14 (m, 3H), 6.66 (dd, 1H), 6.43 (s, 1H) , 6.00 (d, 1H), 4.10 (s, 2H), 3.85 (dd, 1H), 3.24 (m, 2H), 3.02 (m, 4H), 2.85 ( m, 2H), 2.16 (m, 6H), 1.90 (m, 1H), 1.62 (m, 2H), 1.28 (m, 4H), 1.18 (s, 6H).

EXAMPLE 276

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0929] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F EXAMPLE 242H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.27 (s, 1H), 11.12 (m, 1H), 8.60 (m, 2H), 7.85 (dd, 1H), 7.54 (m, 2H), 7.44 (m, 1H), 7.33 (d, 3H), 7.16 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.43 (s, 1H) , 6.00 (d, 1H), 3.85 (m, 2H), 3.28 (m, 4H), 3.02 (m, 4H), 2.73 (s, 2H), 2.15 ( m, 4H), 1.93 (m, 4H), 1.61 (m, 3H), 1.29 (m, 4H), 0.92 (s, 6H).

EXAMPLE 277

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6fluoro- 1H-indol-5-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

174

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EXAMPLE 277A

4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2- (6-fluoro-1 H methyl indol-5-yloxy) benzoate [0930] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE

38F EXAMPLE 154C.

EXAMPLE 277B 4- (4 - ((4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2 (6) acid -fluoro-1H-indol-5-yloxy) benzoic [0931] The title compound was prepared as described in EXAMPLE 38H by replacing EXAMPLE 38G with EXAMPLE 277A.

EXAMPLE 277C

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6fluoro- 1H-indol-5-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0932] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F with EXAMPLE 277B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.30 (m, 1H), 11.21 (s, 1H), 8.61 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.37 (m, 3H), 7.30 (m, 1H), 7.15 (m, 3H), 6.66 (dd, 1H), 6.41 (m, 1H), 6.09 (d, 1H) , 4.10 (s, 2H), 3.84 (dd, 2H), 3.28 (m, 4H), 3.03 (m, 4H), 2.82 (s, 2H), 2.23 ( m, 5H), 1.89 (m, 1H), 1.62 (m, 2H), 1.26 (m, 4H), 1.19 (s, 6H).

EXAMPLE 278

5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-3-ylcarbamate

EXAMPLE 278A

Methyl 2- (5- (tert-butoxycarbonylamino) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0933] EXAMPLE 274B (0.135 g), tert-butyl carbamate (0.028 g) and cesium carbonate (0.106 g) were mixed together in dioxane (2 mL). Diacetoxypalladium (2.425 mg) and (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine) (0.012 g) were added and the reaction was degassed with nitrogen, then sealed and heated to 85 ° C. The reaction was stirred for 16 hours, cooled, loaded onto silica gel (40 g) and eluted using a 0.5% to 7.5% methanol / dichloromethane gradient to afford the product.

EXAMPLE 278B 2- (5- (tert-butoxycarbonylamino) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl acid ) benzoic [0934] The title compound was prepared by substituting EXAMPLE 278A for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 278C

5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-3-ylcarbamate

175

[0935] The title compound was prepared by substituting EXAMPLE 278B for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, CDCl₃) δ 9.75 (s, 1H), 8.84 (d, 1H), 8.51 (d, 1H), 8.32 (d, 1H),

8.13 (dd, 1H), 8.08 (d, 1H), 7.92 (d, 1H), 7.87 (s, 1H), 7.24 (d, 2H), 6.92 (dd , 3H), 6.65 (s, 1H), 6.58 (dd,

1H), 6.06 (d, 1H), 4.02 (dd, 2H), 3.42 (dd, 2H), 3.32 - 3.21 (m, 2H), 3.14 (s, 4H ), 2.77 (s, 2H), 2.22 (d,

6H), 1.98 (s, 3H), 1.70 (t, 2H), 1.56 - 1.36 (m, 13H), 0.95 (s, 6H).

EXAMPLE 279

2 - [(5-aminopyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0936] To EXAMPLE 278C (0.050 g) in dichloromethane (2 mL) was added trifluoroacetic (0.061 mL) and the reaction was stirred at room temperature. After 19 hours of stirring, the reaction was concentrated and then dried under high vacuum. The residue was dissolved in dichloromethane (1 mL) and neutralized with N, N-diisopropylethylamine (0.028 mL). The solution was loaded onto silica gel (GraceResolv 12 g) and the product eluted using a gradient of 0.5% methanol / dichloromethane to 5% methanol / dichloromethane over 30 minutes (flow = 30 ml / min) to afford the title compound.¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H), 8.50 (s, 1H), 8.11 (dd, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.30 - 7.14 (m, 2H), 7.01- 6.83 (m, 3H), 6.69 (t, 1H), 6.58 (dd, 1H), 6.10 (d, 1H), 4.10 - 3.98 (m, 2H), 3.88 (s, 2H), 3.42 (dd, 2H), 3.34 - 3.20 (m, 2H), 3.14 (d, 4H), 2.78 (s, 2H), 2.22 (d, 6H), 1.99 (s, 3H), 1.73 (d, 2H), 1, 62-1.10 (m, 4H), 0.95 (s, 6H).

EXAMPLE 280

4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[({3-nitro-4 - tert-butyl [tetrrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate [0937] The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.33 (br s, 1H), 8.65 (t, 1H), 8.55 (br s, 1H), 8.16 (br s, 1H), 7.82 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 7.35 (d, 2H), 7.32-7.13 (m, 2H), 7.11 (d, 1H), 7 , 06 (d, 2H), 6.71 (d, 1H), 3.86 (dd, 2H), 3.09 (br s, 4H), 2.73 (d, 2H), 2.25-2 , 12 (m, 8H), 1.97 (br s, 2H), 1.91 (m, 1H), 1.66-1.47 (m, 4H), 1.40 (t, 2H), 1 , 31 (s, 9H), 1.24 (t, 2H), 0.94 (s, 6H).

EXAMPLE 281

2 - [(3-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [0938] The title compound was prepared by substitution EXAMPLE 265D instead of EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.34 (s, 1H), 8.48 (d, 1H), 8.15 (d, 1H), 7.74 (dd, 1H), 7.53-7.51 (m, 2H) , 7.37 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 7.00 (d, 1H), 6.87-6.85 (m, 2H), 6.64 (dd, 1H), 6.19 (d, 1H), 3.94 (dd, 2H), 3.75 (m, 1H), 3.28 (dd, 2H), 3.02 (m , 6H), 2.72 (m, 2H), 2.62 (m, 1H), 2.25-2.10 (m, 6H), 2.00 (m, 2H), 1.95 (br. s, 2H), 1.91 (m, 2H), 1.77 (d, 2H), 1.70-1.60 (m, 2H), 1.55-1.45 (m, 2H), 1 , 38 (m, 2H), 0.92 (s, 6H).

176

EP-2507211B1PL

EXAMPLE 282

2 - [(2-aminopyridin-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0939] The title compound was prepared by substituting EXAMPLE 280 for EXAMPLE 1A in

EXAMPLE 1B. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.59 (t, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.73 (m, 1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.16 (d, 1H), 7.14-7.10 (m, 1H), 7.06 (d, 2H), 6.95 (d, 1H), 6.66 ( d, 2H), 6.46 (m, 1H), 6.15 (d, 1H), 3.86 (dd, 2H), 3.07 (br s, 4H), 2.76 (br s, 2H ), 2.30-2.12 (m, 6H), 1.97 (br s, 2H), 1.90 (m, 1H), 1.63 (d, 2H), 1.40 (t, 2H ), 1.35-1.15 (m, 6H), 0.94 (s, 6H).

EXAMPLE 283

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6hydroksypirydyn-3-yl) oxy] N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 283A

Methyl 2- (6- (benzyloxy) pyridin-3-yloxy) -4-fluorobenzoate [0940] Potassium tert-butoxide was added to 6- (benzyloxy) pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL) (5.47 ml, 1.0M in tetrahydrofuran). After stirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2 mL) was added and the reaction was heated to 75 ° C for 1 hour. The reaction was cooled, diluted with ethyl acetate (150 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel (SF40-80 g) using a 5% to 20% ethyl acetate / hexane gradient as eluent gave the title compound.

EXAMPLE 283B

Methyl 2- (6- (benzyloxy) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [0941] The title compound was prepared by substituting EXAMPLE 283A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 283C 2- (6- (benzyloxy) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoic acid [0942] The title compound was prepared by substituting EXAMPLE 283B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 283D

2 - {[6- (benzyloxy) pyridin-3-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- -yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0943] The title compound was prepared by substituting EXAMPLE 283C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 283E

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6hydroksypirydyn-3-yloxy) -N- (3-nitro -4 - ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide

177

[0944] To 2- (6- (benzyloxy) pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1 -yl) -N- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide (0.132 g) in dichloromethane (1 ml) trifluoroacetic acid (0.33 ml) was added and the reaction was sealed in a vial under a nitrogen atmosphere and heated to 40 ° C. After 16 hours of stirring, the reaction was cooled, diluted with dichloromethane (50 mL) and washed with sodium carbonate solution (2 x 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel (GraceResolv 12 g) using a 0.3% to 3% methanol / dichloromethane gradient (flow = 36 ml / minute) over 30 minutes gave the title compound.¹H NMR (300 MHz, CDCl₃) δ 12.51 - 11.38 (m, 1H), 9.78 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.19 (dd, 1H) , 7.92 (d, 1H), 7.43 - 7.33 (m, 2H), 7.24 (d, 2H), 7.00 - 6.89 (m, 3H), 6.74 - 6 , 67 (m, 1H), 6.55 (dd, 1H), 6.00 (d, 1H), 4.00 (d, 2H), 3.42 (dd, 2H), 3.34 - 3, 23 (m, 2H), 3.16 (s, 4H), 2.79 (s, 2H), 2.24 (d, 6H), 1.99 (s, 3H), 1.72 (s, 2H) ), 1.55 - 1.33 (m, 4H), 0.96 (s, 6H).

EXAMPLE 284

2 - {[6- (benzyloxy) pyridin-3-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- -yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0945] The title compound was prepared as described in EXAMPLE 283D. ¹H NMR (300 MHz, CDCl₃) δ 9.93 (s, 1H), 8.88 (d, 1H), 8.52 (t, 1H), 8.17 (dd, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.49 (d, 2H), 7.45 - 7.34 (m, 4H), 7.24 (d, 2H), 6.97 - 6.85 (m, 4H), 6.54 (dd, 1H), 5.95 (d, 1H), 5.41 (s, 2H), 4.02 (dd, 2H), 3.48 3.35 (m, 2H), 3, 30 - 3.23 (m, 2H), 3.15 - 3.02 (m, 4H), 2.77 (s, 2H), 2.23 (dd, 6H), 1.95 (d, 3H) , 1.71 (s, 2H), 1.59 - 1.33 (m, 4H), 1.03 - 0.89 (m, 6H).

EXAMPLE 285

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- (1,4-dioxane-2 ylmethoxy) -3-nitrophenyl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 285A

4 - ((1,4-dioxan-2-yl) methoxy) -3-nitrobenzenesulfonamide (1,4-Dioxan-2-yl) methanol (380 mg) in tetrahydrofuran (30 mL) was treated with sodium hydride (60 %, 245 mg) at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The resulting mixture was stirred at room temperature for 2 hours and another portion of sodium hydride (60%, 245 mg) was added. The reaction mixture was stirred overnight and quenched with ice water (3 mL). The cloudy mixture was filtered and the filtrate was concentrated. The residue was triturated with methanol to afford the title compound.

EXAMPLE 285

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4- (1,4-dioxane-2 -ylmethoxy) -3-nitrophenyl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0947] The title compound was prepared as described in EXAMPLE 110F by replacing EXAMPLE 110E and EXAMPLE 1G, respectively, with EXAMPLE 154E and EXAMPLE 285A. ¹H

NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 2H), 8.38 (d, 1H), 8.10 (d, 1H), 7.52 (d, 1H), 7.47 (d, 1H), 7.38 (t, 1H), 7.32 - 7.36 (m, 3H), 7.27 (d, 1H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.40 ( s, 1H), 6.10 (d, 1H), 4.20 - 4.29 (m, 2H), 3.85 - 3.91 (m, 1H), 3.82 (dd, 1H), 3 , 74 - 3.78 (m, 1H), 3.59 - 3.69 (m, 2H), 3.40 3.51 (m, 2H), 3.06 (s, 4H), 2.82 ( s, 2H), 2.26 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

EXAMPLE 286

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EP-2507211B1PL

2 - [(3-chloro-1H-indol-4-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0948] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.51 (s, 1H), 9.17 (s, 1H), 8.48 (s, 1H), 7.83 (d, 1H), 7.58 (d, 2H), 7.43 (s, 1H),

7.33 (d, 2H), 7.20 (d, 1H), 7.07-7.03 (m, 3H), 6.66 (d, 1H), 6.52 (m, 1H), 6 , 10 (s, 1H), 3.00 (m, 3H), 2.90 (m, 6H), 2.71 (br s, 2H), 2.50 (s, 3H), 2.32 (m , 3H), 2.15 (m, 6H), 1.95 (br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 287

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-methylpiperazin-1- yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide [0949] The title compound was prepared by substituting EXAMPLE 286 for EXAMPLE 265E in EXAMPLE 267. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 10.31 (s, 1H), 8.86 (s, 1H), 8.29 (s, 1H), 7.54 (m, 2H), 7.42 (d, 1H), 7.36 (d, 2H), 7.08 (d, 2H), 6.91 (t, 1H), 6.68 (d, 1H), 6.39 (m, 2H), 6.06 (d, 1H) , 3.34 (m, 4H), 3.27 (s, 2H), 3.08 (br.s, 4H), 2.86 (m, 4H), 2.76 (s, 2H), 2, 28 (s, 3H), 2.25-2.10 (m, 6H), 1.97 ((br.s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 288

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4- yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide

EXAMPLE 288A

2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (4- (1-methylpiperidin-4-ylamino) -3-nitrophenylsulfonyl) benzamide [0950] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 3I instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 288B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1-methylpiperidin-4- yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide [0951] The title compound was prepared by substituting EXAMPLE 288A for EXAMPLE

265E in EXAMPLE 267. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 10.29 (s, 1H), 8.34 (s, 1H), 8.05 (br d, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7 , 36 (d, 2H), 7.07 (d, 2H), 7.01 (d, 1H), 6.91 (t, 1H), 6.68 (d, 1H), 6.38 (m, 2H), 6.08 (d, 1H), 3.80 (br.s, 1H), 3.34 (m, 2H), 3.23 (s, 2H), 3.09 (br.s, 4H) ), 2.84 (m, 2H), 2.76 (s, 2H), 2.62 (br.s, 2H), 2.24 (s, 3H), 2.25-2.05 (m, 6H), 1.98 ((br.s, 2H), 1.76 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 289

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 [(1 tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] phenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide

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EXAMPLE 289A

2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (3-nitro-4- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) phenylsulfonyl) benzamide [0952] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 49C instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 289B

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3-nitro-4- (1- (tetrahydro-2H- pyran-4-yl) piperidin-4-ylamino) phenylsulfonyl) -2- (2-oxoindolin-4-yloxy) benzamide [0953] The title compound was prepared by substituting EXAMPLE 289A for EXAMPLE

265E in EXAMPLE 267. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 10.32 (s, 1H), 8.37 (s, 1H), 8.12 (br. s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7 , 36 (d, 2H), 7.07 (m, 3H), 6.93 (t, 1H), 6.69 (d, 1H), 6.40 (m, 2H), 6.09 (d, 1H), 3.94 (m, 2H), 3.83 (br.s, 1H), 3.34 (m, 7H), 3.23 (s, 2H), 3.12 (br.s, 4H) ), 2.77 (s, 2H), 2.62 (s, 2H), 2.30-2.00 (m, 8H), 1.98 ((br.s, 2H), 1.85 (m , 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 290

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - {[4- (1,4-dioxane-2-ylmethoxy) -3-nitrophenyl] sulfonyl} benzamide [0954] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE, respectively 242H and EXAMPLE 285A. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.25 (s, 1H), 8.37 (d, 1H), 8.09 (m, 1H), 7.48 (m, 4H), 7.33 (m, 3H), 7.05 (m, 3H), 6.65 (dd, 1H), 6.42 (m, 1H), 6.01 (d, 1H), 4.25 (m, 2H), 3:83 (m, 3H) , 3.63 (m, 3H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H), 1.95 ( s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 291

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1,4-dioxan-2-ylmethyl) amino] -3-nitrophenyl} sulfonyl) benzamide EXAMPLE 291A

4 - ((1,4-dioxan-2-yl) methylamino) -3-nitrobenzenesulfonamide [0955] The title compound was prepared as described in EXAMPLE 4A by replacing 3- (Nmorpholinyl) -1-propylamine C- [1,4] dioxane -2-yl-methylamine.

EXAMPLE 291B

2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1,4-dioxan-2-ylmethyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0956] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 242H and EXAMPLE 291A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.25 (s, 1H), 8.37 (d, 1H), 8.09 (dd, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.33 (m, 3H), 7.05 (m, 2H), 6.65 (dd, 1H), 6.42 (s, 1H), 6.01 (d, 1H), 3.83 (m, 3H) , 3.63 (m, 2H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H), 1.95 ( s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 292

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1,4dioksan- 2-ylmethyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

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EP-2507211B1EN [0957] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE

1F and EXAMPLE 1G EXAMPLE 154E and EXAMPLE 291A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.58 (d, 2H), 7.95 (s, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.34 (m,

5H), 7.15 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 3.78 (m, 3H), 3, 61 (m, 2H), 3.46 (m, 3H), 3.03 (m, 4H), 2.89 (s, 3H), 2.73 (m, 2H), 2.15 (m, 4H ), 1.95 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 293 trans-2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0958] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 242H and EXAMPLE 205A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.23 (s, 1H), 8.53 (d, 1H), 8.17 (d, 1H), 7.82 (dd, 1H), 7.53 (t, 2H), 7.41 (t, 1H),

7.33 (d, 2H), 7.24 (s, 1H), 7.11 (d, 1H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.40 (s , 1H), 6.01 (d, 1H), 3.60 (m, 5H), 3.02 (m, 4H), 2.71 (s, 2H), 2.57 (m, 6H), 2 , 03 (m, 12H), 1.39 (m, 6H), 0.92 (s, 6H).

EXAMPLE 294 trans-2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro- 2H-pyran-3-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0959] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and EXAMPLE 205A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.50 (d, 1H), 8.14 (d, 1H), 7.79 (dd, 1H), 7.54 (m, 2H), 7.38 (m, 3H), 7.12 (m, 4H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.02 (d, 1H), 4.10 (s, 2H) , 3.59 (m, 6H), 3.31 (m, 4H), 3.01 (m, 4H), 2.81 (s, 2H), 2.68 (s, 2H), 2.54 ( m, 3H), 2.03 (m, 5H), 1.39 (m, 4H), 1.20 (s, 6H).

EXAMPLE 295

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6fluoro- 1H-indol-5-yl) oxy] -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [0960] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 277B and EXAMPLE 205A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.17 (s, 1H), 8.53 (d, 1H), 8.16 (d, 1H), 7.83 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.20 (dd, 1H), 7.13 (m, 3H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.09 (d, 1H) , 4.10 (s, 2H), 4.01 (s, 1H), 3.61 (m, 4H), 3.02 (m, 4H), 2.81 (s, 2H), 2.59 ( m, 3H), 2.12 (m, 12H), 1.39 (m, 4H), 1.18 (s, 6H).

EXAMPLE 296

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 296A

1,6-dioxaspiro [2.5] octane-2-carbonitrile [0961] A mixture of dihydro-2H-pyran-4 (3H) -one (10.0 g) and 2-chloroacetonitrile (7.5 g) in tert-butanol ( 10 ml) was treated with 1.0 N potassium tert-butoxide (100 ml) dropwise for 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. It was diluted with water (10 ml) and 10% aqueous HCl (20 ml). The reaction mixture was concentrated to one third of its original volume, and

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EP-2507211B1PL was extracted with diethyl ether four times. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20-40% ethyl acetate in hexane.

EXAMPLE 296B

2- (4-fluorotetrahydro-2H-pyran-4-yl) -2-hydroxyacetonitrile EXAMPLE 296A (11.5 g) was dissolved in dichloromethane (40 ml) in a polypropylene bottle. The bottle was cooled to 0 ° C. To this solution, 70% hydrogen fluoride-pyridine solution (10.3 mL) was slowly added. The solution was allowed to warm to room temperature over 3 hours, and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and poured into saturated aqueous NaHCO solution₃. Additional solid NaHCO₃ was used to carefully neutralize the solution until bubble formation disappeared. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times (150 ml each). The combined organic layers were washed with 1% aqueous HCl, brine, dried (MgSO₄), filtered and concentrated to give the desired compound which was used directly in the next reaction.

EXAMPLE 296C (4-fluorotetrahydro-2H-pyran-4-yl) methanol [0963] EXAMPLE 296B (11.8 g) in 2-propanol (150 ml) and water (37 ml) were cooled to 0 ° C. Sodium borohydride (4.2 g) was added to this solution. The solution was stirred and allowed to warm to room temperature over 3 hours. The reaction was quenched with acetone, and stirred for another 1 hour. The clear liquid was separated from the solid by decantation. Additional ethyl acetate was used to wash the solid, and decanted. The combined organic solutions were concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20-40% ethyl acetate in hexane.

EXAMPLE 296D

4 - ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) -3-nitrobenzenesulfonamide EXAMPLE 296C (2.0 g) in tetrahydrofuran (20 ml) was treated with 60% NaH (1.3 g ). The solution was stirred for 20 minutes at room temperature. To this solution, 4-fluoro-3-nitrobenzenesulfonamide (2.8 g) was added in portions. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% aqueous HCl, and extracted with ethyl acetate three times.

The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20% -60% ethyl acetate in hexane.

EXAMPLE 296E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) benzamide [0965] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and EXAMPLE 296D instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.40 (s, 1H), 8.13 (br d, 1H), 7.54 (d, 1H), 7.49 (br d, 1H), 7 , 38 (dd, 1H), 7.33 (d, 3H), 7.28 (br d, 1H), 7.04 (d, 2H), 6.64 (d, 1H), 6.40 (s , 1H), 6.09 (s, 1H), 4.38 (d, 2H),

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3.78 (m, 2H), 3.60 (m, 2H), 3.06 (v br s, 4H), 2.82 (br s, 2H), 2.27 (v br s, 4H), 2.15 (br m, 2H), 1.95 (s,

2H), 1.85 (m, 4H), 1.40 (t, 2H), 0.92 (s, 6H).

EXAMPLE 297

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6fluoro- 1H-indol-5-yl) oxy] -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) benzamide [0966] The title compound was prepared by substituting EXAMPLE 277B instead of EXAMPLE 122C and EXAMPLE 296D instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.43 (s, 1H), 8.16 (br d, 1H), 7.52 (d, 2H), 7.38 (m, 4H), 7, 30 (br d, 1H), 7.11 (d, 2H), 6.64 (d, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 4.40 (d, 2H), 4.10 (s, 2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.07 (v br s, 4H), 2.84 (br s, 2H) , 2.24 (v br s, 4H), 2.16 (s, 2H), 1.85 (m, 4H), 1.18 (s, 6H).

EXAMPLE 298

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -N - {[5cyjano- 6- (tetrahydro-2H-pyran-4-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0967] The title compound was prepared by substituting EXAMPLE 277B for EXAMPLE 122C and EXAMPLE 301B instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.83 (d, 1H), 8.60 (s, 1H), 7.54 (d, 1H), 7.38 (d, 2H), 7.37 (m, 1H),

7.33 (d, 1H), 7.21 (br d, 1H), 7.13 (d, 2H), 6.66 (dd, 1H), 6.38 (s, 1H), 6.12 ( s, 1H), 4.30 (d, 2H), 4.10 (s, 2H), 3.85 (dd, 2H), 3.33 (m, 2H), 3.07 (v br s, 4H ), 2.95 (br s, 2H), 2.31 (v br s, 4H), 2.16 (s, 2H), 2.05 (m, 1H), 1.63 (br m, 2H) , 1.38 (ddd, 2H), 1.18 (s, 6H).

EXAMPLE 299

2 - {[3- (2-aminoethyl) -1H-indol-5-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 299A

Tert-butyl 2- (5-hydroxy-1H-indol-3-yl) ethylcarbamate [0968] For a suspension of 3- (2-aminoethyl) -1H-indol-5-ol hydrochloride (5 g) in dichloromethane (100 ml) N-ethyl-N-isopropylpropan-2-amine (3.19 g) was added, followed by a solution of di-tert-butyl dicarbonate (5.64 g) in dichloromethane (10 mL). The mixture was stirred at ambient temperature under nitrogen for 18 hours. The resulting solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified on silica gel using 1-5% methanol in methylene chloride.

EXAMPLE 299B

Ethyl 2- (3- (2- (tert-butoxycarbonylamino) ethyl) -1H-indol-5-yloxy) -4-fluorobenzoate [0969] The title compound was prepared by substituting EXAMPLE 299A for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 299C

2- (3- (2- (tert-butoxycarbonylamino) ethyl) -1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4dimetylocykloheks-1-enyl) methyl) ethyl piperazin-1-yl) benzoate [0970] The title compound was prepared by substituting EXAMPLE 299B for EXAMPLE 3A in EXAMPLE 3G.

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EXAMPLE 299D 2- (3- (2- (tert-butoxycarbonylamino) ethyl) -1H-indol-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl acid ) methyl) piperazin-1-yl) benzoic [0971] The title compound was prepared by substituting EXAMPLE 299C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 299E

2- (5- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-nitro-4- (( tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonylcarbamoyl) phenoxy) -1H-indol-3-yl) ethyl tert-butylcarbamate [0972] The title compound was prepared by substituting EXAMPLE 299D for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 299F

2 - {[3- (2-aminoethyl) -1H-indol-5-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [0973] Solution of EXAMPLE 299E (146.6 mg) in dichloromethane (10 ml) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (5 ml) was added dropwise over 5 minutes. The reaction mixture was stirred for 15 minutes under a nitrogen atmosphere, the ice bath was removed and the reaction was allowed to come to ambient temperature. The reaction was stirred for 1.5 hours and then concentrated. The crude material was purified by reverse phase chromatography using ammonium acetate buffer in acetonitrile to afford the title compound.¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.86 (d, 1H), 8.39 (d, 1H), 8.33 (t, 1H), 8.06 (br s, 1H), 7.71 (dd, 1H), 7, 53 (d, 1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 7.05 (m, 3H), 6.89 (d, 1H ), 6.70 (dd, 1H), 6.52 (dd, 1H), 6.15 (d, 1H), 3.83 (dd, 2H), 3.22 (m, 3H), 2.82 - 3.00 (m, 8H), 2.72 (s, 2H), 2.16 (m, 6H), 1.96 (s, 2H), 1.88 (m, 4H), 1.60 ( d, 2H), 1.38 (m, 2H), 1.24 (m, 2H), 0.93 (s, 6H).

EXAMPLE 300

2 - {[3- (2-aminoethyl) -1H-indol-5-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 300A

2- (5- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (4- (4-methylpiperazin-1- ylamino) -3-nitrophenylsulfonylcarbamoyl) phenoxy) -1H-indol-3-yl) ethyl tert-butylcarbamate [0974] The title compound was prepared by substituting EXAMPLE 299D for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 300B

2 - {[3- (2-aminoethyl) -1H-indol-5-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [0975] The title compound was prepared by substituting EXAMPLE 300A for EXAMPLE

299E in EXAMPLE 299F. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 10.88 (d, 1H), 8.78 (s, 1H), 8.61 (br s, 1H), 8.38 (d, 1H), 7.76 (dd, 1H), 7, 52 (d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.27 (d, 1H), 7.20 (d,

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1H), 7.05 (m, 3H), 6.71 (dd, 1H), 6.51 (dd, 1H), 6.14 (dm, 1H), 3.02-2.80 (m, 12H ), 2.71 (s, 2H), 2.20 2.11 (m, 9H), 1.95 (s, 2H), 1.90 (s, 6H), 1.38 (m, 2H), 0.93 (s, 6H).

EXAMPLE 301

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (tetrahydro- 2H-pyran-4-ylmethoxy) -pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 301A [0976] (Tetrahydro-2H-pyran-4-yl) methanol (0.65 g) in tetrahydrofuran (20 mL) was treated with 60% sodium hydride (0.895 g). The reaction mixture was stirred for 10 minutes. EXAMPLE 305A (1.519 g) was added to this solution. The reaction mixture was stirred overnight. It was poured into water, neutralized with 10% aqueous HCl, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20% 60% ethyl acetate in hexane to afford the title compound.

EXAMPLE 301B [0977] A mixture of EXAMPLE 301A (0.702 g), dicyanzinc (0.129 g), and tetrakis (triphenylphosphine) palladium (0) (0.231 g) in N, N-dimethylformamide (2 ml) was degassed in a vacuum / nitrogen cycle three times . The reaction mixture was heated at 120 ° C for 3 hours. After cooling, it was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20% -60% tetrakis (triphenylphosphine) palladium (0) in hexane to afford the title compound.

EXAMPLE 301C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (tetrahydro- 2H-pyran-4-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0978] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 301B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.14 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.55 (d, 1H), 7.32-7.34 (m, 3H) , 7.28 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.62 (dd, 1H), 6.33 (s, 1H), 6.11 ( s, 1H), 4.28 (d, 2H), 3.86 (dd, 2H), 2.92-3.06 (m, 4H), 2.35-2.38 (m, 2H), 1 , 95-2.15 (m, 5H), 1.61-1.64 (m, 2H), 1.34-1.40 (m, 4H), 0.91 (s, 6H).

EXAMPLE 302

2 - [(6-amino-5-fluoropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 302A

Methyl 2- (6-chloro-5-fluoropyridin-3-yloxy) -4-fluorobenzoate [0979] To a solution of 6-chloro-5-fluoropyridin-3-ol (0.977 g) in 2-methyltetrahydrofuran (12 ml) was added 2 -methylpropan-2-olane potassium (1.0M in tetrahydrofuran, 7.28 ml). After 15 minutes of stirring at room temperature, methyl 2,4-difluorobenzoate (1.710 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) followed by N, N-dimethylformamide (2 mL), and the reaction was heated to

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75 ° C under a nitrogen atmosphere. After stirring overnight, the reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 40 g) using a 2% to 15% ethyl acetate / hexane gradient as eluent gave the title compound.

EXAMPLE 302B

Methyl 2- (6- (tert-butoxycarbonylamino) -5-fluoropyridin-3-yloxy) -4-fluorobenzoate Methyl 2- (6-Chloro-5-fluoropyridin-3-yloxy) -4-fluorobenzoate (0.875 g ), tert-butyl carbamate (0.410 g), cesium carbonate (1.427 g), diacetoxypalladium (0.033 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine) (0.169 g) were added to dioxane (10 ml). The reaction was degassed with nitrogen and then sealed. The reaction was then heated to 85 ° C. After 16 hours of stirring, the reaction was cooled, diluted with water (25 mL) and the product was extracted into dichloromethane (2 x 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 40 g) using a 5% to 25% ethyl acetate / hexane gradient as eluent gave the title compound.

EXAMPLE 302C

Methyl 2- (6- (tert-butoxycarbonylamino) -5-fluoropyridin-3-yloxy) -4- (piperazin-1-yl) benzoate [0981] 2- (6- (tert-butoxycarbonylamino) -5-fluoropyridin-3 Methyl-yloxy) -4-fluorobenzoate (0.170 g) and piperazine (0.154 g) were dissolved in dimethyl sulfoxide (2 mL) and heated to 85 ° C. After 1 hour, the reaction was cooled, poured into dichloromethane (75 mL), and washed with water (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.

EXAMPLE 302D

2- (6- (tert-butoxycarbonylamino) -5-fluoropyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4dimetylocykloheks-1-enyl) methyl) piperazin-1-yl ) methyl benzoate [0982] The title compound was prepared by substituting EXAMPLE 302C for tert-butyl piperazine-1-carboxylate and EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 302E 2- (6- (tert-butoxycarbonylamino) -5-fluoropyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazinic acid 1-yl) benzoic [0983] The title compound was prepared by substituting EXAMPLE 302D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 302F

5- (5- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3-nitro-4- ((tetrahydro-2H pyran-4-yl) methylamino) phenylsulfonylcarbamoyl) phenoxy) -3-fluoropyridin-2-tert-butylcarbamate [0984] The title compound was prepared by substituting EXAMPLE 302E for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 302G

2- (6-amino-5-fluoro-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide

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[0985] To EXAMPLE 302F (0.115 g) in dichloromethane (2 mL) was added TFA (0.276 mL). After 3 hours of stirring, the reaction was concentrated, dissolved in dichloromethane (50 mL) and washed with aqueous saturated NaHCO solution₃ (30 mL), dried over magnesium sulfate, filtered, and concentrated.

Chromatography on silica gel (GraceResolv 12 g) using a 0.5% to gradient gradient

3% methanol / dichloromethane gave the title compound. ¹H NMR (300 MHz, CDCl₃) δ 9.86 (s, 1H), 8.88 (d, J = 2.2, 1H), 8.52 (s, 1H), 8.17 (dd, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.26 (s, 1H), 7.11 (dd, 1H), 6.93 (dd, 3H), 6.54 (dd, 1H), 5, 98 (d, 1H), 4.69 (s, 2H), 4.02 (dd, 2H), 3.42 (d, 2H), 3.31 - 3.23 (m, 2H), 3.12 (s, 4H), 2.78 (s, 2H), 2.25 (s, 6H), 1.99 (s, 3H), 1.72 (s, 2H), 1.55 - 1.34 ( m, 4H), 0.96 (s, 6H).

EXAMPLE 303

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-chloro-6- (tetrahydro- 2H-pyran-4-ylmethoxy) -pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 303A

5,6-dichloropyridine-3-sulfonamide [0986] The title compound was prepared by substituting 5,6-dichloropyridine-3-sulfonyl chloride for 5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 305A.

EXAMPLE 303B

5-chloro-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridine-3-sulfonamide [0987] The title compound was prepared by substituting EXAMPLE 303A for EXAMPLE 305A and (tetrahydro-2H-pyran-4-yl) methanol instead of (1,3-dioxan-4-yl) methanol in EXAMPLE 305B.

EXAMPLE 303C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-chloro-6- (tetrahydro- 2H-pyran-4-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0988] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and EXAMPLE 303B instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.57 (d, 1H), 8.23 ​​(s, 1H), 7.54 (d, 1H), 7.37 (dd, 1H), 7.35 (m, 3H), 7.26 (br d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.10 (s, 1H ), 4.25 (d, 2H), 3.86 (dd, 2H),

3.33 (m, 2H), 3.06 (v br s, 4H), 2.86 (br s, 2H), 2.30 (v br s, 4H), 2.05 (m, 1H), 2.15 (br m, 2H), 1.95 (s, 2H), 1.63 (br d, 2H), 1.40 (t, 2H), 1.33 (ddd, 2H), 0.92 (s, 6H).

EXAMPLE 304 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [( 4-morpholin-4-yl-cyclohexyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl) oxy] benzamide

EXAMPLE 304A 4-Fluoro-2- (1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy) benzoic acid methyl ester [0989] The title compound was prepared by substituting methyl 2,4-difluorobenzoate for 2, Ethyl 4-difluorobenzoate and 5-hydroxy-3,4-dihydro-2H-isoquinolin-1-one instead of 2-methyl-5-indolol in EXAMPLE 3A, except that the heating took place at 130 ° C.

EXAMPLE 304B

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4- {4- [2- (4-Chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (1-oxo-1,2 acid , 3,4-tetrahydro-isoquinolin-5-yloxy) benzoic [0990] The title compound was prepared by substituting EXAMPLE 304A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 304C 4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- (1-oxo-1,2,3) acid, 4-tetrahydro-isoquinolin-5-yloxy) benzoic [0991] The title compound was prepared by substituting EXAMPLE 304B for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 304D trans-4- (4 - '{[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4- [ (4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl) oxy] benzamide [0992] The title compound was prepared by substitution EXAMPLE 304C instead of EXAMPLE 1F and EXAMPLE 205A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.37 (br s, 1H), 8.22-8.18 (m, 2H), 7.93-7.84 (m, 2H), 7.57-7.52 (m, 1H) , 7.45 (d, 1H), 7.36 (d, 2H), 7.12-7.02 (m, 3H), 6.72 (d, 1H), 6.59 (d, 1H), 6.36 (d, 1H), 3.62 (br s, 4H), 3.13 (br s, 4H), 2.95-2.69 (m, 6H), 2.68-2.35 ( m, 4H), 2.32-3.03 (m, 10H), 2.02-1.84 (m, 4H), 1.42 (m, 6H), 0.94 (t, 6H)

EXAMPLE 305

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (1, 4-dioxan-2-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide EXAMPLE 305A

5-bromo-6-chloropyridine-3-sulfonamide [0993] 5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL) was cooled to 0 ° C. 7N NH was added to this solution₃ in methanol (80 ml). The reaction mixture was stirred overnight. The solvent was removed at low temperature, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give the product.

EXAMPLE 305B

6 - ((1,4-dioxan-2-yl) methoxy) -5-bromopyridine-3-sulfonamide (1,4-Dioxan-2-yl) methanol (211 mg) in tetrahydrofuran (10 mL) was treated 60% sodium hydride (125 mg). The reaction mixture was stirred for 10 minutes. EXAMPLE 305A (211 mg) was added to this solution. The reaction mixture was stirred overnight. It was poured into water, neutralized with 10% aqueous HCl, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to give the product.

EXAMPLE 305C

6 - ((1,4-dioxan-2-yl) methoxy) -5-cyanopyridine-3-sulfonamide [0995] A mixture of EXAMPLE 305B (100 mg), dicyanzinc (20 mg), and tetrakis (triphenylphosphine) palladium (0) (40 mg) in N, N-dimethylformamide (0.5 ml) was degassed in a vacuum / nitrogen cycle three times. The reaction mixture was heated at 120 ° C for 3 hours. After cooling it was poured

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EP-2507211B1EN to water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 2% -5% methanol / dichloromethane to afford the title compound.

EXAMPLE 305D

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (1, 4-dioxan-2-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0996] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 305C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.14 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 7.57 (d, 1H), 7.33 (m, 4H), 7.12 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.34 (s, 1H), 6.14 (s, 1H), 4.44 (d, 2H) , 3.91 (m, 1H), 3.80 (m, 2H), 3.63 (m, 2H), 3.46 (m, 2H), 3.33 (m, 4H), 3.09 ( m, 4H), 2.35 (m, 2H), 2.17 (m, 2H), 1.98 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 306

N - {[5-bromo-6- (1,4-dioxan-2-ylmethoxy) pyridin-3-yl] sulfonyl} -4- (4 - {[2- (4-chlorophenyl) -1 -4,4dimetylocykloheks -en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0997] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 305B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.19 (s, 1H), 8.58 (dd, 1H), 8.37 (d, 1H), 7.55 (d, 1H), 7.35 (m, 4H), 7.26 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.10 (d, 1H), 4.37 (m, 2H) , 3.89 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.06 ( m, 4H), 2.85 (m, 2H), 2.32 (m, 2H), 2.14 (s, 2H), 1.96 (s, 2H), 1.38 (m, 2H), 0.91 (s, 6H).

EXAMPLE 307 trans-N - ({5-bromo-6 - [(4-morpholin-4-ylcyclohexyl) amino] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 307A trans-5-bromo-6 - ((1r, 4r) -4-morpholinocyclohexylamino) pyridine-3-sulfonamide [0998] EXAMPLE 305A (1.0 g), trans-4-morpholinocyclohexanamine (0.95 g) and triethylamine (3.08 mL) in anhydrous dioxane (20 mL) was heated at 110 ° C overnight. The organic solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 2% -8% methanol / dichloromethane to afford the title compound.

EXAMPLE 307B trans-N - ({5-bromo-6 - [(4-morpholin-4-ylcyclohexyl) amino] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [0999] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 307A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.20 (m, 1H), 8.43 (d, 1H), 8.05 (d, 1H), 7.55 (d, 1H), 7.35 (m, 4H), 7.27 (d, 1H), 7.03 (d, 2H), 6.61 (dd, 1H), 6.49 (dd, 1H), 6.40 (dd, 1H), 3.93 (m, 1H) , 3.60 (m, 4H), 3.38 (m, 2H),

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2.98 (m, 4H), 2.70 (s, 2H), 2.60 (m, 4H), 2.34 (m, 1H), 2.15 (m, 6H), 1.92 (d , 6H), 1.37 (m, 6H), 0.92 (s,

6H).

EXAMPLE 308

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({5-cyano-6- [(4 -fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 308A

5-bromo-6 - ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) pyridine-3-sulfonamide [1000] The title compound was prepared by substituting EXAMPLE 296C instead of (tetrahydro-2H-pyran-4-yl) methanol in EXAMPLE 301A.

EXAMPLE 308B

5-cyano-6 - ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) pyridine-3-sulfonamide [1001] The title compound was prepared by substituting EXAMPLE 308A for EXAMPLE 301A in EXAMPLE 301B.

EXAMPLE 308C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({5-cyano-6- [(4 -fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1002] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 308B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.15 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 7.57 (d, 1H), 7.34-7.37 (m, 3H) , 7.30 (d, 1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.35 (s, 1H), 6.13 ( s, 1H), 4.25 (d, 2H), 3.75-3.80 (m, 2H), 3.56-3.62 (m, 2H), 3.09 (s, 4H), 2 , 15-2.60 (m, 4H), 1.80-21.83 (m, 2H), 1.41 (d, 2H), 0.93 (s, 6H).

EXAMPLE 309

2- (3-amino-5-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 309A

2- (3-chloro-5-nitrophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane [1003] 1-Bromo-3-chloro-5-nitrobenzene (0.51 g), bis (pinacolano) diboron (0.60 g), potassium acetate (0.63 g), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.09 g) combined with dimethylformamide (5, 3 ml), purged with nitrogen, heated at 60 ° C overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 5-10% ethyl acetate in hexane as the eluent to give the product. EXAMPLE 309B

3-chloro-5-nitrophenol [1004] EXAMPLE 309A (0.5 g) in tetrahydrofuran (10 ml) was treated with a 4N aqueous solution of sodium hydroxide (2.65 ml), heated at 50 ° C for 4 hours, cooled to 0 ° C, treated dropwise with 30% aqueous hydrogen peroxide (0.65 mL), stirred overnight, warming to room temperature, and then quenched with saturated aqueous sodium thiosulfate. The resulting mixture was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution and the organic portion was set aside. The aqueous layer was acidified to pH 4 with 2N

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HCl aqueous solution and extracted with ethyl acetate (2 x 100 mL). These extracts were combined, washed with brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 5-10% ethyl acetate in hexane as the eluent to give the product.

EXAMPLE 309C

Methyl 2- (3-chloro-5-nitrophenoxy) -4-fluorobenzoate [1005] The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE 309B instead of 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 309D

Methyl 2- (3-amino-5-chlorophenoxy) -4-fluorobenzoate [1006] EXAMPLE 309C (0.31 g) in a 1: 1 mixture of methanol and tetrahydrofuran (9.5 ml) was treated with tin (II) chloride dihydrate (1) , 06 g), heated at 65 ° C for 4 hours and filtered through a pad of celite, washing with ethyl acetate. The filtrate was washed with water and brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 10-20% ethyl acetate in hexane as the eluent to give the product.

EXAMPLE 309E

Methyl 2- (3-amino-5-chlorophenoxy) -4- (piperazin-1-yl) benzoate [1007] The title compound was prepared by substituting piperazine for EXAMPLE 3F and EXAMPLE 309D instead of EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 309F

1-chloro-4- (2- (chloromethyl) -5,5-dimethylcyclohex-1-enyl) benzene [1008] EXAMPLE 3D (0.251 g) in tetrahydrofuran (5 ml) at 0 ° C was treated in turn with N, N diisopropylethylamine (0.524 ml) and methanesulfonyl chloride (0.086 ml), followed by stirring for 1.5 hours. Additional N, N-diisopropylethylamine (0.524 mL) and methanesulfonyl chloride (0.086 mL) were added and stirring continued for another hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), filtered and concentrated. The concentrate was suspended in a 1: 1 mixture of diethyl ether and dichloromethane, and unreacted EXAMPLE 3D was removed by filtration. The filtrate was concentrated. The mixture was mixed with diethyl ether and the liquid was decanted three times. The decanted diethyl ether mixture was concentrated and dried under reduced pressure to give the product.

EXAMPLE 309G

Methyl 2- (3-amino-5-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [1009] EXAMPLE 309F (0.109 g) in N, N-dimethylformamide (2 mL) was treated with EXAMPLE 309E (0.15 g) and cesium carbonate (0.264 g), stirred at ambient temperature for two nights, diluted with ethyl acetate, washed with water and brine. dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 0 to 5% acetone in dichloromethane as the eluent to give the product.

EXAMPLE 309H 2- (3-Amino-5-chlorophenoxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid [ 1010] The title compound was prepared by substituting EXAMPLE 309G for EXAMPLE 1E in EXAMPLE 1F.

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EXAMPLE 309I

2- (3-amino-5-chlorophenoxy) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) - N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1011] The title compound was prepared by substituting EXAMPLE 309H for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.42 (s, 1H), 8.62 (t, 1H), 8.52 (d, 1H), 7.74 (dd, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.74 (dd, 1H), 6.41 (d, 1H), 6.22 (t, 1H) , 5.92 (m, 2H), 5.47 (s, 2H), 3.86 (dd, 2H), 3.32 (m, 4H), 3.18 (m, 4H), 2.80 ( m, 2H), 2.21 (m, 6H), 1.98 (s, 2H), 1.89 (m, 1H), 1.64 (dd, 2H), 1.41 (t, 2H), 1.26 (m, 2H), 0.95 (s, 6H).

EXAMPLE 310

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (2- morpholin-4-ylethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide EXAMPLE 310A

5-bromo-6- (2-morpholinoethoxy) pyridine-3-sulfonamide [1012] The title compound was prepared by substituting 2-morpholinoethanol for (tetrahydro-2H-pyran-4-yl) methanol in EXAMPLE 301A.

EXAMPLE 310B

5-cyano-6- (2-morpholinoethoxy) pyridine-3-sulfonamide [1013] The title compound was prepared by substituting EXAMPLE 310A for EXAMPLE 301A in EXAMPLE 301B.

EXAMPLE 310C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-cyano-6- (2- morpholin-4-ylethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1014] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 310B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.14 (s, 1H), 8.75 (d, 1H), 8.52 (d, 1H), 7.58 (d, 1H), 7.33-7.36 (m, 3H) , 7.28 (d, 1H), 7.09 (d, 1H), 7.05 (d, 2H), 6.62 (dd, 1H), 6.34 (s, 1H), 6.12 ( s, 1H), 4.62 (t, 2H), 3.25-3.61 (m, 4H), 3.05 (s, 4H), 2.93 (s, 4H), 2.68 (s , 4H), 2.32-2.36 (m, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.40 (d, 2H), 0.93 (s, 6H).

EXAMPLE 311 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - ({4 - [(4-morpholin-4-yl-cyclohexyl) oxy] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 311 A trans-4- (4-aminocyclohexyloxy) -3-nitrobenzenesulfonamide [1015] To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.186 g). After 15 minutes of stirring, 4-fluoro-3-nitrobenzenesulfonamide (0.256 g) was added as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60 ° C for 1.5 hours, cooled and poured into a mixture of dichloromethane (100 ml) and water (25 ml). The aqueous layer was adjusted to pH ~ 4 with 1N aqueous HCl and the organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto silica gel (GraceResolv 40 g) and eluted using a 0.5% to 7.5% gradient

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Methanol / dichloromethane for 30 minutes. This solid was directly treated with

HCl (4.0M in dioxane, 5 mL) at room temperature for 1 hour and concentrated to give the title compound.

EXAMPLE 311B trans-4- (4-morpholinocyclohexyloxy) -3-nitrobenzenesulfonamide [1016] For EXAMPLE 311A ​​(0.220 g) and 1-bromo-2- (2-bromoethoxy) ethane (0.177 g) in N, N-dimethylformamide (3 ml) triethylamine (0.338 mL) was added and the reaction heated to 70 ° C for 5 hours. The reaction was cooled and the resulting precipitate was removed by filtration. The reaction was concentrated and loaded onto silica gel and eluted using a 0.5% to 7.5% methanol / dichloromethane gradient to afford the title compound.

EXAMPLE 311C trans-2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazine -1-yl) -N- (4- (4-morpholinocyclohexyloxy) -3-nitrophenylsulfonyl) benzamide [1017] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 311B instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 - 11.09 (m, 1H), 8.29 - 8.13 (m, 2H), 8.03 - 7.88 (m, 1H), 7.54 (s, 1H), 7.33 (d, 4H), 7.21 - 7.11 (m, 1H), 7.04 (d, 2H), 6.97 - 6.89 (m, 1H), 6.66 - 6, 51 (m, 1H), 6.43 - 6.31 (m, 1H), 6.08 (s, 1H), 4.62 - 4.49 (m, 1H), 3.62 (s, 4H) , 2.98 (s, 4H), 2.68 (d, 7H), 2.19 (s, 8H), 1.95 (s, 4H), 1.38 (s, 6H), 0.92 ( s, 6H).

EXAMPLE 312

N - ({5-bromo-6 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] pyridin-3-yl} sulfonyl) -4- (4 {[2- (4- chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 312A

5-bromo-6- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-ylamino) pyridine-3-sulfonamide The title compound was prepared by substituting EXAMPLE 49B for trans-4-morpholinocyclohexanamine in EXAMPLE 307A.

EXAMPLE 312B

N - ({5-bromo-6 - [(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl) amino] pyridin-3-yl} sulfonyl) -4- (4 {[2- (4- chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1Hindol-5-yl) oxy] benzamide [1018] The title compound was prepared by substitution of EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 312A instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.16 (s, 1H), 8.40 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.32 (m, 4H), 7.19 (m, 1H), 7.04 (d, 2H), 6.58 (d, 1H), 6.38 (s, 1H), 6.05 (s, 1H), 4.05 (m, 1H) , 3.93 (d, 2H), 3.24 (m, 8H), 2.96 (m, 4H), 2.72 (m, 3H), 2.15 (m, 6H), 1.93 ( m, 2H), 1.85 (m, 4H), 1.55 (m, 2H), 1.38 (t, 2H), 1.17 (t, 2H), 0.91 (s, 6H).

EXAMPLE 313

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4fluorotetrahydro-2H- pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol4-yl) oxy] benzamide EXAMPLE 313 A

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2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (4 - ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) -3-nitrophenylsulfonyl) benzamide [1019] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 313B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4fluorotetrahydro-2H- pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol4-yl) oxy] benzamide [1020] The title compound was prepared by substituting EXAMPLE 313A for EXAMPLE

265E in EXAMPLE 267. ¹H NMR (500 MHz, methylene chloride-d₂) δ 8.44 (d, 1H), 8.24 (dd, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.24 (m, 3H), 7.19 (d, 1H), 6.97 (d, 2H), 6.77 (d, 1H), 6.62 (d, 2H), 6.14 (d, 1H), 4.19 (d, 2H) , 3.84 (m, 2H), 3.75 (m, 2H), 3.39 (s, 2H), 3.14 (br.s, 4H), 2.77 (s, 2H), 2, 30-2.10 (m, 6H), 1.99 ((br.s, 2H), 1.95-1.87 (m, 4H), 1.55 (m, 2H), 1.43 (t , 2H), 0.95 (s, 6H).

EXAMPLE 314 trans-2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[5- (4-chlorophenyl) -2,3,6,7-tetrahydrooksepin-4-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-yl-cyclohexyl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

EXAMPLE 314A oxsepan-4-one [1021] Tetrahydro-2H-pyran-4-one (5 g) was placed in methanol (30 ml) in the presence of barium oxide (0.85 g). Nitrosomethylurethane (6.6 g) was slowly added to the reaction mixture. Barium oxide (1.0 g) was added in small portions during the addition. The reaction mixture was stirred for 3 hours at room temperature and then filtered. The methanol was evaporated, then diethyl ether was added to the residue, and a precipitate formed. The mixture was filtered and the diethyl ether evaporated to give the product.

EXAMPLE 314B (Z) -5-chloro-2,3,6,7-tetrahydroxepine-4-carboxaldehyde [1022] Phosphorus oxychloride (3.45 ml) was added dropwise to the cooled (0 ° C) solution of EXAMPLE 314A (4.2 g) in N, N-dimethylformamide (12 ml) and dichloromethane (30 ml). The mixture was then stirred at room temperature overnight then diluted with ethyl acetate (300 mL) and washed with aqueous sodium acetate, water (3x), brine, and dried over Na₂SO₄. After filtration and concentration, the crude product was used directly in the next reaction without further purification.

EXAMPLE 314C (Z) -5- (4-chlorophenyl) -2,3,6,7-tetrahydroxepine-4-carboxaldehyde [1023] To a mixture of 4-chlorophenylboronic acid (6.10 g), EXAMPLE 314B (5.2 g ), palladium (II) acetate (146 mg, 0.65 mmol), K₂WHAT₃ (13.5 g) and tetrabutylammonium bromide (10.5 g) added water (200 ml). The mixture was stirred at 50 ° C for 4 hours. The mixture was diluted with ethyl acetate (400 mL) and washed with water (3x) and brine and dried over Na₂SO₄. After filtration and concentration, the residue was applied to a column and eluted with 5 to 20% ethyl acetate in hexane to give pure product.

EXAMPLE 314D

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(Z) -2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((5- (4-chlorophenyl) -2,3,6,7-tetrahydrooksepin-4- ethyl) methyl) piperazin-1-yl) benzoate [1024] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE

38F and EXAMPLE 38E EXAMPLE 242F and EXAMPLE 314C.

EXAMPLE 314E (Z) -2- (6-chloro-1H-indol-5-yloxy) -4- (4 - ((5- (4-chlorophenyl) -2,3,6,7-tetrahydrooksepin-4-yl) acid methyl) piperazin-1-yl) benzoic [1025] The title compound was prepared as described in EXAMPLE 38G by replacing EXAMPLE 34B with EXAMPLE 314D.

EXAMPLE 314F trans-4- (4-morpholinocyclohexylamino) -3- (trifluoromethylsulfonyl) benzenesulfonamide [1026] The title compound was prepared by substituting trans-4-morpholinocyclohexanamine for

3- (N-morpholinyl) -1-propylamine and EXAMPLE 131C instead of 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 314G trans-2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[5- (4-chlorophenyl) -2,3,6,7-tetrahydrooksepin-4-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide [1027] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 314E and EXAMPLE 314F, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.38 (s, 1H), 8.20 (m, 1H), 7.98 (dd, 1H), 7.53 (m, 4H), 7.38 (m, 3H), 7.13 (m, 3H), 6.98 (m, 1H), 6.72 (m, 3H), 6.45 (d, 1H), 3.86 (m, 12H), 3.36 (m, 3H) , 3.02 (m, 6H), 2.74 (d, 8H), 2.18 (m, 4H), 1.65 (m, 2H).

EXAMPLE 315 trans-2 - [(6-chloro-1H-indol-5-yl) oxy] -4- (4 - {[5- (4-chlorophenyl) -2,3,6,7-tetrahydrooksepin-4-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [1028] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 314E and EXAMPLE 205A, respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆6) δ 11.09 (s, 1H), 8.38 (d, 1H), 8.01 (d, 1H), 7.70 (dd, 1H), 7.57 (d, 1H), 7, 46 (s, 1H), 7.34 (m, 3H), 7.07 (d, 2H), 6.91 (m, 2H), 6.57 (m, 2H), 6.30 (s, 1H ), 6.02 (d, 1H), 3.61 (m, 10H), 2.98 (m, 12H), 2.28 (m, 8H), 1.95 (m, 4H), 1.36 (m, 2H).

EXAMPLE 316

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -2 - [(6fluoro- 1H-indol-5-yl) oxy] -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [1029] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G EXAMPLE 277B and EXAMPLE 184A respectively. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.18 (s, 1H), 9.16 (s, 1H), 8.52 (d, 1H), 7.89 (dd, 1H), 7.56 (m, 2H), 7.31 (m, 5H), 7.13 (d, 2H), 6.62 (dd, 1H), 6.39 (s, 1H), 6.07 (d, 1H), 4.09 (m, 2H) , 2.95 (m, 9H), 2.81 (s, 2H), 2.35 (s, 3H), 2.16 (m, 6H), 1.18 (s, 6H).

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EXAMPLE 317

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(4-morpholin-4-ylbut-2-ynyl) oxy] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 317A

4-morpholinobut-2-yn-1-ol [1030] To a solution of morpholine (4.36 g) in toluene (15 ml) was added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene ( 5 ml). The solution was stirred at 85 ° C for 3 hours. After cooling, the solid was filtered off. The filtrate was subjected to vacuum distillation to obtain the title compound.

EXAMPLE 317B

4- (4-morpholinobut-2-ynyloxy) -3-nitrobenzenesulfonamide [1031] The title compound was prepared by substituting EXAMPLE 317A for (tetrahydro-2H-pyran-4-yl) methanol in EXAMPLE 264A.

EXAMPLE 317C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({4 - [(4-morpholin-4-ylbut-2-ynyl) oxy] -3-nitrophenyl} sulfonyl) benzamide [1032] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 317B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.12 (s, 1H), 8.39 (d, 1H), 8.14 (dd, 1H), 7.52-7.54 (m, 2H), 7.34-7.39 ( m, 3H), 7.32-7.35 (m, 3H), 7.29 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.41 (s , 1H), 6.09 (d, 1H), 5.16 (s, 2H), 3.523.55 (m, 4H), 3.05 (s, 4H), 2.82 (s, 4H), 2 , 37-2.39 (m, 4H), 2.26 (s, 4H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).

EXAMPLE 318

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 318A

Methyl 4-fluoro-2- (6-nitropyridin-3-yloxy) benzoate [1033] To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and 2-nitro-5-chloropyridine (21.9 g) cesium carbonate (45 g) was added in N, N-dimethylformamide (120 mL). The mixture was stirred at 50 ° C overnight. The mixture was diluted with ethyl acetate (800 mL) and washed three times with water and brine. After drying over Na₂SO₄ and filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (2% ethyl acetate in dichloromethane) to afford the title compound.

EXAMPLE 318B

Methyl 2- (6-aminopyridin-3-yloxy) -4-fluorobenzoate [1034] EXAMPLE 318A (12.995 g) and methanol (150 ml) were added to Raney nickel moistened with water (6.50 g) in a 250 ml pressure bottle stainless steel and stirred for 2 hours at 30 psi (207 kPa) and room temperature. The mixture was filtered through a nylon membrane and concentrated to afford the title compound.

EXAMPLE 318C

Methyl 2- (6-amino-5-chloropyridin-3-yloxy) -4-fluorobenzoate

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[1035] EXAMPLE 318B (3.0 g) and 1-chloropyrrolidine-2,5-dione (1.680 g) were mixed together in N, N-dimethylformamide (30 ml) at room temperature under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (200 mL) and washed with water (75 mL), brine (75 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (GraceResolv 80 g) using a 5% to 35% ethyl acetate / hexane gradient over 40 minutes (flow = 40 ml / minute) as the eluent gave the title compound.

EXAMPLE 318D

Methyl 2- (6-amino-5-chloropyridin-3-yloxy) -4- (piperazin-1-yl) benzoate [1036] A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g) in dimethyl sulfoxide ( 100 ml) heated to 85 ° C. After 3 hours of stirring, the reaction was cooled, diluted with ethyl acetate (400 mL) and washed with water (2 x 250 mL), brine (250 mL), dried over magnesium sulfate and concentrated to afford the title compound.

EXAMPLE 318E

2-chloro-4,4-dimethylcyclohex-1-enocarboxaldehyde [1037] In a 250 mL round bottom flask, N, N-dimethylformamide (3.5 mL) was added to dichloromethane (30 mL). The mixture was cooled to -10 ° C, and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was slowly added. The mixture was refluxed overnight. The reaction was quenched with a 0 ° C sodium acetate solution (25 g in 50 mL water). The aqueous layer was extracted with ether (3 x 200 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and dried under reduced pressure.

EXAMPLE 318F

2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enocarboxaldehyde [1038] EXAMPLE 324E (6.8 g), 4-chlorophenylboronic acid (6.5 g) and palladium acetate (II) were added to a 1 L round bottom flask. ) (0.2 g) in water (100 ml) to give a suspension. Potassium carbonate (15 g) and tetrabutylammonium bromide (10 g) were added. After degassing by subjecting to pressure reduction and nitrogen treatment, the mixture was stirred at 45 ° C for 4 hours. After filtration through silica gel, ether (4 x 200 mL) was used to extract the product. The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated and purified by flash chromatography on silica using 0 to 10% ethyl acetate in hexane to afford the title compound.

EXAMPLE 318G

Methyl 2- (6-amino-5-chloropyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [ 1039] To a solution of EXAMPLE 318D (9.0 g) in dichloromethane (75 mL) was added EXAMPLE 318F (7.40 g) as a solution in dichloromethane (25 mL). To the solution, sodium triacetoxyborohydride (7.89 g) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with a saturated solution

NaHCO₃ (100 ml) and extracted with dichloromethane (3 x 100 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel (Reveleris 330 g) using a 10% to 75% ethyl acetate / hexane gradient over 40 minutes as the eluent (flow = 90 ml / min) gave the title compound.

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EXAMPLE 318H 2- (6-Amino-5-chloropyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-yl) methyl) piperazin-1-yl) acid benzoic [1040] To a solution of EXAMPLE 318G (12.5 g) in tetrahydrofuran (50 mL) and methanol (25 mL) was added lithium hydroxide (1.0 M, 52.5 mL) and the reaction was heated to 55 ° C. The reaction was stirred for 4 hours, cooled, diluted with dichloromethane (300 mL) and water (50 mL) and quenched with 1N aqueous HCl (1.0M, 50 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to afford the title compound.

EXAMPLE 318I

3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonamide [1041] 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl) methylamine (1.14 g), and triethylamine (1 g) was stirred in tetrahydrofuran (30 ml) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH solution₂AFTER₄ and brine, and dried (Na₂SO₄), filtered and concentrated. The product was triturated from ethyl acetate.

EXAMPLE 318J

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1042] EXAMPLE 318H (7.18 g), EXAMPLE 318I ( 3.89 g) and N, N-dimethylpyridine-4-amine (4.53 g) were stirred together in dichloromethane (50 ml) for 15 minutes. N hydrochloride was added in one portion¹- ((ethylimino) methylene) -N³N³-dimethylpropane-1,3-diamine (3.55 g) and the stirred reaction was left at room temperature under a nitrogen atmosphere for 36 hours. The reaction was diluted with dichloromethane (250 mL) and washed with saturated ammonium chloride solution (3 x 200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude material was applied to a silica gel column (Reveleris 330 g) and eluted using a 0.5% to 2.5% gradient over 45 minutes (flow = 120 ml / minute). Product containing fractions were combined and concentrated. Acetonitrile (100 ml) was added and the product dissolved with gentle heating. The solution was cooled and the resulting solid was collected by filtration, washed with acetonitrile (20 ml) and dried in a vacuum oven at 85 ° C for 2 days to give the title compound.¹H NMR (300 MHz, CDCl₃) δ 9.86 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.17 (dd, 1H), 7.96 - 7.83 (m, 2H) , 7.36 (d, 1H), 7.23 (s, 1H), 6.99 - 6.86 (m, 3H), 6.54 (dd, 1H), 5.97 (d, 1H), 4.95 (s, 2H), 4.01 (d, 2H), 3.42 (d, 2H), 3.32 - 3.22 (m, 2H), 3.12 (s, 4H), 2 , 78 (s, 2H), 2.22 (d, 6H), 1.99 (s, 2H), 1.72 (s, 2H), 1.50 - 1.34 (m, 5H), 0, 96 (s, 6H).

EXAMPLE 319

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(4 - {[1- (methylsulfonyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 319A

4- (1-methanesulfonyl-piperidin-4-ylamino) -3-nitro-benzenesulfonamide [1043] The title compound was prepared by substituting tert-butyl 1- (methylsulfonyl) piperidin-4-amine for tert-butyl 4-aminopiperidine-1-carboxylate in an EXAMPLE 140A.

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EXAMPLE 319B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(4 - {[1- (methylsulfonyl) piperidin-4-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [1044] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 319A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 (br s, 1H), 8.59 (d, 1H), 8.26 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H), 7, 38 (t, 1H), 7.34 (d, 2H), 7.31 (t, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.04 (d, 2H) ), 6.66 (dd, 1H), 6.40 (t, 1H), 6.10 (d, 1H), 3.82 (m, 1H), 3.56 (dt, 2H), 3.09 (br s, 4H), 2.96 (dd, 2H), 2.92 (s, 3H), 2.73 (m, 2H), 2.25-2.08 (m, 6H), 2.02 (dd, 2H), 1.95 (br s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 320 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [( 4-morpholin-4-yl-cyclohexyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide

EXAMPLE 320A trans-2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1 -yl) -N- (4- (4-morpholinocyclohexylamino) -3-nitrophenylsulfonyl) benzamide [1045] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 205A instead of EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 320B trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [( 4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide [1046] The title compound was prepared by substituting EXAMPLE 320A for EXAMPLE

265E in EXAMPLE 267. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 10.37 (s, 1H), 8.41 (s, 1H), 8.17 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.13 (d, 1H), 7.06 (d, 2H), 6.95 (t, 1H), 6.74 (d, 1H), 6.44 (m, 2H) , 6.12 (d, 1H), 3.70-3.58 (m, 4H), 3.34 (m, 2H), 3.24 (s, 2H), 3.16 (br.s, 4H ), 2.79 (m, 6H), 2.25 (m, 3H), 2.18 (m, 3H), 2.12 (m, 2H), 1.98 (m, 4H), 1.55 -1.40 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 321

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(2-methoxyethyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide EXAMPLE 321A

2- (3-chloro-1H-indol-4-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) - N- (4- (2-methoxyethylamino) -3-nitrophenylsulfonyl) benzamide [1047] The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE 1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 321B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(2-methoxyethyl) amino] -3-nitrophenyl} sulfonyl) -2 - [(2-oxo-2,3-dihydro-1H-indol-4-yl) oxy] benzamide [1048] The title compound was prepared by substituting EXAMPLE 321A for EXAMPLE

265E in EXAMPLE 267. ¹H NMR (500 MHz, methylene chloride-d₂) δ 9.80 (br.s, 1H), 8.73 (d, 1H), 8.56 (t, 1H), 8.00 (dd, 1H), 7.87 (d, 1H), 7 , 76 (br. S, 1H), 7.25 (d, 2H), 7.22 (t, 1H), 7.96 (d, 2H), 6.94 (d,

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1H), 6.74 (d, 1H), 6.62 (m, 2H), 6.16 (d, 1H), 3.68 (t, 2H), 3.54 (t, 2H), 3, 41 (s, 3H), 3.37 (s, 2H), 3.13 (br.s, 4H), 2.77 (m, 2H), 2.30-2.18 (m, 6H), 1 , 99 (br.s, 2H), 1.43 (t, 2H), 0.95 (s, 6H).

EXAMPLE 322

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-ethynyl-6- (tetrahydro- 2H-pyran-4-ylmethoxy) -pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 322A

6 - ((tetrahydro-2H-pyran-4-yl) methoxy) -5 - ((triisopropylsilyl) ethynyl) pyridine-3-sulfonamide [1049] EXAMPLE 301B (0.176 g), bis (triphenylphosphine) palladium (II) chloride ( 0.176 g), copper (I) iodide (0.010 g), N, N-dimethylacetamide (2.5 ml) and triethylamine (0.105 ml) were combined, purged with nitrogen and stirred for 2 minutes. (Triisopropyl) acetylene (0.135 mL) was added and the reaction mixture was purged with nitrogen again, heated at 60 ° C overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 10-30% ethyl acetate in hexane as the eluent to give the product. EXAMPLE 322B

5-ethynyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridine-3-sulfonamide [1050] EXAMPLE 322A (0.205 g) in tetrahydrofuran (3 mL) was treated at ambient temperature with tetrabutylammonium fluoride (1 M in tetrahydrofuran) (0.906 ml) and stirred at ambient temperature for 4 hours. Additional tetrabutylammonium fluoride (1 M in tetrahydrofuran) (1.8 mL) was added and the mixture was heated at 40 ° C for 45 minutes. Solid tetrabutylammonium fluoride (0.253 g) was added and heating continued for 30 minutes. The reaction mixture was concentrated and then chromatographed on silica gel using 0-2% methanol in dichloromethane as the eluent to give the product.

EXAMPLE 322C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[5-ethynyl-6- (tetrahydro- 2H-pyran-4-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1051] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 322B instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 1H), 8.62 (d, 1H), 8.22 (d, 1H), 7.53 (d, 1H), 7.35 (m, 5H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.41 (m, 1H), 6.08 (s, 1H), 4.56 (s, 1H), 4.25 (d, 2H) , 3.86 (dd, 2H), 3.35 (m, 2H), 3.05 (m, 4H), 2.81 (m, 2H), 2.24 (m, 6H), 2.04 ( m, 1H), 1.95 (s, 2H), 1.64 (dd, 2H), 1.36 (m, 4H), 0.92 (s, 6H).

EXAMPLE 323

4- (4 - {[4- (4-chlorophenyl) -6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl] methyl} piperazin-1-yl) -N - {[5etynylo- 6- (tetrahydro-2H-pyran-4-ylmethoxy) pyridin-3-yl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1052] The title compound was prepared by substituting EXAMPLE 277B for EXAMPLE 1F and EXAMPLE 322B instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 12.39 (s, 1H), 9.27 (d, 1H), 8.90 (d, 1H), 8.09 (d, 1H), 7.52 (t, 1H), 7.46 (m, 4H), 7.10 (m, 2H), 6.68 (dd, 2H), 6.60 (m, 1H), 6.50 (d, 1H), 4.49 (s, 1H) , 4.38 (m, 2H), 4.22 (d, 2H), 3.95 (dd, 2H), 3.29 (td, 2H), 2.98 (m, 4H), 2.82 ( s, 2H), 2.21 (m, 2H), 2.09 (m, 4H), 1.98 (m, 1H), 1.63 (dd, 2H), 1.42 (m, 2H), 1.29 (s, 6H).

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EXAMPLE 324 trans-2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-yl-cyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide

EXAMPLE 324A

Methyl 4-fluoro-2- (6-nitropyridin-3-yloxy) benzoate [1053] To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and 2-nitro-5-chloropyridine (21.9 g) cesium carbonate (45 g) was added in N, N-dimethylformamide (120 mL). The mixture was stirred at 50 ° C overnight. The mixture was diluted with ethyl acetate (800 mL) and washed with water (3x) and brine. After drying over Na₂SO₄ and filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (2% ethyl acetate in dichloromethane) to afford the title compound.

EXAMPLE 324B

Methyl 2- (6-aminopyridin-3-yloxy) -4-fluorobenzoate [1054] EXAMPLE 324A (12.995 g) and methanol (150 ml) were added to Raney nickel moistened with water (6.50 g) in a 250 ml pressure bottle stainless steel and stirred for 2 hours at 30 psi (207 kPa) and room temperature. The mixture was filtered through a nylon membrane and concentrated to afford the title compound.

EXAMPLE 324C

Methyl 2- (6-amino-5-chloropyridin-3-yloxy) -4-fluorobenzoate [1055] EXAMPLE 324B (3.0 g) and 1-chloropyrrolidine-2,5-dione (1.680 g) were mixed together in N, N-dimethylformamide (30 ml) at room temperature under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (200 mL) and washed with water (75 mL), brine (75 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (GraceResolv 80 g) using a 5% to 35% ethyl acetate / hexane gradient over 40 minutes (flow = 40 ml / min) as the eluent gave the title compound.

EXAMPLE 324D

Methyl 2- (6-amino-5-chloropyridin-3-yloxy) -4- (piperazin-1-yl) benzoate [1056] A solution of EXAMPLE 324C (8.90 g) and piperazine (10.34 g) in dimethyl sulfoxide ( 100 ml) heated to 85 ° C. After 3 hours of stirring, the reaction was cooled, diluted with ethyl acetate (400 mL) and washed with water (2 x 250 mL), brine (250 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound.

EXAMPLE 324E

2-chloro-4,4-dimethylcyclohex-1-enocarbaldehyde [1057] To a 250 mL round bottom flask was added N, N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to -10 ° C, and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was refluxed overnight. The reaction was quenched with a 0 ° C sodium acetate solution (25 g in 50 mL water). The aqueous layer was extracted with ether (3x 200 mL). The organic layers were combined, dried over

On₂SO₄, filtered, and dried under reduced pressure to obtain the title compound.

EXAMPLE 324F

2- (4-chlorophenyl) -4,4-dimethyl-1-enokarboksyaldehyd

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EP-2507211B1EN [1058] EXAMPLE 324E (6.8 g), 4-chlorophenyl boronic acid (6.5) was added to a 1 L round bottom flask.

g) and palladium (II) acetate (0.2 g) in water (100 ml) to form a suspension. Potassium carbonate (15 g) and tetrabutylammonium bromide (10 g) were added. After degassing by subjecting to pressure reduction and nitrogen treatment, the mixture was stirred at 45 ° C for 4 hours. After filtration through silica gel, ether (4 x 200 mL) was used to extract the product. The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated and purified by flash chromatography on silica using 0 to 10% ethyl acetate in hexane to afford the title compound.

EXAMPLE 324G

2- (6-amino-5-chloro-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate methyl [1059] To a solution of EXAMPLE 324D (9.0 g) in dichloromethane (75 ml) was added EXAMPLE 324F (7.40 g) as a solution in dichloromethane (25 ml). Sodium triacetoxyborohydride (7.89 g) was added to the solution, and the reaction was stirred at room temperature overnight. The reaction was quenched with a saturated solution

NaHCO₃ (100 ml) and extracted with dichloromethane (3 x 100 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel (Reveleris 330 g) using a 10% to 75% ethyl acetate / hexane gradient over 40 minutes as the eluent (flow = 90 ml / min) gave the title compound.

EXAMPLE 324H 2- (6-Amino-5-chloropyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) acid benzoic [1060] To a solution of EXAMPLE 324G (12.5 g) in tetrahydrofuran (50 mL) and methanol (25 mL) was added lithium hydroxide (1.0 M, 52.5 mL) and the reaction was heated to 55 ° C. The reaction was stirred for 4 hours, cooled, diluted with dichloromethane (300 mL) and water (50 mL) and quenched with 1N aqueous HCl (1.0M, 50 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.

EXAMPLE 324I tert-butyl trans-4-morpholinocyclohexylcarbamate [1061] A solution of tert-butyl trans-4-aminocyclohexylcarbamate (20.32 g), 1-bromo-2- (2-bromoethoxy) ethane (14.30 ml) and triethylamine (33, 0 ml) in N, N-dimethylformamide (200 ml) was stirred for 16 hours at 70 ° C. The reaction mixture was cooled to room temperature and concentrated, and the product was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution (15% aq.), Dried (Na₂SO₄) and concentrated to give the title compound.

EXAMPLE 324J bis trans-4-morpholinocyclohexanamine hydrochloride [1062] To a solution of EXAMPLE 324I (19.2 g) in dichloromethane (100 mL) was added HCl (100 mL, 4M in dioxane) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ether and the solid salt was filtered off and dried to give the title compound.

EXAMPLE 324K

4- (trans-4-morpholinocyclohexylamino) -3-nitrobenzenesulfonamide [1063] To the suspension of EXAMPLE 324J (1.00 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.90 g) in tetrahydrofuran (15 ml) was added diisopropylethylamine (4 , 75 ml) and the reaction was stirred at temperature

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EP-2507211B1EN overnight. The reaction was filtered and the solid washed with dichloromethane. The reaction mixture was combined with the washes and concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound.

EXAMPLE 324L trans-2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-morpholin-4-ylcyclohexyl) amino] -3-nitrophenyl} sulfonyl) benzamide [1064] EXAMPLE 324H suspension (0.72 g), EXAMPLE 324K (0 , 48 g), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (0.36 g) and 4- (dimethylamino) pyridine (0.45 g) was stirred in dichloromethane (5 ml). After 1 hour, N, N-dimethylformamide (10 drops) was added and the reaction stirred overnight. Additional N, N-dimethylformamide (2 mL) and dichloromethane (5 mL) were added to the reaction and stirring continued for an additional 24 hours. The reaction was loaded onto silica gel (Reveleris 330 g) and eluted using a gradient of 0.5% to 7.5% methanol / dichloromethane over 40 minutes (flow = 100 ml / minute). The resulting solid was triturated with acetonitrile at 60 ° C for 1 hour, cooled to room temperature, filtered and dried in a vacuum oven at 75 ° C overnight to afford the title compound. ¹H NMR (500 MHz, pyridine-d₅) δ 9.31 (d, 1H), 8.44 (dd, 1H), 8.40 (d, 1H), 8.08 - 7.99 (m, 2H), 7.47 - 7.43 ( m, 2H), 7.41 (d, 1H), 7.11 - 7.07 (m, 2H), 7.05 (d, 1H), 6.90 (s, 2H), 6.72 (dd , 1H), 6.53 (d, 1H), 3.79 - 3.70 (m, 4H), 3.52 - 3.38 (m, 1H), 3.16 - 3.07 (m, 4H ), 2.79 (s, 2H), 2.54 - 2.45 (m, 4H), 2.28 (t, 2H), 2.25 - 2.13 (m, 5H), 2.08 ( d, 2H), 1.99 (s, 2H), 1.92 - 1.83 (m, 2H), 1.45 - 1.18 (m, 6H), 0.95 (s, 6H).

EXAMPLE 326

N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 326A

5-chloro-6 - ((4-fluorotetrahydro-2H-pyrene n-4-yl) methoxy) pyridine-3-sulfonamide [1065] The title compound was prepared by substituting EXAMPLE 303A for EXAMPLE 305A and EXAMPLE 296C for (1,3- dioxan-4-yl) methanol in EXAMPLE 305B.

EXAMPLE 326B

N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1066] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 122C and EXAMPLE 326A instead of EXAMPLE 11A in EXAMPLE 137. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.18 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.55 (d, 1H), 7.34 (m, 4H), 7.23 (br d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 4.53 (d, 2H ), 3.77 (m, 2H), 3.60 (m, 2H), 3.06 (v br s, 4H), 2.82 (br s, 2H), 2.27 (v br s, 4H ), 2.15 (br m, 2H), 1.95 (s, 2H), 1.85 (m, 4H), 1.40 (t, 2H), 0.92 (s, 6H).

EXAMPLE 327

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4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylopiperydyn yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1067] The title compound was prepared as described in EXAMPLE 1H by replacing EXAMPLE 1F and EXAMPLE 1G, respectively EXAMPLE 154E and EXAMPLE 65A. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 1H), 8.57 (d, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.33 (m, 5H), 7.18 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H) , 3.70 (m, 1H), 2.98 (m, 6H), 2.73 (s, 2H), 2.23 (m, 6H), 1.93 (m, 4H), 1.76 ( m, 1H), 1.57 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H), 0.43 (m, 5H).

EXAMPLE 328

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(3-4etylomorfolin yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 328A (4-ethylmorpholin-3-yl) methanol [1068] Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in N, N-dimethylformamide were treated with K₂WHAT₃ (1.1 g) overnight. The reaction mixture was diluted with water and extracted with ethyl acetate.

The organic layer was dried over Na₂SO₄ and concentrated to give the title compound.

EXAMPLE 328B

4 - ((4-ethylmorpholin-3-yl) methoxy) -3-nitrobenzenesulfonamide [1069] The title compound was prepared as described in EXAMPLE 285A by replacing (1,4-dioxan-2-yl) methanol with EXAMPLE 328A.

EXAMPLE 328C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(3-4etylomorfolin yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1070] The title compound was prepared as described in EXAMPLE 110F by replacing EXAMPLE 110E and EXAMPLE 1G, respectively EXAMPLE 154E and EXAMPLE 328B. ¹H

NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 2H), 8.37 (d, 1H), 8.10 (dd, 1H), 7.52 (t, 2H), 7.37 (t, 1H), 7.31 - 7.36 (m, 3H), 7.26 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.09 ( d, 1H), 4.43 (dd, 1H), 4.24 (dd, 1H), 3.80 (dd, 1H), 3.64 - 3.74 (m, 1H), 3.49 - 3 , 61 (m, 2H), 3.03 (s, 4H), 2.92 (s, 1H), 2.78 (s, 4H), 2.52 - 2.60 (m, 1H), 2, 45 (s, 1H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H), 1.00 (t, 3H ), 0.92 (s, 6H).

EXAMPLE 329

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[(3S) -1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 329A (T) -1- (tetrahydro-2H-pyran-4-yl) piperidin-3-ylcarbamate tert-butyl [1071] The title compound was prepared by substituting dihydro-2H-pyran-4 (3H) -one for 4 ' chlorobiphenyl-2-carboxaldehyde and tert-butyl (S) -piperidin-3-ylcarbamate instead of tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 329B (S) -1- (tetrahydro-2H-pyran-4-yl) piperidin-3-amine

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[1072] The title compound was prepared by substituting EXAMPLE 329A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 329C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(3-nitro-4 - {[(3S) -1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl] amino} phenyl) sulfonyl] benzamide [1073] The title compound was prepared by substituting EXAMPLE 329B for 2-amino-2- (tetrahydro-2H-pyran-4-yl) ethanol in EXAMPLE 240B. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.92 (br s, 1H), 8.58 (br s, 1H), 7.85 (m, 1H), 7.52 (d, 1H), 7.37 (m, 1H), 7 , 33 (m, 3H), 7.28 (br s, 1H), 7.10 (br s, 1H), 7.03 (d, 2H), 6.65 (m, 1H), 6.40 ( br s, 1H), 6.08 (m, 1H), 3.98 (br s, 1H), 3.90 (m, 2H), 3.27 (m, 2H), 3.01 (m, 4H ), 2.77 (m, 4H), 2.60 (m, 2H), 2.16 (m, 6H), 1.94 (m, 2H), 1.64 (m, 5H), 1.50 (m, 3H), 1.38 (m, 2H), 1.23 (m, 1H), 0.94 (s, 6H).

EXAMPLE 330

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) benzamide [1074] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 296D instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, CDCl₃) δ 9.88 (s, 1H), 8.58 (d, 1H), 8.38 (dd, 1H), 7.91 (t, 2H), 7.36 (d, 1H), 7.29 - 7.11 (m, 3H), 6.94 (d, 2H), 6.62 6.47 (m, 1H), 5.96 (s, 1H), 4.96 (s, 2H), 4 , 19 (d, 2H), 3.81 (dt, 4H), 3.13 (s, 4H), 2.78 (s, 2H), 2.22 (d, 6H), 2.07 - 1, 78 (m, 6H), 1.44 (s, 2H), 0.97 (d, 6H).

EXAMPLE 331

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1,1dioksydotiomorfolin- 4-yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 331A

3-nitro-4- (dioxydothiomorpholinoamino) benzenesulfonamide [1075] The title compound was prepared by substituting 4-aminothiomorpholine 1,1-dioxide for instead of 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 331B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(1,1dioksydotiomorfolin- 4-yl) amino] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1076] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 331A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.22 (s, 1H), 9.65 (s, 1H), 8.56 (d, 1H), 7.88 (m, 2H), 7.51 (d, 1H), 7.35 (m, 5H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.41 (d, 1H), 6.07 (d, 1H), 3.46 (m, 4H) , 3.18 (m, 4H), 3.02 (m, 4H), 2.73 (s, 2H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 ( t, J = 6.15 Hz, 2H), 0.92 (s, 6H).

EXAMPLE 332

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(tetrahydrofuran-3-ylmethyl) amino] phenyl} sulfonyl) benzamide EXAMPLE 332A

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3-nitro-4 - ((tetrahydrofuran-3-yl) methylamino) benzenesulfonamide [1077] The title compound was prepared by substituting 2-aminomethyl tetrahydrofuran for 3- (Nmorpholinyl) -1-propylamine in EXAMPLE 4A.

EXAMPLE 332B

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - ({3-nitro-4 - [(tetrahydrofuran-3-ylmethyl) amino] phenyl} sulfonyl) benzamide [1078] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 332A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.30 (br.s, 1H), 11.23 (s, 1H), 8.66 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H), 7 , 50 (d, 1H), 7.38 (t, 1H), 7.34 (m, 3H), 7.30 (d, 1H), 7.16 (d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.10 (s, 1H), 3.80 (q, 1H), 3.70 (t, 1H), 3, 63 (q, 1H), 3.51 (dd, 1H), 3.40 (m, 2H), 3.06 (br.s, 4H), 2.80 (m, 2H), 2.58 (m , 2H), 2.35-2.10 (m, 5H), 2.00-1.90 (m, 3H), 1.65 (m, 1H), 1.39 (t, 2H), 0, 94 (s, 6H).

EXAMPLE 333 trans-N - ({5-bromo-6 - [(4-morpholin-4-ylcyclohexyl) oxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 333A trans-4-morpholinocyclohexanol [1079] trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2- (2-bromoethoxy) ethane (1.07 g) and triethylamine (2.42 ml) were dissolved in anhydrous acetonitrile (20 ml). The reaction mixture was heated at 60 ° C overnight. The organic solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 7-10% methanol in dichloromethane to afford the title compound.

EXAMPLE 333B trans-5-bromo-6- (4-morpholinocyclohexyloxy) pyridine-3-sulfonamide [1080] The title compound was prepared by substituting EXAMPLE 333A instead of (1,4-dioxan-2-yl) methanol in EXAMPLE 305B.

EXAMPLE 333C trans-N - ({5-bromo-6 - [(4-morpholin-4-ylcyclohexyl) oxy] pyridin-3-yl} sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1081] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 333B instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.15 (s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 7.57 (d, 1H), 7.33 (m, 4H), 7.18 (d, 1H), 7.05 (d, 2H), 6.60 (dd, 1H), 6.37 (s, 1H), 6.07 (d, 1H), 5.02 (m, 1H) , 3.68 (m, 4H), 2.99 (m, 4H), 2.74 (m, 7H), 2.23 (m, 8H), 1.95 (m, 4H), 1.41 ( m, 6H), 0.92 (s, 6H).

EXAMPLE 334 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[ 4 (dicyclopropylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 334A (trans) -4- (dicyclopropylamino) tert-butyl cyclohexylcarbamate

206

[1082] Suspension of tert-butyl (trans) -4-aminocyclohexylcarbamate (1 g), 3A molecular sieves (1 g), acetic acid (2.67 ml), (1-ethoxycyclopropoxy) trimethylsilane (3.74 ml) ) and sodium cyanoborohydride (0.880 g) in dry methanol (10 ml) was heated to reflux for 3 hours. Insoluble substances were filtered off, the resulting solution was basified with aqueous NaOH (6 M) to pH 14, and extracted with ether. The combined extracts were washed with brine, dried and concentrated. The residue was purified by flash chromatography (80 g silica gel, 30-100% acetone / hexane) to afford the product.

EXAMPLE 334B bis (2,2,2-trifluoroacetate) (trans) -N¹N¹-dicyclopropylcyclohexane-1,4-diamine [1083] The title compound was prepared by substituting EXAMPLE 334A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 334C trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[ 4- (dicyclopropylamino) cyclohexyl] amino} -3-nitrophenyl) sulfonyl] -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1084] EXAMPLE 240A suspension (0.14 g), EXAMPLE 334B (0.110 g) and N, N-diisopropylethylamine (0.303 mL) in dioxane (3 mL) was stirred for 3 days at 100 ° C. The mixture was concentrated and purified by RP HPLC (C8, 30% - 100% CH₃CN / water / 0.1% TFA). ¹H NMR (500 MHz, pyridine-d₅) δ 12.38 (s, 1H), 9.31 (d, 1H), 8.48 (dd, 1H), 8.38 (d, 1H), 8.15 (d, 1H), 7.47 - 7.53 (m, 3H), 7.41 - 7.46 (m, 3H), 7.01 - 7.08 (m, 3H), 6.72 (dd, 1H), 6.54 - 6 , 59 (m, 2H), 3.45 (ddd, 1H), 3.01 - 3.07 (m, 4H), 2.72 - 2.79 (m, 3H), 2.24 (t, 2H ), 2.10 (d, 6H), 2.00 - 2.06 (m, 2H), 1.96 (s, 2H), 1.88 (d, 2H), 1.67 (qd, 2H) , 1.34 - 1.40 (m, 2H), 1.20 - 1.29 (m, 2H), 0.93 (s, 6H), 0.48 (d, 8H).

EXAMPLE 335 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - [(3-nitro-4 - {[4- (tetrahydro-2H-pyran-4-ylamino) cyclohexyl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 335A (tert-butyl) (trans) -4- (tetrahydro-2H-pyran-4-ylamino) cyclohexylcarbamate [1085] The title compound was prepared by substituting tertbutyl (trans) -4-aminocyclohexylcarbamate for tert-butyl piperazine-1-carboxylate and dihydroxyl -2H-pyran-4 (3H) -one instead of 4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 335B bis (2,2,2-trifluoroacetate) (trans) -N¹- (tetrahydro-2H-pyran-4-yl) cyclohexane-1,4-diamine [1086] The title compound was prepared by substituting EXAMPLE 335A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 335C trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - [(3-nitro-4 - {[4- (tetrahydro-2H-pyran-4-ylamino) cyclohexyl] amino} phenyl) sulfonyl] benzamide [1087] The title compound was prepared by substitution of EXAMPLE 335B for EXAMPLE

334B in EXAMPLE 334C. ¹H NMR (500 MHz, pyridine-d₅) δ 12.35 (s, 1H), 9.30 (d, 1H), 8.40 (dd, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.51 (dd, 2H), 7.46 - 7.49 (m, 2H), 7.43 (d, 2H), 7.05 (d, 2H), 6.92 (d, 1H),

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6.73 (dd, 1H), 6.54 - 6.59 (m, 2H), 3.99 - 4.04 (m, 2H), 3.45 - 3.52 (m, 1H), 3, 41 (t, 2H), 3.10 (s, 1H), 3.01

- 3.07 (m, 4H), 2.91 (s, 1H), 2.75 (s, 2H), 2.21 - 2.26 (m, 2H), 2.11 (d, 5H), 2.08 (d, 3H), 1.96 (s, 4H), 1.59 (s, 2H), 1.54 (d, 2H), 1.30 - 1.40 (m, 4H), 0 , 93 (s, 6H).

EXAMPLE 336 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - [(3-nitro-4 - {[4- (4-tetrahydro-2H-pyran-4-yl-piperazin-1-yl) cyclohexyl] amino} phenyl) sulfonyl] benzamide

EXAMPLE 336A

Tert-butyl 4- (tetrahydro-2H-pyran-4-yl) piperazine-1-carboxylate [1088] For tert-butyl piperazine-1-carboxylate solution (5.15 g) and dihydro-2H-pyran-4 (3H ) -one (3.05 g) in titanium (IV) isopropoxide (16.20 mL) stirred for 24 hours at room temperature, methanol (5 mL) added followed by careful addition of sodium borohydride (2.092 g). The reaction was quenched with water / NaOH solution, extracted with ether, dried over magnesium sulfate, filtered, and concentrated to give the product. The crude product was used in the next step.

EXAMPLE 336B 1- (Tetrahydro-2H-pyran-4-yl) piperazine dihydrochloride [1089] To a solution of EXAMPLE 336A (3.92 g) in ether was added HCl (25 mL, 2M in ether) and the reaction mixture was stirred for 16 hours in room temperature. The solid product was filtered off, dried and used in the next step without further purification.

EXAMPLE 336C tert-butyl trans-4- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) cyclohexylcarbamate [1090] For the solution of EXAMPLE 336B (1 g) and tert-butyl 4-oxocyclohexylcarbamate g) in titanium (IV) isopropoxide (2.410 mL) stirred for 24 hours at room temperature, methanol (2 mL) was added followed by careful addition of sodium borohydride (0.311 g). The reaction was quenched with water, extracted with ether, dried and concentrated. The crude product was purified by flash chromatography (silica 80 g, 50% - 100% acetone / hexane) to give the product.

EXAMPLE 336D tris (2,2,2-trifluoroacetate) trans-4- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) cyclohexanamine [1091] The title compound was prepared by substituting EXAMPLE 336C for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 336E trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - [(3-nitro-4 - {[4- (4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl) cyclohexyl] amino} phenyl) sulfonyl] benzamide [ 1092] The title compound was prepared by substituting EXAMPLE 336D for EXAMPLE 334B in EXAMPLE 334C. ¹H NMR (500 MHz, pyridine-d₅) δ 12.38 (s, 1H), 9.30 - 9.34 (m, 1H), 8.41

- 8.46 (m, 1H), 8.37 (d, 1H), 8.15 (d, 1H), 7.48 - 7.53 (m, 3H), 7.41 - 7.46 (m , 3H), 7.04 (d, 2H), 6.96 (t, 1H), 6.69 - 6.74 (m, 1H), 6.54 - 6.59 (m, 2H), 3, 99 - 4.05 (m, 2H), 3.29 - 3.36 (m, 2H), 3.05 (s, 4H), 2.74 (s, 2H), 2.62 (s, 5H) , 2.57 (s, 3H), 2.27 - 2.36 (m, 2H), 2.19 - 2.27 (m, 3H), 2.11 (s, 6H), 1.96 (s , 2H), 1.91 (s, 1H), 1.87 (s, 1H), 1.70 (s, 2H), 1.64 (s, 1H), 1.56 (td, 2H), 1 , 35 - 1.43 (m, 4H), 1.29 (s, 2H), 0.93 (s, 6H).

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EXAMPLE 337

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 337A (4-fluorotetrahydro-2H-pyran-4-yl) methyl methanesulfonate [1093] A mixture of EXAMPLE 296C (1.4 g), methanesulfonyl chloride (1.054 mL), triethylamine (2.99 mL), and 4- (dimethylamino ) pyridine (0.051 g) in CH₂cl₂ (20 ml) was stirred at 0 ° C for 2 hours, concentrated and chromatographed on silica gel using 30% ethyl acetate in hexane as the eluent to give the product.

EXAMPLE 337B

2 - ((4-fluorotetrahydro-2H-pyran-4-yl) methyl) isoindoline-1,3-dione [1094] A mixture of EXAMPLE 337A (1.8 g) and potassium phthalimide (2.356 g) in N, N-dimethylformamide (30 ml) was heated at 150 ° C overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 30% ethyl acetate in hexane as the eluent to give the product.

EXAMPLE 337C (4-fluorotetrahydro-2H-pyran-4-yl) methanamine [1095] A mixture of EXAMPLE 337B (1.4 g) and hydrazine (1.548 ml) in ethanol (40 ml) was heated at 70 ° C overnight, cooled to room temperature, suspended in CH₂cl₂ (200 ml) and the solid removed by filtration. The filtrate was concentrated and chromatographed on silica gel with 100: 5: 1 ethyl acetate / methanol / NH₄OH as the eluent to obtain the product.

EXAMPLE 337D

4 - ((4-fluorotetrahydro-2H-pyran-4-yl) methylamino) -3-nitrobenzenesulfonamide [1096] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE 337C (0.266 g), and triethylamine ( 1.11 ml) in tetrahydrofuran (10 ml) was heated at 70 ° C overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel using 50% ethyl acetate in hexane as the eluent to give the product.

EXAMPLE 337E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6-fluoro-1H-indol-5- yl) oxy] -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [1097] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 337D instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 (m, 2H), 8.63 (t, 1H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.33 (m, 6H), 7.03 (m, 2H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.09 (d, 1H), 3.74 (m, 4H) , 3.52 (m, 2H), 3.03 (m, 4H), 2.74 (m, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.80 ( m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 338 trans-4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(6fluoro-1H- indol-5-yl) oxy] -N - [(4 - {[(4-hydroxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

209

[1098] A mixture of EXAMPLE 240A (153 mg), trans-4- (aminomethyl) cyclohexanol (73.5 mg) and Netyl-N-isopropylpropane-2-amine (0.16 ml) in dioxane (2 ml) heated at 100 ° C for hours and concentrated. The residue was dissolved in dimethyl sulfoxide-methanol (1: 1) and purified by HPLC, eluting with 40% -65% acetonitrile in water with 0.1% TFA for 40 minutes to afford the title compound.¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.22 (s, 2H), 8.56 - 8.62 (m, 2H), 7.85 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H) , 7.29 - 7.36 (m, 4H), 7.12 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 4.51 (d, 1H), 3.24 (t, 2H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16 (d , 6H), 1.95 (s, 2H), 1.83 (d, 2H), 1.74 (d, 2H), 1.56 (dd, 1H), 1.38 (t, 2H), 0 , 95-1.16 (m, 4H), 0.92 (s, 6H).

EXAMPLE 339

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({3- [3- (dimethylamino) propyl ] -1H-indol-4-yl} oxy) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 339A

Methyl 2- (1H-indol-4-yloxy) -4-fluorobenzoate [1099] Methyl 2,4-difluorobenzoate (1.53 g), K₃AFTER₄ (1.89 g) and 4-hydroxyindole (1.08 g) were stirred at 110 ° C in diglyme (12 ml) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M aqueous NaOH, and brine, and dried over Na₂SO₄. The solution was then concentrated, and the crude product was chromatographed on silica gel using 20% ​​ethyl acetate / hexane.

EXAMPLE 339B

Methyl 2- (1H-indol-4-yloxy) -4- (piperazin-1-yl) benzoate [1100] EXAMPLE 339A (1425 mg), piperazine (452 ​​mg), and HK₂AFTER₄ (958 mg) was stirred in dimethyl sulfoxide (20 mL) at 140 ° C for 24 hours. The reaction was diluted with ethyl acetate, washed three times with water, washed with brine, dried over Na₂SO₄, and concentrated. The crude product was chromatographed on silica gel using a methanol / methylene chloride gradient. EXAMPLE 339C

Methyl 2- (3-bromo-1H-indol-4-yloxy) -4- (piperazin-1-yl) benzoate [1101] A solution of EXAMPLE 339B (1 g) in dichloromethane (50 ml) and N, N-dimethylformamide ( 5 ml) cooled in an ice bath. N-bromosuccinimide (0.582 g) was added and the mixture was stirred overnight as it warmed to ambient temperature. The reaction was concentrated and the crude product was chromatographed on silica gel using a methanol / methylene chloride gradient.

EXAMPLE 339D

Tert-butyl 3-bromo-4- (5- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- (methoxycarbonyl) phenoxy) -1H-indol-1-carboxylate [1102] EXAMPLE 339C (388 mg) and di-tert-butyl dicarbonate (590 mg) was dissolved in a mixture of acetonitrile (20 mL), and dichloromethane (20 mL). N-ethyl-N-isopropylpropan-2-amine (0.165 ml) was added followed by N, N-dimethylpyridin-4-amine (33.0 mg) and the mixture was stirred for 18 hours. The reaction was concentrated and the crude product was purified on a silica gel layer with 15% ethyl acetate in hexane.

EXAMPLE 339E (E) -4- (3- (3- (3- (dimethylamino) prop-1-enyl) -1H-indol-4-yloxy) -4- (methoxycarbonyl) phenyl) piperazine tert- carboxylate butyl

210

EP-2507211B1EN [1103] A mixture of EXAMPLE 339D (175 mg), (E) -N, N-dimethyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prop-2 -ene-1-amine (103 mg), sodium carbonate (73.5 mg) and bis (triphenylphosphine) palladium (II) dichloride (9.74 mg) in a mixture of 1,2-dimethoxyethane (3.0 ml) and water (1.5 ml) was heated in a CEM Discover microwave reactor at 150 ° C for 30 minutes. The reaction was partitioned between brine and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel using a gradient of 7N ammonia in methanol / methylene chloride.

EXAMPLE 339F

Tert-butyl 4- (3- (3- (3- (dimethylamino) propyl) -1H-indol-4-yloxy) -4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate [1104] A mixture of EXAMPLE 339E (715 mg) and 5% palladium on carbon (143 mg) in methanol (20 ml) was hydrogenated at 30 psi (207 kPa) for 16 hours at ambient temperature. The reaction mixture was filtered, concentrated and the crude product was chromatographed on silica gel using a 7N ammonia in methanol / methylene chloride gradient.

EXAMPLE 339G

Methyl 2- (3- (3- (dimethylamino) propyl) -1H-indol-4-yloxy) -4- (piperazin-1-yl) benzoate [1105] A solution of EXAMPLE 339F (484 mg) in dichloromethane (22 ml) cooled in an ice bath and 2,2,2-trifluoroacetic acid (11 ml) added. The reaction was stirred for 2 hours, concentrated and the crude product was chromatographed on silica gel using a 7N ammonia in methanol / methylene chloride gradient.

EXAMPLE 339H

4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (3- (dimethylamino) propyl) -1H-indole Methyl-4-yloxy) benzoate [1106] To a solution of EXAMPLE 339G (285 mg) and EXAMPLE 60D (171 mg) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (208 mg) in portions over a few minutes. The reaction was stirred for 72 hours at ambient temperature, quenched by the slow addition of saturated aqueous sodium bicarbonate solution (100 mL) and extracted with methylene chloride (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel using a gradient of 7N ammonia in methanol / methylene chloride.

EXAMPLE 339I 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (3- (3- (dimethylamino) propyl) - 1H-indol-4-yloxy) benzoic [1107] The title compound was prepared by substituting EXAMPLE 399H for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 399J

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({3- [3- (dimethylamino) propyl ] -1H-indol-4-yl} oxy) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1108] The title compound was prepared by substitution EXAMPLE 339I instead of EXAMPLE 1F in

EXAMPLE 1H. 1 H NMR (500 MHz, pyridine-d₅) δ 12.00 (s, 1H), 9.24 (s, 1H), 8.49 (m, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.11 (d, 2H), 7.00 (t, 1H), 6.81 (m, 3H), 6.63 (d, 1H) , 3.96

211

EP-2507211B1PL (d, 2H), 3.30 (t, 2H), 3.06 (m, 10H), 2.82 (m, 7H), 2.49 (m, 2H), 2.24 (m , 5H), 1.99 (m, 1H), 1.76 (m, 1H),

1.55 (m, 2H), 1.41 (m, 2H), 1.25 (m, 4H), 0.96 (m, 6H), 0.84 (m, 2H).

EXAMPLE 340

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({3- [3- (dimethylamino) propyl ] -1H-indol-4-yl} oxy) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl sulfonyl) benzamide [1109] The title compound was prepared by substituting EXAMPLE 339I for EXAMPLE 1F and EXAMPLE 184A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridinium₅) δ 11.98 (s, 1H), 9.19 (d, 1H), 8.97 (s, 1H), 8.48 (m, 1H), 8.42 (m, 1H), 7.63 (d, 1H), 7.46 (d, 2H), 7.25 (m, 2H), 7.11 (d, 2H), 7.00 (m, 1H), 6.80 (m, 2H) , 6.64 (m, 1H), 3.04 (m, 8H), 2.82 (m, 10H), 2.49 (m, 3H), 2.28 (m, 3H), 2.22 ( m, 6H), 2.16 (m, 3H), 2.08 (m, 1H), 1.99 (m, 2H), 1.40 (t, 2H), 0.96 (m, 6H), 0.84 (m, 2H).

EXAMPLE 341

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylo fluoro-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 341A

Tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate [1110] 4-Ethyl 1-tert-butyl 4-fluoro-piperidine-1,4-dicarboxylate (1.0 g) in tetrahydrofuran (5 mL) was treated using 1.0 N LiAlH₄ (2.54 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. Water (0.6 mL) was added dropwise to the reaction mixture, followed by 2 N aqueous NaOH (0.2 mL). The reaction was stirred for another 1 hour. The solid was removed by filtration through a celite pad and washed with ethyl acetate. The filtrate was washed with brine, dried over MgSO₄, filtered, and concentrated to give the product.

EXAMPLE 341B

Tert-butyl 4-fluoro-4 - ((2-nitro-4-sulfamoylphenoxy) methyl) piperidine-1-carboxylate [1111] The title compound was prepared by substituting EXAMPLE 341A for ((tetrahydro-2H-pyran-4-yl) methanol in EXAMPLE 264A .

EXAMPLE 341C

4 - ((4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide [1112] The title compound was prepared by substituting EXAMPLE 341B for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 341D

4 - ((1-cyclopropyl-4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide [1113] To EXAMPLE 341C (0.24 g) in methanol (3 ml) 3A molecular sieves (0.1 g) were added , followed by acetic acid (0.31 mL), (1-ethoxycyclopropoxy) trimethylsilane (0.64 mL), and sodium cyanoborohydride (0.148 g). The reaction was refluxed overnight. After cooling, the reaction mixture was added to a silica gel column. After drying, the column was eluted with 100: 2: 0.2 ethyl acetate / methanoul / NH₄OH to obtain the title compound.

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EP-2507211B1PL

EXAMPLE 341E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({4 - [(4-1cyklopropylo fluoropiperidin-4-yl) methoxy] -3-nitrophenyl} sulfonyl) -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1114] The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 341D instead EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.20 (s, 1H), 8.37 (d, 1H), 8.10 (d, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.32 -7.37 (m, 4H), 7.24 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.39 (s, 1H), 6.09 ( d, 1H), 4.34 (d, 2H), 3.05 (s, 4H), 2.90 (s, 2H), 2.78 (s, 2H), 2.14-2.26 (m , 6H), 1.68-1.82 (m, 4H), 1.38 (d, 2H), 0.92 (s, 6H), 0.40-0.49 (m, 4H).

EXAMPLE 342

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[1- (4-methoxybenzyl) -1H- 1,2,3-benzotriazol-4-yl] oxy} -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 342A

4- (tert-Butyl-dimethyl-silanyloxy) -1H-benzotriazole [1115] To 4-hydroxybenzotriazole (5.000 g) in tetrahydrofuran (250 ml) was added sodium hydride (60%, 0.932 g). The solution was stirred at room temperature for 20 minutes, cooled to 0 ° C, tert-butyldimethylchlorosilane (5.860 g) was added, the solution was allowed to warm to room temperature, and stirred for 16 hours. Additional sodium hydride (60%, 0.500 g) was added, the solution was stirred for 15 minutes, additional tert-butyldimethylchlorosilane (3.000 g) was added, and the solution was stirred for three hours at room temperature. The solution was then added to a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 20-30% ethyl acetate in hexane.

EXAMPLE 342B

4- (tert-Butyl-dimethyl-silanyloxy) -1- (4-methoxy-benzyl) -1H-benzotriazole [1116] To EXAMPLE 342A (2.00 g) in dimethylformamide (40 ml), sodium hydride (60%) was added. 0.353 g). The solution was stirred for 10 minutes at room temperature and 4-methoxybenzyl chloride (1.382 g) was added. The solution was heated at 80 ° C for 16 hours, cooled, added to water, and extracted with 50% ethyl acetate in hexane. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexane.

EXAMPLE 342C

1- (4-Methoxy-benzyl) -1H-benzotriazol-4-ol [1117] To a solution of EXAMPLE 342B (2.59 g) in tetrahydrofuran (40 mL) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 21.03 mL). The solution was stirred at room temperature for two hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was filtered under reduced pressure through a silica gel pad. The filtrate was concentrated and purified by flash column chromatography on silica gel using 35% ethyl acetate in hexane.

EXAMPLE 342D

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4-Fluoro-2- [1- (4-methoxy-benzyl) -1H-benzotriazol-4-yloxy] benzoic acid methyl ester [1118] For the solution of EXAMPLE 342C (990 mg) and methyl 2,4-difluorobenzoate (734 mg ) in diglyme (40 ml) potassium tert-butoxide (1M in tetrahydrofuran, 4.07 ml) was added. The solution was heated to 100 ° C for 16 hours, cooled, added to a saturated ammonium chloride solution, and extracted with 70% ethyl acetate in hexane. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane.

EXAMPLE 342E

2- [1- (4-methoxy-benzyl) -1H-benzotriazol-4-yloxy] -4-piperazin-1-benzoic acid methyl ester [1119] To a solution of EXAMPLE 342D (650 mg) in dimethyl sulfoxide (12 mL) was added piperazine ( 618 mg). The solution was heated at 100 ° C for one hour, cooled, added to dichloromethane, extracted with water three times, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure.

EXAMPLE 342F

4- {4- [2- (4-Chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- [1- (4-methoxy-benzyl) - methyl ester 1H-Benzotriazol-4-yloxy] benzoic [1120] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 342E for tert-butyl piperazine-1-carboxylate in

EXAMPLE 1A.

EXAMPLE 342G

4- {4- [2- (4-Chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] -piperazin-1-yl} -2- [1- (4-methoxy-benzyl) -1H- acid benzotriazol-4-yloxy] benzoic [1121] The title compound was prepared by substituting EXAMPLE 342F for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 342H

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - {[1- (4-methoxybenzyl) -1H- 1,2,3-benzotriazol-4-yl] oxy} -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1122] The title compound was prepared by substituting EXAMPLE 342G for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.59 (t, 1H), 8.37 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.38-7.23 (m, 3H) , 7.30 (d, 2H), 7.23 (t, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 6.91 (d, 2H), 6.80 ( dd, 1H), 6.51 (d, 1H), 6.37 (d, 1H), 5.87 (s, 2H), 3.85 (dd, 2H), 3.71 (s, 3H), 3.28 (m, 4H), 3.16 (bs, 2H), 2.78 (bs, 2H), 2.57 (bs, 2H), 2.29-2.14 (m, 6H), 1 , 97 (bs, 2H), 1.89 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.93 (s, 6H).

EXAMPLE 343

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [1123] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.04 - 10.47 (m, 1H), 9.19 (s, 1H), 8.50 (d, 1H), 7.90 - 7.83 (m, 1H), 7.70 ( d

214

EP-2507211B1PL

1H), 7.64 (s, 1H), 7.47 (d, 1H), 7.33 (dd, 3H), 7.06 (d, 2H), 6.63 (d, 1H), 6, 20 (d, 1H), 6.07 (s, 2H), 3.08 (s, 4H), 2.95 (s, 4H), 2.75 (s, 3H), 2.42 (s, 4H ), 2.19 (m, 8H), 1.97 (s, 2H), 1.41 (d, 2H), 0.94 (s, 6H).

EXAMPLE 344

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - {[4- (1,4-dioxane-2-ylmethoxy) -3-nitrophenyl] sulfonyl} benzamide [1124] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 285A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.54 - 11.15 (m, 1H), 8.35 (t, 2H), 8.05 (dd, 1H), 7.75 (d, 1H), 7.45 (d, 1H) , 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (d, 2H), 6.62 (d, 1H), 6.21 - 6.15 (m, 3H), 3.85 - 3.75 (m, 3H), 3.51 (m, 6H), 3.12 (m, 4H), 2.79 (s, 2H), 2.21 (m, 6H), 1 , 97 (s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 345 trans-2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[(4-methoxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 345A (4-methoxycyclohexyl) methanamine [1125] (4-Methoxyphenyl) methanamine (1 g) in ethanol (10 ml) was treated with 5% Rh-Al₂ABOUT₃(99.8 mg) in the atmosphere of H₂ (500 psi = 3.45 MPa) at 50 ° C for 16 hours. An additional 5% Rh-Al was added₂ABOUT₃ (0.4 g). The resulting mixture was stirred under H atmosphere₂ (500 psi = 3.45 MPa) at 60 ° C for 2 hours. Insoluble material was filtered off and the filtrate was concentrated to give a mixture of cis and trans product as an oil which was used for the next step without further purification.

EXAMPLE 345B

4 - ((trans-4-methoxycyclohexyl) methylamino) -3-nitrobenzenesulfonamide [1126] 4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 345A (1 g) in tetrahydrofuran (20 ml) was treated with diisopropylethylamine (0.871 ml) for night. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography, and eluted with 40-55% acetonitrile in a solution of 0.1% trifluoroacetic acid in water for 25 minutes to give the title compound.

EXAMPLE 345C trans-2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[(4-methoxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [1127] The title compound was prepared as described in EXAMPLE 110F by replacing EXAMPLE 110E and EXAMPLE, respectively 1G EXAMPLE 318H and EXAMPLE 345B. ¹H

NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.62 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d, 2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s, 3H) , 3.26 - 3.33 (m, 4H), 3.22 (s, 3H), 3.12 (s, 4H), 3.03 - 3.09 (m, 1H), 2.79 (s , 2H), 2.24 (s, 4H), 2.17 (s, 2H), 1.93 - 2.03 (m, 4H), 1.80 (d, 2H), 1.62 (dd, 1H), 1.40 (t, 2H), 0.98 - 1.14 (m, 4H), 0.94 (s, 6H).

EXAMPLE 346

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(1,4-dioxan-2-ylmethyl) amino] -3-nitrophenyl} sulfonyl) benzamide

215

EP-2507211B1EN [1128] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 291A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.54 - 11.15 (m, 1H), 8.59 (t, 2H), 7.87 (dd, 1H), 7.74 (d, 1H), 7.44 (d, 1H) .

7.34 (s, 3H), 7.20 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.21 - 6.15 (m, 3H), 3 , 84 - 3.75 (m, 3H), 3.51 (m,

6H), 3.12 (s, 4H), 2.79 (s, 2H), 2.21 (d, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0, 94 (s, 6H).

EXAMPLE 347

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(3-morpholin-4-ylpropyl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

EXAMPLE 347A

4- (3-morpholinopropylamino) -3- (trifluoromethylsulfonyl) benzenesulfonamide [1129] 3-Morpholinopropane-1-amine (376 mg), EXAMPLE 131C (800 mg) and N-ethyl-Nisopropylpropane-2-amine (1.4 ml ) in tetrahydrofuran (15 ml) was heated at 55 ° C for 3 hours. The solvent was removed and the residue was dissolved in ethyl acetate and washed with water and brine.

The organic layer was dried over Na₂SO₄, filtered, and concentrated to give the title compound.

EXAMPLE 347B

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(3-morpholin-4-ylpropyl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide [1130] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 347A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.31 - 10.55 (m, 1H), 8.14 (s, 1H), 7.96 (d, 1H), 7.73 (d, 1H), 7.44 (d, 1H) , 7.36 (d, 4H), 7.12 (d, 1H), 7.06 (d, 2H), 6.64 (d, 1H), 6.17 (d, 3H), 3.61 ( s, 4H), 3.42 (d, 2H), 3.10 (s, 4H), 2.77 (s, 2H), 2.48 - 2.41 (m, 4H), 2.23 (s , 8H), 1.97 (s, 2H), 1.76 (s, 2H), 1.40 (s, 2H), 0.94 (s, 6H).

EXAMPLE 348

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3- [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

EXAMPLE 348A

4 - ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) -3- (trifluoromethylsulfonyl) benzenesulfonamide [1131] To a solution of EXAMPLE 296C (0.500 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.596 g). Tetrahydrofuran (25 mL) was added and the mixture was stirred for 30 minutes, then EXAMPLE 131C (1.145 g) was added as a solution in tetrahydrofuran (5 mL). After stirring for 2 hours, the reaction was partitioned between 1N aqueous HCl (50 mL) and dichloromethane (200 mL). The dichloromethane layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was chromatographed on silica gel (Reveleris 80 g) using a 0.5% to 7.5% methanol / dichloromethane gradient over 30 minutes (flow = 40 mL / min) to afford the title compound.

EXAMPLE 348B

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3- [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide

216

[1132] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 348A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.42 (s, 1H), 8.37 - 8.28 (m, 1H), 7.70 (s, 1H), 7.65 - 7.55 (m, 1H), 7.46 ( d, J = 8.8, 1H), 7.37 (d, J = 8.4, 3H), 7.07 (d, J = 8.4, 2H), 6.67 (s, 1H), 6.23 (s, 1H), 6.12 (s, 2H), 4.47 (d, J = 20.7, 2H), 3.76 (s, 2H), 3.60 (s, 2H) , 3.21 - 3.02 (m, 4H), 2.18 (s, 6H), 2.01 - 1.79 (m, 8H), 1.42 (s, 2H), 0.95 (s , 6H).

EXAMPLE 349

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -N - ({5-chloro-6 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] pyridin-3-yl } sulfonyl) -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-yl) benzamide [1133] The title compound was prepared by substitution EXAMPLE 326A instead of EXAMPLE 1G and EXAMPLE 318H instead of EXAMPLE 110E in EXAMPLE 110F. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.53 (s, 1H), 8.22 (s, 1H), 7.72 (s, 1H), 7.34-7.38 (m, 13H), 7.07 (d, 2H) , 6.66 (dd, 1H), 6.23 (s, 1H), 6.12 (s, 2H), 4.55 (d, 2H), 3.756-3.79 (m, 2H), 3, 57-3.62 (m, 2H), 3.15 (br s, 4H), 2.18 (m, 2H), 1.99 (s, 2H), 1.82-1.91 (m, 4H ), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 350

2 - [(6-amino-5-bromo-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 350A

Methyl 2- (6-amino-5-bromopyridin-3-yloxy) -4-fluorobenzoate [1134] A mixture of EXAMPLE 318B (1.6 g) in N, N-dimethylformamide (50 ml) was cooled to 0 ° C and then a solution of N-bromosuccinimide (1.195 g) in N, N-dimethylformamide (10 ml) was added. The reaction mixture was stirred at 0 ° C for 1 hour, and quenched with saturated aqueous NaHCO solution₃ chilled ice. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified using a flash chromatography column using 30-40% ethyl acetate / hexane to afford the title compound.

EXAMPLE 350B

2- (6-amino-5-bromo-pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate methyl [1135] The title compound was prepared by substituting EXAMPLE 350A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 350C 2- (6-Amino-5-bromopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-yl) methyl) piperazin-1-yl) benzoic [1136] The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 350D

2 - [(6-amino-5-bromo-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

217

EP-2507211B1EN [1137] The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.52 (m, 2H), 7.79 (dd, 1H),

7.73 (d, 1H), 7.49 (d, 1H), 7.40 (s, 1H), 7.36 (d, 2H), 7.13 (d, 1H), 7.06 (d , 2H), 6.64 (dd, 1H), 6.23 (d,

1H), 5.98 (s, 2H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.75 (s, 2H), 2, 19 (m, 6H), 1.93 (m, 4H), 1.63 (m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H ).

EXAMPLE 351

2-amino-5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- {[({ 3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} -phenoxy) -nicotinamide

EXAMPLE 351A

Methyl 2- (6-amino-5-cyanopyridin-3-yloxy) -4-fluorobenzoate [1138] EXAMPLE 350A (150 mg), zinc cyanide (28 mg) and tetrakis (triphenylphosphine) palladium (0) (61 mg) were dissolved in N, N-dimethylformamide (0.5 mL), N was blown three times₂. The reaction mixture was heated at 120 ° C for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography using 2.5-5% methanol / dichloromethane to afford the title compound.

EXAMPLE 351B

2- (6-amino-5-cyano-pyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate methyl [1139] The title compound was prepared by substituting EXAMPLE 351A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 351C 2- (6-Amino-5-carbamoylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-yl) methyl) piperazin-1-yl) acid benzoic [1140] The title compound was prepared by substituting EXAMPLE 351B for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 351D

2-amino-5- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- {[({ 3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) nicotinamide [1141] The title compound was prepared by substituting EXAMPLE 351C for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.50 (m, 2H), 7.91 (m, 1H), 7.79 (m, 3H), 7.50 (d, 1H), 7.36 (d, 2H), 7.31 (m, 1H), 7.07 (m, 5H), 6.59 (dd, 1H), 6.16 (s, 1H), 3.84 (dd, 2H), 3.27 (m, 4H) , 3.05 (s, 4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.98 (m, 3H), 1.90 (m, 1H), 1.63 ( m, 2H), 1.39 (m, 2H), 1.26 (m, 2H), 0.94 (s, 6H).

EXAMPLE 352

2 - [(6-amino-5-cyano-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 352A

218

2- (6-Amino-5-cyanopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl acid ) benzoic [1142] The title compound was prepared by substituting EXAMPLE 351B for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 352B

2 - [(6-amino-5-cyano-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1143] The title compound was prepared by substituting EXAMPLE 352A for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.46 (m, 2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.52 (d, 1H), 7.36 (m, 3H), 7.08 (m, 3H), 6.65 (dd, 1H), 6.59 (s, 2H), 6.28 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H) , 3.09 (s, 4H), 2.76 (s, 2H), 2.20 (m, 6H), 1.93 (m, 5H), 1.64 (m, 2H), 1.40 ( t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).

EXAMPLE 353

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(3R) -1- (2,2-difluoroethyl) pyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 353A (tert-butyl) (R) -1- (2,2-difluoroethyl) pyrrolidine-3-ylcarbamate [1144] tert-butyl (R) -pyrrolidin-3-ylcarbamate (500 mg) was combined with 1,1-difluoro- 2-iodoethane (618 mg) and N-ethyl-N-isopropylpropane-2-amine (1.4 ml) in N, N-dimethylformamide (6 ml) in a 20 ml vial. The reaction was heated to 70 ° C for 48 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography, eluting with a 0-5% methanol in dichloromethane gradient to afford the title compound.

EXAMPLE 353B (R) -1- (2,2-difluoroethyl) pyrrolidine-3-amine [1145] The title compound was prepared by substituting EXAMPLE 353A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 353C (R) -4- (1- (2,2-difluoroethyl) pyrrolidin-3-ylamino) -3-nitrobenzenesulfonamide [1146] The title compound was prepared by substituting EXAMPLE 353B for 3- (N-morpholinyl) 1-propylamine for EXAMPLE 4A.

EXAMPLE 353D

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(3R) -1- (2,2-difluoroethyl) pyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [1147] The title compound was prepared by substituting EXAMPLE 318H instead of EXAMPLE 1F and EXAMPLE 353C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.58 (d, 1H), 8.41 (d, 1H), 7.89 (dd, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.36 (m, 3H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.27, 6.13, 5.99 (each t, ​​together 1H ), 6.18 (d, 1H), 6.17 (br s, 2H), 4.31 (m, 1H), 3.12 (m, 4H), 2.92 (m, 5H), 2, 80 (m, 3H), 2.55 (m, 1H), 2.25 (m, 4H), 2.17 (m, 2H), 1.97 (s, 2H), 1.74 (m, 1H ), 1.40 (t, 2H), 0.94 (s, 6H).

219

EP-2507211B1PL

EXAMPLE 354

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(1-methylpiperidin-4-yl) amino] -3 - [(trifluoromethyl) sulfonyl] phenyl} sulfonyl) benzamide [1148] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 131D instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.07 (d, 1H), 7.90 (dd, 1H), 7.63 (d, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.16 (s, 1H), 7.07 (m, 3H), 7.63 (dd, 1H), 6.54 (br s, 1H), 6.26 (d, 1H), 5.95 (br s, 2H), 3.78 (m, 1H), 3.19 (m, 2H), 3.06 (m, 5H), 2.86 (m, 2H), 2.76 (m, 2H), 2, 63 (m, 2H), 2.23 (m, 4H), 2.18 (m, 2H), 2.07 (m, 2H), 1.97 (s, 2H), 1.63 (m, 2H) ), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 355

2 - {[6- (acetylamino) pyridin-3-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 355A

Methyl 2- (6-aminopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [1149] The title compound was prepared by substituting EXAMPLE 318B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 355B

Methyl 2- (6-acetamidopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [1150] EXAMPLE 355A (200 mg) was dissolved in anhydrous tetrahydrofuran (5 mL) followed by the addition of triethylamine (0.15 mL) and acetyl chloride (0.3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified on a flash chromatography column using 20-40% ethyl acetate / hexane to afford the title compound.

EXAMPLE 355C 2- (6-Acetamidopyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoic acid [1151] The title compound was prepared by substituting EXAMPLE 355B for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 355D

2 - {[6- (acetylamino) pyridin-3-yl] oxy} -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1- -yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1152] The title compound was prepared by substituting EXAMPLE 355C for EXAMPLE 110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.36 (s, 1H), 8.39 (m, 2H), 7.92 (d, 1H), 7.83 (s, 1H), 7.64 (m, 1H), 7.57 (d, 1H), 7.36 (d, 2H), 7.15 (m, 1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.68 (dd, 1H) , 6.34 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.76 (s, 2H), 2.20 ( m, 6H), 2.06 (s, 3H), 1.99 (m, 3H), 1.89 (m, 1H), 1.62 (m, 2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H)

220

EP-2507211B1PL

EXAMPLE 356

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({6 [(methylsulfonyl) amino] pyridin -3-yl} oxy) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 356A

Methyl 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6- (methylsulfonamido) pyridin-3-yloxy) benzoate [1153] The title compound was prepared by substituting methanesulfonyl chloride for acetyl chloride in EXAMPLE 355B.

EXAMPLE 356B 4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) -2- (6- (methylsulfonamido) pyridin-3-yloxy) acid benzoic [1154] The title compound was prepared by substituting EXAMPLE 356A for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 356C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - ({6 [(methylsulfonyl) amino] pyridin -3-yl} oxy) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1155] The title compound was prepared by substituting EXAMPLE 356B for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.30 (s, 1H), 8.41 (s, 2H), 7.83 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.16 (d, 1H), 7.05 (m, 3H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.35 (d, 1H) , 3.84 (dd, 2H), 3.27 (m, 7H), 3.09 (s, 4H), 2.76 (s, 2H), 2.20 (m, 6H), 1.98 ( m, 3H), 1.90 (m, 1H), 1.63 (m, 2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.95 (s, 6H).

EXAMPLE 357

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4 - ({(3R) - 1 [2-fluoro-1- (fluoromethyl) ethyl] pyrrolidin-3-yl} amino) -3-nitrophenyl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide

EXAMPLE 357A (R) -1- (1,3-difluoropropan-2-yl) pyrrolidin-3-amine [1156] To a solution of tert-butyl (R) -pyrrolidin-3-ylcarbamate (0.500 g) and 1.3- difluoropropan-2-one (0.278 g) in dichloromethane (5 ml) sodium triacetoxyborohydride (0.853 g) was added. After stirring for 1 hour, the reaction was quenched with saturated NaHCO solution₃ (5 ml). The product was extracted into dichloromethane (25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was treated with a solution of HCl (4.0M in dioxane, 4 mL) and methanol (1 mL) and stirred for 1 hour. The mixture was concentrated to give the title compound.

EXAMPLE 357B (R) -4- (1- (1,3-difluoropropan-2-yl) pyrrolidin-3-ylamino) -3-nitrobenzenesulfonamide [1157] To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and (R ) -1- (1,3-difluoropropan-2-yl) pyrrolidine-3-amine (0.195 g) in tetrahydrofuran (3.0 mL), N-ethyl-N-isopropylpropane-2-amine (0.512 mL) was added and the reaction stirred in room temperature. After 6 hours of stirring, the reaction was concentrated, loaded onto silica gel (Reveleris 40 g) and the product purified by flash chromatography using a 25% to 100% ethyl acetate / hexane gradient over 30 minutes to afford the title compound.

221

EP-2507211B1PL

EXAMPLE 357C

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - {[4 - ({(3R) - 1- [2-fluoro-1- (fluoromethyl) ethyl] pyrrolidin-3-yl} amino) -3-nitrophenyl] sulfonyl} -2 - [(6-fluoro-1H-indol-5-yl) oxy] benzamide [1158] Compound the title was made by substituting EXAMPLE 154E for EXAMPLE 1F and EXAMPLE 357B instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.21 (s, 2H), 8.58 (d, 1H), 8.39 (d, 1H), 7.89 (d, 1H), 7.51 (d, 1H), 7.40 - 7.25 (m, 5H), 7.13 (d, 1H), 7.03 (d, 2H), 6.67 (s, 1H), 6.40 (s, 1H), 6.09 ( s, 1H), 4.62 (dd, 4H), 4.31 - 4.18 (m, 1H), 3.04 (s, 6H), 2.73 (s, 4H), 2.39 - 2 , 23 (m, 2H), 2.19 (s, 6H), 1.95 (s, 2H), 1.79 - 1.60 (m, 1H), 1.38 (s, 2H), 0, 92 (s, 6H).

EXAMPLE 358

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(1-cyclopropylpiperidin-4-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [1159] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.56 (d, 1H), 8.24 (d, 1H), 7.85 (dd, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.35 (m, 3H), 7.22 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.19 (d, 1H), 6.12 (br s, 2H ), 3.74 (m, 2H), 3.11 (m, 5H), 2.91 (m, 2H), 2.76 (m, 3H), 2.22 (m, 6H), 1.97 (m, 4H), 1.58 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H), 0.46 (m, 2H), 0.36 (m, 2H) .

EXAMPLE 359

2 - [(6-amino-5-bromo-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-methylpiperazin-1-yl) amino] -3-nitrophenyl} sulfonyl) benzamide [1160] The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE 110E and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.96 (s, 1H), 8.41 (d, 1H), 7.77 (dd, 1H), 7.67 (d, 1H), 7.53 (dd, 2H), 7.36 (d, 2H), 7.29 (d, 1H), 7.07 (d, 2H), 6.62 (dd, 1H), 6.26 (d, 1H), 5.85 (s, 2H) , 3.28 (m, 4H), 3.06 (s, 4H), 2.90 (m, 4H), 2.75 (s, 2H), 2.31 (s, 3H), 2.20 ( m, 7H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 360

2 - [(6-amino-5-bromo-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(4-fluorotetrahydro-2H-pyran-4-yl) methoxy] -3-nitrophenyl} sulfonyl) benzamide [1161] The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE 110E and EXAMPLE 296D instead of EXAMPLE 1G in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.19 (d, 1H), 7.85 (dd, 1H), 7.62 (d, 1H), 7.57 (d, 1H), 7.36 (d, 2H), 7.31 (d, 1H), 7.22 (d, 1H), 7.08 (d, 2H), 6.63 (dd, 1H), 6.30 (d, 1H), 5.81 (s, 2H) , 4.34 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.06 (s, 4H), 2.76 (s, 2H), 2.21 ( m, 6H), 1.97 (s, 2H), 1.86 (m, 4H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 361

2 - [(6-amino-5-bromo-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({4 - [(1,4-dioxan-2-ylmethyl) amino] -3-nitrophenyl} sulfonyl) benzamide

222

EP-2507211B1EN [1162] The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE

110E and EXAMPLE 291A instead of EXAMPLE 1G in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.48 (m, 2H), 7.78 (m, 1H), 7.68 (m, 1H), 7.50 (m, 1H), 7.35 (m, 3H), 7.06 (m,

3H), 6.62 (m, 1H), 6.25 (m, 1H), 5.92 (m, 2H), 3.79 (m, 3H), 3.63 (m, 2H), 3, 49 (m, 2H), 3.40 (m, 3H),

3.08 (s, 4H), 2.76 (s, 2H), 2.19 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94 (s , 6H).

EXAMPLE 362

2 - [(6-amino-5-methylpyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 362A

Methyl 2- (6-amino-5-methylpyridin-3-yloxy) -4-fluorobenzoate [1163] EXAMPLE 350A (260 mg), dicyclohexyl (2 ', 6'-dimethoxybiphenyl-2-yl) phosphine (25 mg), and palladium (II) acetate (7 mg) were suspended in anhydrous tetrahydrofuran (2 mL). The mixture was purged with N₂ three times and stirred at room temperature for 5 minutes, followed by the addition of methyl zinc (II) chloride (0.45 mL). The reaction mixture was stirred at room temperature for 3 hours.

The reaction was quenched with a saturated aqueous NH solution₄Cl and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified on a flash column using 60-100% ethyl acetate / hexane to afford the title compound.

EXAMPLE 362B

Methyl 2- (6-amino-5-methylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [ 1164] The title compound was prepared by substituting EXAMPLE 362A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 362C 2- (6-Amino-5-methylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-yl) methyl) piperazin-1-yl) benzoic [1165] The title compound was prepared by substituting EXAMPLE 362B for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 362D

2 - [(6-amino-5-methylpyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1166] The title compound was prepared by substituting EXAMPLE 362C for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.57 (m, 2H), 7.86 (dd, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.19 (d, 1H), 7.05 (m, 3H), 6.60 (dd, 1H), 6.10 (d, 1H), 5.61 (s, 2H), 3.85 (dd, 2H) , 3.25 (m, 4H), 3.05 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.97 (m, 7H), 1.63 ( m, 2H), 1.39 (t, 2H), 1.25 (m, 2H), 0.94 (s, 6H).

EXAMPLE 363

2 - [(6-amino-5-chloropyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1- yl ] methyl} piperazine- 1-yl) -N - [(4 - {[(4-fluorotetrahydro-2H-pyran-4-yl) methyl] amino-3-nitrophenyl) sulfonyl] benzamide

223

[1167] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 337D instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 11.53 - 11.08 (m, 1H), 8.66 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H) .

7.38 (ddd, 5H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s, 3H), 3.77 (dd, 4H), 3.52 (dd , 2H), 3.12 (s, 4H), 2.81 (s, 2H), 2.22 (d, 6H), 2.03 - 1.67 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 364

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(1-oxetane-3-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 364A

Tert-butyl 1- (oxetan-3-yl) piperidin-4-ylcarbamate [1168] The title compound was prepared by substituting tert-butyl piperidin-4-ylcarbamate for tert-butyl piperazine-1-carboxylate and oxetane-3-one instead of 4 '-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 364B

1- (oxetan-3-yl) piperidin-4-amine [1169] The title compound was prepared by substituting EXAMPLE 364A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 364C

3-nitro-4- (1- (oxetan-3-yl) piperidin-4-ylamino) benzenesulfonamide [1170] The title compound was prepared by substituting EXAMPLE 364B for 1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.

EXAMPLE 364D

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(1-oxetan-3-ylpiperidin-4-yl) amino] phenyl} sulfonyl) benzamide [1171] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 364C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.57 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.36 (m, 3H), 7.23 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.17 (m, 3H), 4.55 (t, 2H) , 4.44 (t, 2H), 3.76 (br s, 1H), 3.46 (br s, 1H), 3.11 (m, 5H), 2.77 (m, 2H), 2, 67 (m, 2H), 2.20 (m, 6H), 2.08 (m, 1H), 1.97 (m, 4H), 1.65 (m, 2H), 1.40 (t, 2H ), 0.94 (s, 6H).

EXAMPLE 365

2 - [(6-amino-5-izopropylpirydyn-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 365A

Methyl 2- (6-amino-5-isopropylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [ 1172] The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE 350A and isopropyl zinc (II) chloride instead of methyl zinc (II) chloride in EXAMPLE 362A.

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EP-2507211B1PL

EXAMPLE 365B 2- (6-Amino-5-isopropylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) acid benzoic [1173] The title compound was prepared by substituting EXAMPLE 365A for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 365C

2 - [(6-amino-5-izopropylpirydyn-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1174] The title compound was prepared by substituting EXAMPLE 365B for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.61 (m, 2H), 7.88 (m, 1H), 7.61 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.22 (dd, 1H), 7.07 (m, 3H), 6.60 (dd, 1H), 6.06 (dd, 1H), 5.71 (d, 2H), 3.85 (dd, 1H) , 3.27 (m, 4H), 3.06 (s, 4H), 2.90 (m, 1H), 2.74 (s, 2H), 2.38 (t, 1H), 2.17 ( m, 6H), 1.92 (m, 3H), 1.63 (m, 2H), 1.52 (m, 1H), 1.39 (t, 2H), 1.26 (m, 2H), 1.11 (d, 6H), 0.93 (s, 6H).

EXAMPLE 366

2 - [(6-amino-5-cyklopropylpirydyn-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 366A

Methyl 2- (6-amino-5-cyclopropylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1enyl) methyl) piperazin-1-yl) benzoate [ 1175] The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE 350A and cyclopropyl zinc (II) chloride instead of methyl zinc (II) chloride in EXAMPLE 362A.

EXAMPLE 366B 2- (6-Amino-5-cyclopropylpyridin-3-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-yl) methyl) piperazin-1-yl) acid benzoic [1176] The title compound was prepared by substituting EXAMPLE 366A for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 366C

2 - [(6-amino-5-cyklopropylpirydyn-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1177] The title compound was prepared by substituting EXAMPLE 366B for EXAMPLE

110E in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.64 (t, 1H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.35 (d, 2H), 7.23 (d, 1H), 7.06 (d, 2H), 6.91 (d, 1H), 6.61 (dd, 1H), 6.04 (d, 1H) , 5.83 (s, 2H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.75 (s, 2H), 2.18 ( m, 6H), 1.97 (m, 3H), 1.65 (m, 3H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H), 0.87 (m, 2H), 0.49 (m, 2H).

EXAMPLE 367 trans-2 - [(6-amino-5-bromopyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1en-1-yl] methyl} piperazin-1-yl) -N - [(4 - {[(4-methoxycyclohexyl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

225

EP-2507211B1EN [1178] The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE

110E and EXAMPLE 345B instead of EXAMPLE 1G in EXAMPLE 110F. ¹1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.50 (m, 2H), 7.78 (d, 1H), 7.73 (d, 1H), 7.48 (d, 1H), 7.40 (s, 1H), 7.36 (d, 2H),

7.07 (m, 3H), 6.64 (dd, 1H), 6.22 (s, 1H), 5.98 (s, 2H), 3.27 (m, 4H), 3.22 (s , 3H), 3.06 (m, 4H), 2.76 (s,

2H), 2.20 (m, 6H), 1.99 (m, 4H), 1.80 (d, 2H), 1.62 (s, 1H), 1.40 (t, 2H), 1, 04 (m, 4H), 0.94 (s, 6H).

EXAMPLE 368

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(3-methyl-2-oxo-2 3-dihydro-1 H-benzimidazol-4-yl) oxyl-N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 368A

Methyl 4-fluoro-2- (3-fluoro-2-nitrophenoxy) benzoate [1179] To a solution of methyl 4-fluoro-2-hydroxybenzoate (1.225 g) in anhydrous tetrahydrofuran (25 ml), potassium tert-butoxide (0.808 g) was added . The mixture was stirred for 20 minutes at room temperature. A solution of 1,3-difluoro-2-nitrobenzene (0.955 g) in tetrahydrofuran (6 mL) was then added dropwise. The resulting mixture was stirred at room temperature for 1 hour, then at 80 ° C overnight. The reaction was quenched with water (40 mL) and extracted with dichloromethane.

The organic solution was dried (MgSO₄), filtered and concentrated. The residue was purified on a silica gel column, eluting with 25% ethyl acetate in hexane to afford the title compound. EXAMPLE 368B

Methyl 2- (3- (bis (4-methoxyphenyl) methylamino) -2-nitrophenoxy) -4-fluorobenzoate [1180] Solution of EXAMPLE 368A (1.33 g), bis (4-methoxyphenyl) methanamine (1.046 g) and N -ethyl-Nisopropylpropan-2-amine (1.127 mL) in anhydrous 1-methyl-2-pyrrolidinone (20 mL) was stirred at 120 ° C overnight. The mixture was concentrated and the residue was dissolved in water (100 mL) and extracted with dichloromethane. The residue was absorbed onto silica and purified by silica gel column chromatography, eluting with 25% ethyl acetate in hexane to afford the title compound.

EXAMPLE 368C

Methyl 2- (2-amino-3- (bis (4-methoxyphenyl) methylamino) phenoxy) -4-fluorobenzoate [1181] A solution of EXAMPLE 368B (1.1 g) in methanol was hydrogenated on Raney nickel at psi pressure ( 414 kPa) H.₂ in room temperature. The filtered solution was concentrated to give the title compound.

EXAMPLE 368D

Methyl 2- (1- (bis (4-methoxyphenyl) methyl) -2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4-yloxy) -4-fluoro benzoate [1182] Solution of EXAMPLE 368C (0.58 g) and N-ethyl-N-isopropylpropan-2-amine (0.804 mL) in dichloromethane (8 mL) was cooled using an ice bath. 20% by weight was then added dropwise. a solution of phosgene in toluene (0.850 ml). The mixture was stirred at room temperature overnight.

The mixture was diluted with dichloromethane and washed with 5% aqueous NaHCO₃. The material was then absorbed onto silica and purified on a silica gel column, eluting with 50% ethyl acetate in hexane to afford the title compound.

EXAMPLE 368E

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Methyl 2- (1- (4-methoxyphenyl) methyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4-yloxy) -4-fluoro benzoate [1183] For solution of EXAMPLE 368D (250 mg) in anhydrous N, N-dimethylformamide (6 mL) was added sodium hydride (34.1 mg). The mixture was stirred at 50 ° C for 30 minutes. Then iodomethane (35.6 μθ) was added and the mixture was stirred at 50^:C through the night. The reaction was quenched with water (30 mL) then extracted with ethyl acetate. The solution was dried (MgSO₄), filtered and concentrated to afford the title compound.

EXAMPLE 368F

2- (1- (bis (4-methoxyphenyl) methyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yloxy) -4- (piperazin-1-yl) methyl benzoate [1184] The flask was filled with EXAMPLE 368E (281 mg), anhydrous N, N-dimethylformamide (6 ml) and piperazine (268 mg). The mixture was stirred at 75 ° C overnight. The solvent was evaporated and the residue redissolved in ethyl acetate. The crude product was purified on a silica gel column, eluting with 5% methanol in dichloromethane to afford the title compound.

EXAMPLE 368G

2- (1- (bis (4-methoxyphenyl) methyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yloxy) -4- (4 ((2- Methyl (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoate [1185] To a solution of EXAMPLE 368F (275 mg) and EXAMPLE 60D (169 mg) in anhydrous dichloromethane (5 ml ) sodium triacetoxyborohydride (172 mg) was added in several portions over 5 minutes. The resulting mixture was stirred at ambient temperature overnight. The reaction of the mixture was quenched with 5% aqueous Na₂WHAT₃ (10 ml) and extracted with dichloromethane. The crude product was purified on a silica gel column eluted with 45% ethyl acetate in hexane to afford the title compound.

EXAMPLE 368H 2- (1- (bis (4-methoxyphenyl) methyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4-yloxy) -4- (4 - (( 2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic [1186] This EXAMPLE was performed by substituting EXAMPLE 368G for EXAMPLE 38G in EXAMPLE 38H.

EXAMPLE 368I

2- (1- (bis (4-methoxyphenyl) methyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yloxy) -4- (4 ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide [1187] This EXAMPLE was performed by substituting EXAMPLE 368H for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 368J

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(3-methyl-2-oxo-2 3-dihydro-1H-benzimidazol-4-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide [1188] Solution of EXAMPLE 368I (140 mg) in dichloromethane (10 mL) was cooled using an ice bath. Trifluoroacetic acid (10 ml) was added. The resulting solution was allowed to warm to

227

Room temperature and stirred for 48 hours. The solution was concentrated and the residue was triturated with diethyl ether. The resulting solid was purified by reverse phase HPLC using a Waters Preparative LC4000 system with a Phenomenex Luna C18 column and an ammonium acetate buffered water-acetonitrile mobile phase to provide the title compound.¹H NMR (500 MHz, pyridine-d₅) δ 12.34 (s, 1H), 9.20 (d, 1H), 8.87 (t, 1H), 8.44 (dd, 1H), 8.01 (d, 1H), 7.44 (d, 2H), 7.08 (d, 2H), 7.01 (d, 1H), 6.86-6.79 (m, 3H), 6.74 (d, 1H), 6.52 ( dd, 1H), 3.96 (dd, 2H), 3.65 (s, 3H), 3.30 (d, 2H), 3.24 (m, 2H), 3.19 (m, 4H), 2.81 (s, 2H), 2.30-2.28 (m, 2H), 2.23 (m, 4H), 1.97 (s, 2H), 1.85-1.75 (m, 1H), 1.58 (d, 2H), 1.40 (t, 2H), 1.33 (dq, 2H), 0.94 (s, 6H).

EXAMPLE 369

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(4-cyklopropylomorfolin-2-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 369A

Tert-butyl 2 - ((2-nitro-4-sulfamoylphenylamino) methyl) morpholine-4-carboxylate [1189] The title compound was prepared by substituting tert-butyl 2- (aminomethyl) morpholine-4-carboxylate for 3- (N-morpholinyl) - 1-propylamine in EXAMPLE 4A.

EXAMPLE 369B

4- (morpholin-2-ylmethylamino) -3-nitrobenzenesulfonamide [1190] A solution of EXAMPLE 369A (0.8 g) in methylene chloride (10 ml) and trifluoroacetic acid (10 ml) was stirred at room temperature for 2 hours. The solvents were evaporated and the residue was triturated with diethyl ether. The resulting solid was dissolved in a 5% aqueous solution in sodium carbonate (20 mL). The mixture was concentrated to dryness and the resulting solid was triturated with a solution of 10% methanol in methylene chloride several times. Evaporation of the organic solvent gave the title compound.

EXAMPLE 369C

4 - ((4-cyclopropylmorpholin-2-yl) methylamino) -3-nitrobenzenesulfonamide [1191] Solution of EXAMPLE 369B (0.633 g) and (1-ethoxycyclopropoxy) trimethylsilane (1.601 ml) in anhydrous methanol (15 ml) and acetic acid ( 1.717 ml) was refluxed for 30 minutes and allowed to cool to room temperature. Then sodium cyanoborohydride (0.377 g) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness. The residue was mixed with a 5% aqueous Na solution₂WHAT₃ (25 ml) and extracted with ethyl acetate. The crude product was purified on a silica gel column, eluting with 5% to 10% methanol in dichloromethane to afford the title compound.

EXAMPLE 369D

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(4-cyclopropylmorpholin-2-yl) methyl] amino} -3-nitrophenyl) sulfonyl] benzamide [1192] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 369C for EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 11.34 (br s, 1H), 8.63 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 1H), 7, 45 (d, 1H), 7.38 (d, 1H), 7.36 (d, 2H), 7.20 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H ), 6.19 (d, 1H), 6.17 (br s, 2H), 3.83

228

EP-2507211B1PL (m, 1H), 3.64 (m, 1H), 3.56 (m, 1H), 3.45 (m, 2H), 3.12 (m, 4H), 2.91 (m , 1H), 2.74 (m, 3H), 2.26 (m, 5H),

2.15 (m, 3H), 1.97 (m, 2H), 1.66 (m, 1H), 1.40 (t, 2H), 0.94 (s, 6H), 0.42 (m , 2H), 0.33 (m, 2H).

EXAMPLE 370

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(3R) -1-cyklopropylopirolidyn-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide

EXAMPLE 370A tert-butyl (R) -1-cyclopropylpyrrolidine-3-ylcarbamate [1193] The title compound was prepared by substituting tert-butyl (R) -pyrrolidin-3-ylcarbamate instead of tert-butyl (trans) -4-aminocyclohexylcarbamate in EXAMPLE 334A .

EXAMPLE 370B (R) -1-cyclopropylpyrrolidine-3-amine [1194] The title compound was prepared by substituting EXAMPLE 370A for EXAMPLE 1A in EXAMPLE 1B.

EXAMPLE 370C (R) -4- (1-cyclopropylpyrrolidin-3-ylamino) -3-nitrobenzenesulfonamide [1195] The title compound was prepared by substituting EXAMPLE 370B for 1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.

EXAMPLE 370D

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - [(4 - {[(3R) -1-cyclopropylpyrrolidin-3-yl] amino} -3-nitrophenyl) sulfonyl] benzamide [1196] The title compound was prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 370C instead of EXAMPLE 1G in EXAMPLE 1H. ¹1 H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.52 (d, 1H), 8.33 (d, 1H), 7.84 (dd, 1H), 7.69 (d, 1H), 7.46 (d, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.21 (d, 1H) , 6.09 (br s, 2H), 4.27 (m, 1H), 3.09 (m, 4H), 3.01 (m, 1H), 2.91 (m, 1H), 2.76 (m, 3H), 2.62 (m, 1H), 2.22 (m, 6H), 1.97 (m, 2H), 1.76 (m, 1H), 1.68 (m, 1H) , 1.40 (t, 2H), 0.94 (s, 6H), 0.43 (m, 2H), 0.37 (m, 2H).

EXAMPLE 371

2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - {[4 - ({4-fluoro-1- [2-fluoro-1- (fluoromethyl) ethyl] piperidin-4-yl} methoxy) -3-nitrophenyl] sulfonyl} benzamide

EXAMPLE 371 A

4 - ((1- (1,3-difluoropropan-2-yl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide [1197] For the suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropane 2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N, N-dimethylformamide was added dropwise until an orange solution was formed (~ 15 drops). After stirring overnight, additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient

0.5-5% methanol / dichloromethane for 30 minutes (flow = 40 ml / minute) to afford the title compound.

EXAMPLE 371B

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2 - [(6-amino-5-chloro-pyridin-3-yl) oxy] -4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin- 1-yl) -N - {[4 - ({4-fluoro-1- [2-fluoro-1- (fluoromethyl) ethyl] piperidin-4-yl} methoxy) -3-nitrophenyl] sulfonyl} benzamide [1198] Title compound prepared by substituting EXAMPLE 318H for EXAMPLE 1F and EXAMPLE 371A instead of EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.05 - 10.74 (m, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.73 (d, 1H), 7.50 (dd, 2H) , 7.37 (d, 3H), 7.07 (d, 2H), 6.65 (d, 1H), 6.18 (d, 3H), 4.62 (dd, 4H), 4.38 ( d, 2H), 3.16 (s, 5H), 2.97 - 2.60 (m, 8H), 2.18 (s, 4H), 2.07 - 1.60 (m, 6H), 1 , 42 (s, 2H), 0.94 (s, 6H).

EXAMPLE 372

6-Bromo-4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- {[({ Tert-butyl 3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate

EXAMPLE 372A 2- (2,6-Dibromo-pyridin-4-yloxy) -4-fluorobenzoic acid methyl ester [1199] Methyl 4-fluoro-2-hydroxybenzoate solution (2.00 g), 2,6-dibromo-4 -nitropyridine (3.65 g), and cesium carbonate (4.21 g) in N, N-dimethylformamide (100 mL) heated to 55 ° C for 16 hours, cooled, added to water, and extracted with 50% acetate ethyl in hexane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 3050% ethyl acetate in hexane.

EXAMPLE 372B 2- (2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy) -4-fluorobenzoic acid methyl ester [1200] EXAMPLE 372A (1400 mg), tert-butyl carbamate (405 mg), and cesium carbonate (1689 mg) was added to 1,4-dioxane (24 mL). The solution was degassed and purged with nitrogen three times. Palladium (II) acetate (39 mg) and 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (200 mg) were added, and the solution was heated at 80 ° C for 2.5 hours, cooled, added to water, and extracted with 50% ethyl acetate in hexane. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 10-20% ethyl acetate in hexane.

EXAMPLE 372C 2- (2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy) -4-piperazin-1-benzoic acid methyl ester [1201] The title compound was prepared by substituting EXAMPLE 372B for EXAMPLE 342D in EXAMPLE 342E.

EXAMPLE 372D 2- (2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl acid methyl ester ] -piperazin-1-yl} benzoic [1202] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 372C for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 372E

230

2- (2-bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] acid EP-2507211B1EN -piperazin-1-yl} benzoic [1203] The title compound was prepared by substituting EXAMPLE 372D for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 372F

6-Bromo-4- (5- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2- {[({ Tert-butyl 3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) amino] carbonyl} phenoxy) pyridin-2-ylcarbamate [1204] The title compound was prepared by substituting EXAMPLE 372E for EXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.93 (s, 1H), 8.58 (bs, 1H), 8.47 (d, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 7.37 (d, 2H), 7.18 (d, 1H), 7.08 (d, 1H), 7.07 (d, 2H), 6.83 (dd, 1H), 6.63 (bs, 1H) , 6.40 (d, 1H), 3.87 (dd, 2H), 3.35-3.25 (m, 8H), 2.85 (bs, 2H), 2.40-2.15 (m , 6H), 1.97 (bs, 2H), 1.93 (m, 1H), 1.65 (d, 2H), 1.41 (t, 2H), 1.40 (s, 9H), 1 , 36-1.22 (m, 2H), 0.95 (s, 6H).

EXAMPLE 373

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(2,6-bis-tertbutoksykarbonyloamino- pyridin-4-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

EXAMPLE 373A 2- (2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy) -4-fluoro-benzoic acid methyl ester [1205] The title compound was prepared during the synthesis of EXAMPLE 372B.

EXAMPLE 373B 2- (2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy) -4-piperazin-1-benzoic acid methyl ester [1206] The title compound was prepared by substituting EXAMPLE 373A for EXAMPLE 342D in EXAMPLE 342E.

EXAMPLE 373C 2- (2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy) -4- {4- [2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enylmethyl acid methyl ester ] -piperazin-1-yl} benzoic [1207] The title compound was prepared by substituting EXAMPLE 60D for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 373B for tert-butyl piperazine-1-carboxylate in

EXAMPLE 1A.

EXAMPLE 373D 2- (2,6-bis-tert-butoxycarbonylamino-pyridin-4-yloxy) -4- {4- [2- (4-chloro-phenyl) -4,4-dimethyl-cyclohex-1-enylmethyl] - acid piperazin-1-yl} benzoic [1208] The title compound was prepared by substituting EXAMPLE 373C for EXAMPLE 1E in EXAMPLE 1F.

EXAMPLE 373E

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -2 - [(2,6-bis-tertbutoksykarbonyloamino- pyridin-4-yl) oxy] -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) benzamide

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