DK2757099T3 - APOPTOSE PROMOTERS - Google Patents

Description

DESCRIPTION

FIELD OF THE INVENTION

[0001] This invention comprises compounds which inhibit the activity of anti-apoptotic Bcl-2 family protein members, compositions containing the compounds and said compounds for use in treating diseases during which are expressed one or more than one of an anti-apoptotic family protein. member.

BACKGROUND OF THE INVENTION

[0002] Anti-apoptotic family protein members are associated with a number of diseases and thus are under investigation as potential therapeutic drug targets. Important targets for interventional therapy are the Bcl-2 family of proteins which inelude, for example, Bcl-2, Bcl-X1 and Bcl-w. Recently inhibitors of Bcl-2 family members have been reported in the literature, see, for example, WO 2005/049594, US 6,720,338 and US 7,030,115. While this art teaches inhibitors having high binding to the target enzyme, this is only one of many parameters that must be considered as a compound is investigated forfurther or continued drug development. This invention is directed to a series of compounds that promote apoptosis and that demónstrate enhanced and unexpected properties with respect to cellular poteney, oral bioavailability, pharmacodynamic activity, and/or efficacy.

BRIEF DESCRIPTION OF THE FIGURES

[0003] FIG. 1 shows comparitive antitumorgenesis of EXAMPLE 1, etoposide and combinations thereof on B-cell lymphoma. FIG. 2 shows comparitive antitumorgenesis of EXAMPLE 1, vincristine and combinations thereof on B-cell lymphoma. FIG. 3 shows comparitive antitumorgenesis of EXAMPLE 1, CHOP and combinations thereofon B-cell lymphoma. FIG. 4 shows comparitive antitumorgenesis of EXAMPLE 1, rituximab and combinations thereofon B-cell lymphoma. FIG. 5 shows comparitive antitumorgenesis of EXAMPLE 1, rapamycin and combinations thereofon B-cell lymphoma. FIG. 6 shows comparitive antitumorgenesis of EXAMPLE 1, R-CHOP and combinations thereof on mantle cell lymphoma. FIG. 7 shows comparitive antitumorgenesis of EXAMPLE 1, bortezomib and combinations thereof on mantle cell lymphoma.

SUMMARY OF THE INVENTION

[0004] One embodiment of this invention comprises compounds having formula (II)

and therapeutically acceptable salts, thereof, wherein X3 is Cl or F; X4 is azepan-1-yl, morpholin-1-yl, pyrrolidin-1-yl, N(CH3)2, N(CH3)(CH(CH3)2), 7- azabicyclo[2.2.1]heptan-1-yl or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and R° is

wherein X5 is C(CH3)2, and X6 and X7 are both hydrogen ¡and X8 is F, Cl, Br or I.

[0005] Still another embodiment comprises 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- ((trlfluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1- yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1- ((phenylsulfanyl)methyl)propyl)amino)benzenesulfonam¡de, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-1-cyclohex-1-en-1- yl)methyl)piperaz¡n-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1- ((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1 -yl)methyl)piperazin-1-yl)benzoyl)-4- (((1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)am¡no)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chloxophenyl)-1-cyclohepten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((IR)-3- (isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonam¡de, 3- ((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperaz¡n-1-yl)benzoyl)-4-(((1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-l-en-1-yl)methyl)piperazin-l-yl)benzoyl)-4-(((1R)-3- (morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 4- (((1 R)-3-(7-azabicyclo[2.2.1]hept-7-y1)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2- oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)bcnzoyl)-4-(((1 R)-3-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-C(phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2- oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfanamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(2-oxa-5-azabicyclo[2.2.1]hept-5-y1)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(isopropyt(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(1,4- oxazepan-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 4-(((1 R)-3-(azepan-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4- chlorophenyl)-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3- (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(dimethylamina)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(dimethylamina)-3-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoyl)-4- (((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)prapyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1 -yl)benzoyl)-4-((( 1 R)-3-(isopropyl(methyl)amino)-1 -((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1 -yl)benzoyl)-4-((( 1 R)-3-(isopropyl(methyl)amino)-1 -((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4- (((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((tr¡fluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1- yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1- ((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1- ((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfanamide, N-(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-1- ((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1- yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1- yl)propyl)amino)benzenesulfonamide, 3-((chloro(difluoro)methyl)sulfonyl)-N(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1- yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1- yl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- (isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-1-((phenylsulfanyl)methyl)-3-(pyrrolid¡n-1-yl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 3-((chloro(difluoxo)methyl)sulfonyl)-N-(4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-((1 R)1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, N-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-((1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl)-1 - ((phenylsulfanyl)methyl)propyl)amino)-3-((triffuoromethyl)sulfonyl)benzenesulfonamide N-(4-(4-((4'-chloro(1,1'-b¡phenyl)-2-yl)methyl)-1-p¡peraz¡nyl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and N-(4-(4-((4'-chloro(1,1'biphenyl)-2-yl)methyl)-1-p¡peraz¡nyl)benzoyl)-4-(((1R)-3-(4- morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide, and therapeutically acceptable salts thereof.

[0006] Still another embodiment comprises compositions for use in treating diseases during which are expressed one or more than one of antiapoptotic BcI-Xl, protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein, said compositions comprising an excipient and a therapeutically effective amount of the compound having formula (II).

[0007] Still another embodiment comprises a compound having formula (II) for use in treating diseases in a patient during which are expressed one or more than one of antiapoptotic Bcl-X|_ protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein, by administering to the patient a therapeutically effective amount of a compound having formula (II).

[0008] Still another embodiment comprises compositions comprising an excipient and a therapeutically effective amount of the compound having formula (H) for use in treating diseases of abnormal cell growth and/or dysregulated apoptosis, such as cáncer, mesothioloma, bladder cáncer, pancreatic cáncer, skin cáncer, cáncer of the head or neck, cutaneous or intraocular melanoma, ovarían cáncer, breast cáncer, uterine cáncer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cáncer, ovarían cáncer, cervical cáncer, colon cáncer, rectal cáncer, cáncer of the anal región, stomach cáncer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia, esophageal cáncer, cáncer of the small intestine, cáncer of the endocrine system, cáncer of the thyroid gland, cáncer of the parathyroid gland, cáncer of the adrenal gland, sarcoma of soft tissue, cáncer of the urethra, cáncer of the penis, testicular cáncer, hepatocellular cáncer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, múltiple myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer, cáncer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cáncer, gall bladder cáncer, cáncer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination thereof.

[0009] Still another embodiment comprises a compound having formula (II) for use in treating mesothioloma, bladder cáncer, pancreatic cáncer, skin cáncer, cáncer of the head or neck, cutaneous or intraocular melanoma, ovarían cáncer, breast cáncer, uterine cáncer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cáncer, ovarían cáncer, cervical cáncer, colon cáncer, rectal cáncer, cáncer of the anal región, stomach cáncer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia, esophageal cáncer, cáncer of the small intestine, cáncer of the endocrine system, cáncer of the thyroid gland, cáncer of the parathyroid gland, cáncer of the adrenal gland, sarcoma of soft tissue, cáncer of the urethra, cáncer of the penis, testicular cáncer, hepatocellular cáncer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, múltiple myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer, cáncer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cáncer, gall bladder cáncer, cáncer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers in a patient, by administering thereto a therapeutically effective amount of a compound having formula (II).

[0010] Still another embodiment comprises compositions comprising an excipient and a therapeutically effective amount of the compound having formula (II) for use in treating bladder cáncer, brain cáncer, breast cáncer, bone marrow cáncer, cervical cáncer, chronic lymphocytic leukemia, colorectal cáncer, esophageal cáncer, hepatocellular cáncer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer and spleen cáncer.

[0011] Still another embodiment comprises a compound having formula (II) for use in treating bladder cáncer, brain cáncer, breast cáncer, bone marrow cáncer, cervical cáncer, chronic lymphocytic leukemia, colorectal cáncer, esophageal cáncer, hepatocellular cáncer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer and spleen cáncer in a patient, by administering to the patient a therapeutically effective amount of a compound having formula (II).

[0012] Still another embodiment comprises compositions comprising an excipient and a therapeutically effective amount of the compound having formula (II) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent for use in treating diseases in a patient during which are expressed one or more than one of antiapoptotic Bcl-X|_ protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein.

[0013] Still another embodiment comprises a compound having formula (II) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent for use in treating diseases in a patient during which is expressed one or more than one of antiapoptotic Bcl-X|_ protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein, by administering to the patient a therapeutically effective amount of a compound having formula (II) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

[0014] Still another embodiment comprises compositions comprising an excipient and therapeutically effective amount of a compound having formula (II) and one additional therapeutic agent or more than one additional therapeutic agent for use in treating mesothioloma, bladder cáncer, pancreatic cáncer, skin cáncer, cáncer of the head or neck, cutaneous or intraocular melanoma, ovarían cáncer, breast cáncer, uterine cáncer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cáncer, ovarían cáncer, cervical cáncer, colon cáncer, rectal cáncer, cáncer of the anal región, stomach cáncer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia, esophageal cáncer, cáncer of the small intestine, cáncer of the endocrine system, cáncer of the thyroid gland, cáncer of the parathyroid gland, cáncer of the adrenal gland, sarcoma of soft tissue, cáncer of the urethra, cáncer of the penis, testicular cáncer, hepatocellular cáncer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, múltiple myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer, cáncer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cáncer, gall bladder cáncer, cáncer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers.

[0015] Still another embodiment comprises a compound having formula (II) and one additional therapeutic agent or more than one additional therapeutic agent for use in treating mesothioloma, bladder cáncer, pancreatic cáncer, skin cáncer, cáncer of the head or neck, cutaneous or intraocular melanoma, ovarían cáncer, breast cáncer, uterine cáncer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cáncer, ovarían cáncer, cervical cáncer, colon cáncer, rectal cáncer, cáncer of the anal región, stomach cáncer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia, esophageal cáncer, cáncer of the small intestine, cáncer of the endocrine system, cáncer of the thyroid gland, cáncer of the parathyroid gland, cáncer of the adrenal gland, sarcoma of soft tissue, cáncer of the urethra, cáncer of the penis, testicular cáncer, hepatocellular cáncer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, múltiple myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer, cáncer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cáncer, gall bladder cáncer, cáncer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers in a patient, by administering thereto therapeutically effective amounts of a compound having formula (II) and one additional therapeutic agent or more than one additional therapeutic agent.

[0016] Still another embodiment comprises a compound having formula (II) and one or more than one of etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP or bortezomib for use in treating mesothioloma, bladder cáncer, pancreatic cáncer, skin cáncer, cáncer of the head or neck, cutaneous or intraocular melanoma, ovarían cáncer, , breast cáncer, uterine cáncer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cáncer, ovarían cáncer, cervical cáncer, colon cáncer, rectal cáncer, cáncer of the anal región, stomach cáncer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia, esophageal cáncer, cáncer of the small intestine, cáncer of the endocrine system, cáncer of the thyroid gland, cáncer of the parathyroid gland, cáncer of the adrenal gland, sarcoma of soft tissue, cáncer of the urethra, cáncer of the penis, testicular cáncer, hepatocellular cáncer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, múltiple myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer, cáncer of the kidney and ureter, renal cell carcinoma, carcinoma ofthe renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cáncer, gall bladder cáncer, cáncer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers in a patient, by administering thereto therapeutically effective amounts of a compound having formula (II) and one or more than one of etoposide, vincristine CHOP, rituximab, rapamycin, R-CHOP or bortezomib.

[0017] Still another embodiment comprises a compound having formula (II) and etoposide for use in treating B-cell lymphoma in a patient by administering thereto a therapeutically acceptable amounts of a compound having formula (II) and etoposide.

[0018] Still another embodiment comprises a compound having formula (II) and vincristine for use in treating B-cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and vincristine.

[0019] Still another embodiment comprises a compound having formula (II) and CHOP for use in treating B-cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and CHOP.

[0020] Still another embodiment comprises a compound having formula (II) and rituximab for use in treating B-cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and rituximab.

[0021] Still another embodiment comprises a compound having formula (II) and rapamycin for use in treating B-cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and rapamycin.

[0022] Still another embodiment comprises a compound having formula (II) and R-CHOP for use in treating mantle cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and R-CHOP.

[0023] Still another embodiment comprises a compound having formula (II) and bortezomib for use in treating mantle cell lymphoma in a patient by administering thereto therapeutically acceptable amounts of a compound having formula (II) and bortezomib.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Variable moieties of compounds herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and maybe specifically embodied.

[0025] It is meant to be understood that proper valences are maintained for all moieties and combinations thereof and that monovalent moieties having more than one atom are attached through their left ends.

[0026] It is also meant to be understood that a specific embodiment of a variable moiety may be the same or different as another specific embodiment having the same identifier.

[0027] The term "antitumorigenesis," as used herein, means reduction of tumor growth.

[0028] Compounds of this invention may contain asymmetrically substituted carbón atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in Puré Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbón atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diastereoisomers of the compounds thereof.

[0029] Compounds of this invention may also contain carbon-carbon double bonds or carbón- nitrogen double bonds in the Z or E configuration, in which the term "Z" represente the larger two substituents on the same side of a carbon-carbon or carbon-nitrogen double bond and the term "E" represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as a mixture of "Z" and "E" isomers.

[0030] Compounds of this invention may also exist as tautomers or equilibrium mixtures thereof wherein a protón of a compound shifts from one atom to another. Examples of tautomers inelude, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like.

[0031] Compounds having formula (II) having NH, C(0)OH, OH or SH moieties may have attached thereto prodrug-forming moieties. The prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed NH, C(0)OH, OH or SH in vivo. Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.

[0032] Metabolites of compounds having formula (II), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with expression of an anti-apoptotic family protein member such as of BCI-X|_ protein, Bcl-2 protein or Bcl-w protein.

[0033] Compounds having formula (II) may also be radiolabeled with a radioactive isotope such as a radioactive isotope of carbón (i.e. 13C), hydrogen (i.e. 3H), nitrogen (i.e. 15N), phosphorus (i.e. 32P), sulfur (i.e. 35S)or iodide (i.e. 125l). Radioactive isotopes may be incorporated into the compounds having formula (II) by reacting the same and a radioactive derivitizing agent or by incorporating a radiolabeled intermedíate into their syntheses. The radiolabeled compounds of formula (II) are useful for both prognostic and diagnostic applications as well as for in vivo and in vitro imaging.

[0034] Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having formula (II) may also have utility for treating diseases associated with expression of an anti-apoptotic family protein member such as of BCI-X|_ protein, Bcl-2 protein or Bcl-w protein.

[0035] Compounds having formula (II) may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having formula (II) are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound having formula (II) with acid. Accordingly, salts including the acétate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsufonate, digluconate, fórmate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maléate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecanoate salts of the compounds having formula (II) are meant to be embraced by this invention. Basic addition salts of compounds are those derived from the reaction of the compounds having formula (II) with the bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.

[0036] Compounds having formula (II) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusión, and placement in the body, such as, for example, the vasculature by means of, for example, a stent.

[0037] Therapeutically effective amounts of a compound having formula (II) depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered. The amount of a compound having formula (II) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.

[0038] Compounds having formula (II) may be administered with or without an excipient. Excipients inelude, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extendere, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.

[0039] Excipients for preparation of compositions comprising a compound having formula (II) to be administered orally inelude, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acétate, cocoa butter, corn starch, com oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl lauréate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, tale, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (II) to be administered ophthalmically or orally inelude, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (II) to be administered osmotically include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. Excipiente for preparation of compositions comprising a compound having formula (II) to be administered parenterally inelude, but are not limited to, 1,3-butanediol, castor oil, com oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (II) to be administered rectally or vaginally inelude, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.

[0040] This invention also comprises a pharmaceutical composition comprising a compound having formula (II) and a therapeutically effective amount of one or more than one additional therapeutic agents or ionizing radiation for use in treating disease conditions involving abnormal cell growth and/or dysregulated apoptosis, such as cáncer, in a patient by administering thereto a therapeutically effective amount of a pharmaceutical composition comprising a compound having formula (II) and a therapeutically effective amount of one or more than one additional therapeutic agents or ionizing radiation.

[0041] The compositions of a compound having formula (II) and one or more than one additional therapeutic agents or ionizing radiation may be administered to a patient using any desired dosing and/or scheduling regimen.

[0042] Compounds having formula (II) may be administered with one or more than one additional therapeutic agents, wherein the additional therapeutic agents inelude ionizing radiation or chemotherapeutic agents, wherein chemotherapeutic agents inelude, but are not limited to, carboplatin, cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide, fludarabine, irinotecan, CHOP (C: Cytoxan® (cyclophosphamide); H: Adriamycin® (hydroxydoxorubicin); O: Vincristine (Oncovin®); P: prednisone), paclitaxel, rapamycin, Rituxin® (rituximab), vincristine and the like.

[0043] Compounds having formula (H) are also expected to be useful as chemotherapeutic agents in combination with therapeutic agents that inelude, but are not limited to, angiogenesis inhibitors, antiproliferative agents, kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDS), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum containing agents, growth factor inhibitors, ionizing radiation, cell eyele inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids/deltoids plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors and combinations thereof as well as other antitumor agents.

[0044] Angiogenesis inhibitors inelude, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, thrombospondin analogs such as thrombospondin-1 and N-Ac-Sar-Gly-Val-D-allone-Thr-Nva-lle-Arg-Pro-NHCH2CH3 or a salt thereof and analogues of N-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 such as N-Ac-GlyVal-D-alle-Ser-Gln-lle-Arg-ProNHCH2CH3 or a salt thereof.

[0045] Examples of EGFR inhibitors inelude, but are not limited to, Iressa (gefitinib), Tarceva (erlotinib or OSI-774), Erbitux (cetuximab), EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusión protein, EGF-vaccíne, anti-EGFr immunoliposomes and Tykerb (lapatinib).

[0046] Examples of PDGFR inhibitors inelude, but are not limited to, CP-673,451 and CP-868596.

[0047] Examples of VEGFR inhibitors inelude, but are not limited to, Avastin (bevacizumab), Sutent (sunitinib, SU 11248), Nexavar (sorafenib, BAY43-9006), CP-547,632, axitinib (AG13736), Zactima (vandetanib, ZD-6474), AEE788, AZD-2171, VEGF trap, Vatalanib (PTK-787, ZK-222584), Macugen, IM862, Pazopanib (GW786034), ABT-869 and angiozyme.

[0048] Examples of thrombospondin analogs inelude, but are not limited to, TSP-1 and ABT-510.

[0049] Examples of aurora kinase inhibitors inelude, but are not limited to, VX-680, AZD-1152 and MLN-8054.

[0050] Example of polo-like kinase inhibitors inelude, but are not limited to, BI-2536.

[0051] Examples of bcr-abl kinase inhibitors inelude, but are not limited to, Gleevec (imatinib) and Dasatinib (BMS354825).

[0052] Examples of platinum containing agents ineludes, but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin) or satraplatin.

[0053] Examples of mTOR inhibitors ineludes, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, FtAD001, and AP-23573.

[0054] Examples of HSP-90 inhibitors ineludes, but are not limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS-683664, Mycograb, CNF-2024, PU3, PU24FCI, VER49009, IPI-504, SNX-2112 and STA-9090.

[0055] Examples of histone deacetylase inhibitors (HDAC) ineludes, but are not limited to, Suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA, LAQ-824, Trapoxin, and Depsipeptide.

[0056] Examples of MEK inhibitors inelude, but are not limited to, PD325901, ARRY-142886, ARRY-438162 and PD98059.

[0057] Examples of CDK inhibitors inelude, but are not limited to, flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, R-roscovitine), ZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387,032, PD0332991 and AZD-5438.

[0058] Examples of COX-2 inhibitors inelude, but are not limited to, CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 Lumiracoxib), BMS347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381, 4-Methyl-2-(3,4-dmethylphenyl)-1-(4-sulfamoyl-phenyl-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).

[0059] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) inelude, but are not limited to, Salsalate (Amigesic), Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol) and Oxaprozin (Daypro).

[0060] Exambles of ErbB2 receptor inhibitors inelude, but are not limited to, CP-724-714, ΟΙ 033, (canertinib), Herceptin (trastuzumab), Omitarg (2C4, petuzumab), TAK-165, GW-572016 (lonafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti-HER/2neu bispecific antibody, B7.her2lgG3, AS HER2 trifunctional bispeefie antibodies, mABAR-209 and mAB2B-1.

[0061] Examples of alkylating agents inelude, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide, Chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2170, mafosfamide, and mitolactol, carmustine (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decarbazine and Temozolomide.

[0062] Examples of antimetabolites inelude but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, uracil analogues such as 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemeitabine), fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethnylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine, mycophenolic acid, tiazofurin, Ribavirin, EICAR, hydroxyurea and deferoxamine.

[0063] Examples of antibiotics inelude intercalating antibiotics but are not limited to, aclarubicin, actinomycins such as actinomycin D, amrubicin, annamycin, adriamycin, bleomycin a, bleomycin b, daunorubicin, doxorubicin, elsamitrucin, epirbucin, glarbuicin, idarubicin, mitomycin C, nemorubicin, neocarrzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, vah-ubicin, zinostatin and combinations thereof.

[0064] Examples of topoisomerase inhibiting agents inelude, but are not limited to, one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCL (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, orathecin (Supergen), BN-80915, mitoxantrone, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.

[0065] Examples of antibodies inelude, but are not limited to, Rituximab, Cetuximab, Bevacizumab, Trastuzimab, specific CD40 antibodies and specific IGF1R antibodies, [0066] Examples of hormonal therapies inelude, but are not limited to, exemestane (Aromasin), leuprolide acétate, anastrozole (Arimidex), fosrelin (Zoladex), goserelin, doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen), Casodex, Abarelix, Trelstar, finasteride, fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole, flutamide, bicalutamide, megesterol, mifepristone, nilutamide, dexamethasone, predisone and other glucocorticoids.

[0067] Examples of retinoids/deltoids inelude, but are not limited to, seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, Aliretinoin, Bexarotene and LGD-1550.

[0068] Examples of plant alkaloids inelude, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine.

[0069] Examples of proteasome inhibitors inelude, but are not limited to, bortezomib (Velcade), MG132, NPI-0052 and PR-171.

[0070] Examples of immunologicals inelude, but are not limited to, interferons and numerous other immune enhancing agents. Interferons inelude interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof. Other agents inelude flgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, decarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAC-CL, sargaramostim, tasonermin, teoleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFG1), Provenge (Dendreon), CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and agents capable of blocking CTLA4 such as MDX-010.

[0071] Examples of biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents inelude krestin, lentinan, sizofiran, picibanil and ubenimex.

[0072] Examples of pyrimidine analogs include, but are not limited to, 5-Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, cytarabine (ara C), Cytosine arabinoside, Fludarabine, and Gemcitabine.

[0073] Examples of purine analogs inelude but are not limited to, Mercaptopurine and thioguanine.

[0074] Examples of antimitotic agents inelude, but are not limited to, ABT-751, paclitaxel, docetaxel, epothilone D (KOS-862) and ZK-EPO.

[0075] Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy. Examples of radiotherapy inelude but are not limited to, external beam radiotherapy (XBRT), or teletherapy, brachtherapy or sealed source radiotherapy, unsealed source radiotherapy.

[0076] Additionally, compounds having formula (II) may be combined with other antitumor agents selected from the following agents: Genasense, Panitumumab, Zevalin, Bexar (Corixa), Abarelix, Alimta, EPO906, discodermolide, Neovastat, enzastaurin, Combrestatin A4P, ZD-6126, AVE-8062, DMXAA, Thymitaq, Temodar, Revlimid, Cypat, Histerelin, Plenaizis, Atrasentan, Satraplatin, thalomide (Thalidomide), theratope, Temilifene, ABI-007, Evista, Atamestane, Xyotax, Targretin, Triazone, Aposyn, Nevastat, Ceplene, Orathecin, Virulizin, Gastrimmune, DX-8951Í, Onconase, BEC2, Xcytrin, CeaVac, NewTrexin, OvaRex, Osidem, Advexin, RSR13 (efaproxiral, Cotara, NBI-3001 (IL-4), Canvaxin, GMK. vaccine, PEG Interferon A, Taxoprexin, gene therapy agents such as TNFerade (GeneVac), Interferon-alpha, Interferon-gamma, Tumor necrosis factor, Lovastatin, staurosporine, dactinomycin, zorubicin, Bosentan, ampligen, ibandronic acid, miltefosine, L-asparaginase, procarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta, tretinoin, acitretin, zolendronic acid, halofuginone, rebimastat, removab, squalamine, ukrain, paditaxel, Zinecard, Vitaxin, anthracyclines, antifolates, antiestrogen agents, antimicrotubule agents, anti- androgens, aromatase inhibitors, Ca2+ adenosine triphosphate (ATP)ase inhibitors, cytosine analogs, deldihydrofolate reductase inhibitors, deoxyribonucleic acid (DNA) topoisomerase inhibitors, (HSP)-90 inhibitors, immunotherapeutic agents, inosine monophosphate (IMP) dehydrogenase inhibitors, isoprenylation inhibitors, luteinizing hormone-releasing hormone agonists, mammalian target of rapomycin (mtor) inhibitors, multi-drug resistance (MDR) inhibitors, mytomycins, photodyamic therapies, ribonuclotide reductase inhibitors, thrombospondin mimetics, vinca alkaloids, vitamin D3 analogs, 17-allylamino-17-demethoxygeldanamycin, N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea or a salt thereof, N-(4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl)-N'-(2-fluoro-5-(trifluoromethyl)phenyl)urea or a salt thereof, campathecins, CB1093, CHIR258, CNF-101, CNF-1001, CP547632, demethoxyhypocrellin A, 17-dimethylanunoethylamino-17-demethoxygeldanamycin, EB1089, eothilone D, epirubicin, 5-ethynyl-1-3-D-ribofuranosylimidazole-4-carboxamide (EICAR), erlotinib, N-(2-(4-hydroxyanilino)-3-pyridinyl)-4-methoxybenzenesulfonamide or a salt thereof, imatinab, IPI-504, KH 1060, LAQ824, lomustine, 1-methyl-4-phyenylpyridinium, MLN-518, nitrosoureas, photosensitizer Pc4, phtalocyanine, plicamycin, retinoids such as pheuretinide, sunitinib, taxol, teniposide, thapsigargin, trichostatin A, verapamil, vertoporfin, ZK-EP, Polo-like kinase inhibitors, proteasome inhibitors or combinations thereof.

[0077] BAX and BAD peptides are reported in Zhang, H. C., Nimmer, P, Rosenberg, S. H., Ng, S. C., and Joseph, M. (2002). Development of a High-Throughput Fluorescence Polarization Assay for Bcl-x(L). Analytical Biochemistry 307, 70-75.

[0078] Binding affinity of compounds having formula (II) to Bcl-X|_ protein is indicia of their inhibition of the activity of this protein. To determine the binding affinity of compounds having formula (II) to Bcl-X|_ protein, representative examples were diluted in DMSO to concentrations between 100 μΜ and 1 pM and added to each well of a 96-well microtiter píate. A mixture comprising 125 pl_ per well of assay buffer (20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 50 mM NaCI, 0.05% PF-68), 6 nM of Bcl-X|_ protein (prepared as described in Science 1997,275, 983-986), 1 nM fluorescein-labeled BAD peptide (prepared in-house) and the DMSO solution of the compound was shaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems, CA). Anegative control (DMSO, 15 nM BAD peptide, assay buffer) and a positive control (DMSO, 1 nM BAD peptide, 6 nM Bcl-X|_, assay buffer) were used to determine the range of the assay. Polarization was measured at room temperature using a continuous Fluorescein lamp (excitation 485 nm, emission 530 nm). Percentage of inhibition was determined by (1-((mP valué of well-negative control)/range)) χ 100%. The results are shown in TABLE 1.

[0079] Binding affinity of compounds having formula (II) to Bcl-2 protein is indicia of their inhibition of the activity of this protein. To determine the binding affinity of compounds having formula (II) to Bcl-2, representative examples were diluted in DMSO to concentrations between 10 μΜ and 10 pM and added to each well of a 96-well microtiter píate. A mixture comprising 125 L per well of assay buffer (20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 50 mM NaCI, 0.05% PF-68), 10 nM of Bcl-2 protein (prepared according to the procedure described in PNAS 2001, 98,3012 - 3017), 1 nM fluorescein-labeled BAX peptide (prepared in-house) and the DMSO solution of the representative EXAMPLE was shaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems, CA. Polarization was measured at room temperature using a continuous Fluorescein lamp (excitation 485 nm, emission 530 nm). The results are also shown in TABLE 1.

[0080] These data demónstrate the utility of compounds having formula (II) as binders to and inhibitors of anti-apopotic BCI-X|_ protein and anti-apopotic Bcl-2.

[0081] It is expected that, because compounds having formula (II) bind to and inhibit the activity of BCI-X|_ and Bcl-2, they would also have utility as inhibitors of anti-apopotic family protein members having cióse structural homology to BCI-X|_ and Bcl-2 such as, for example, anti-apopotic Bcl-w protein.

[0082] Accordingly, compounds having formula (II) are expected to have utility in treatment of diseases during which anti-apopotic Bcl-X|_ protein, anti-apopotic Bcl-2 protein, anti-apopotic Bcl-w protein or a combination thereof, are expressed.

Determination of Cellular Efficacy in Human Tumor Cell Line [0083] NCI-H146 (ATCC, Manassas, VA.) human small cell lung carcinoma cells were plated 50,000 cells per well in 96-well tissue culture plates in a total volume of 100 pL tissue culture médium supplemented with 10% human serum (Invitrogen, Carlsbad, CA.) instead of fetal bovine serum and treated with a 2-fold serial dilution of the compounds of interest from 10 μΜ to 0.020 pM. Each concentration was tested in duplícate at least 3 sepárate times. The number of viable cells following 48 hours of compound treatment was determined using the CelITiter 96® AQueous non-radioactive cell prollferatlon MTS assay accordlng to manufacturer's recommendations (Promega Corp., Madison, Wl). The results are also shown in TABLE 1.

Pharmacokinetic Evaluation of Selected Compounds in Rat [0084] The pharmacokinetic behavior of compounds of this invention was determined following a single 2 mg/kg intravenous or 5 mg/kg oral dose in male Sprague-Dawley derived rats (n=3 per group). The compounds were prepared as 2 mg/ml_ solution in a 10% DMSO in PEG-400 formulation for both oral and intravenous administration. The1 mL/kg intravenous dose was administered as a slow bolus (about 1-2 minutes) in the jugular vein of a rat under light ether anesthetic. The oral dose was administered by gavage. Serial blood samples were obtained from a tail vein of each rat prior 0.1 (IV only), 0,25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing. The heparinized samples were thoroughly mixed and placed in an ice bath. Plasma was separated by centrifugation and stored frozen prior to analysis. The results are also shown in TABLE 1.

[0085] The compounds of interest were separated from the plasma using protein precipitation with acetonitrile. A plasma (100-200 pL, sample or spiked standard) aliquot was combined with 50 pL of ¡nternal standard (structurally related analog prepared in acetonitrile) and 1 mi acetonitrile in a 96-well polypropylene deep well píate. The plates were vortexed for 30 seconds followed by centrifugation (3500 rpm x 15 minutes, 4°C). In an automated manner, the supernatant was transferred to a clean 96-well píate. The samples were evaporated to near dryness on a Micro-Vap™ under a stream of dry nitrogen over low heat (~37°C). The samples were reconstituted vortexing with 0.2 mL 5% DMSO in acetonitrile. A 0.1-0.2 mi aliquot of acetonitrile: 0.1% trifluoroacetic acid (20:80, by volume) was added to each well, followed by an additional 30 second vortexing. The plates were centrifuged (3500 rpm x 15 minutes, 4°C) prior to HPLC-MS/MS analysis. Samples were analyzed simultaneously with spiked plasma standards. All samples from each study were analyzed as a single batch on the LC-MS/MS.

[0086] The compounds of interest and the ¡nternal standard were separated from each other and co-extracted contaminants on a 50 x 3 mm Keystone Betasil CN 5 pm column with an acetonitrile: 0.1% trifluoroacetic acid mobile phase (50:50, by volume) at a flow rate of 0.7 ml/min. Analysis was performed on a Sciex API 300™ Biomolecular Mass Analyzer using a heated nebulizer interface. Peak areas of the title compounds and internal standards were determined using the Sciex MacQuan™ software. Calibration curves were derived from peak area ratio (parent drug/internal standard) of the spiked rat plasma standards using least squares linear regression of the ratio versus the theoretical concentration. The methods were generally linear over the range of the standard curve (correlation coefficients > 0.99) with an estimated quantitation limit of 0.01 pg/mL. The plasma concentration data for each animal were submitted to multi-exponential curve fitting using WinNonlin. The area under the plasma concentration-time curve from 0 to t hours (time of the last measurable plasma concentration) after dosing (AUCo-t) was calculated using the linear trapezoidal rule for the plasma concentration-time profiles. The residual area extrapolated to infinity, determined as the final measured plasma concentration (Ct) divided by the terminal elimination rate constant (β), was added to AUCo-t to produce the total area under the curve. The resulte are also shown in TABLE 1. TABLE 1

[0087] The compounds of the present invention were also tested against compounds disclosed in WO 2005/049594, identified herein as EXAMPLES A-N, by determining the ratio of potency to exposure. This measure, sometimes reported as AUC/EC50, is well known to those skilled in the art of pharmaceutical drug discovery and drug development as a useful measurement of pharmacodynamic activity.

[0088] The examples of the present invention and compounds disclosed in WO 2005/049594 were tested in both H146 cell assay and for pharmacokinetic evaluation in rat, both as previously described herein. The results are shown in TABLES 2 and 3. As can be seen with reference to the data, the compounds of the present invention have a more preferred pharmacodynamic profile as compared to the compounds known in the art. From these results a number of observations can be drawn. It can be observed that the compounds having a NO2 moiety at position W1 tend to have good to excellent cellular potency. However, when the oral bioavailability of these same compounds is determined, it can be seen that the exposure is poor, resulting in AUC/EC50 ratios of from 0.5 to 19.7. On the other hand, when compounds having a CF3 moiety at position W1 are tested in the cellular assay, the results demónstrate that these derivatives have relatively poor potency while at the same time having suitable oral exposure. Again, this combination provides overall ratios from about 2.8 to about < 7.4. Surprisingly, compounds of the present invention demónstrate cellular potency on par with compounds having an NO2 moiety while maintaining the oral bioavailability of compounds having the CF3 moiety. The resulting ratios for the compounds of the invention are from about 20 to about 550.

i-Pr means iso-propyl [0089] As shown in Figures 1-7, studies pertaining to the efficacy of EXAMPLE 1 in combination with etoposide, vincristine, CHOP, rituximab, rituximab with CHOP, rapamycin, and velcade demonstrated that EXAMPLE 1 synergistically enhanced efficacy of these cytotoxic agents during combination therapy.

[0090] Further, combinations comprising EXAMPLE 1 and vincristine resulted in 10% complete tumor regression.

[0091] Still further, combinations comprising EXAMPLE 1 and rituximab resulted in 70% complete tumor regression whereas no tumor regressions were observed for rituximab alone.

[0092] Still further, combinations comprising EXAMPLE 1 and rapamycin resulted in 70% complete tumor regression whereas 10% tumor regressions were observed for rapamycin alone.

[0093] Still further, combinations comprising EXAMPLE 1 and rituximab with CHOP resulted in 90% complete tumor regression whereas 10% tumor regressions were observed for rituximab with CHOP only.

[0094] Still further, combinations comprising EXAMPLE 1 and bortexomib resulted in 10% complete tumor regression whereas no tumor regressions were observed for bortexomib alone.

[0095] Diseases during which anti-apopotic Bcl-X|_ protein, anti-apopotic Bcl-2 protein, anti-apopotic Bcl-w protein or a combination thereof, are expressed inelude, but are not limited to, cáncer and autoimmune disorders, wherein cáncer ineludes, but is not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytio), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cáncer, brain cáncer, breast cáncer, bronchogenic carcinoma, cervical cáncer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, colorectal cáncer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metapiasias), embryonal carcinoma, endometrial cáncer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cáncer, estrogen-receptor positive breast cáncer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cáncer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cáncer, hormone insensitive prostate cáncer, leiomyosarcoma, liposarcoma, lung carcinoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, páncreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, múltiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cáncer, oligodendroglioma, oral cáncer, osteogenic sarcoma, ovarían cáncer, pancreatic cáncer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cáncer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cáncer squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenstróm's macroglobulinemia, testicular tumors, uterine cáncer and Wilms' tumor, (Cáncer Res., 2000, 60, 6101-10 and Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia (1985)); autoimmune disorders inelude, but are not limited to, acquired immunodeficiency disease syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia (Current Allergy and Asthma Reporte 2003, 3:378-384; Br. J. Haematol. 2000 Sep; 110(3): 584-90; Blood 2000 Feb 15;95(4): 1283-92; and New England Journal of Medicine 2004 Sep; 351(14): 1409-1418).

[0096] It is also expected that compounds having formula (II) would inhibit the growth of cells derived from a cáncer or neoplasm such as breast cáncer (including estrogen-receptor positive breast cáncer), colorectal cáncer, endometrial cáncer, lung cáncer (including small cell lung cáncer), lymphoma (including follicular or Diffuse Large B-cell), lymphoma (including non-Hodgkin's lymphoma), neuroblastoma, ovarían cáncer, prostate cáncer (including hormone-insensitive prostate cáncer), testicular cáncer (including germ cell testicular cáncer).

[0097] It is also expected that compounds having formula (II) would inhibit the growth of cells derived from a pediatric cáncer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous syatem, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cáncer (commonly-owned United States Application Ser No. 10/988,338), Cáncer Res., 2000,60,6101-10); autoimmune disorders inelude, but are not limited to, acquired immunodeficiency disease syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia (Current Allergy and Asthma Reports 2003,3:378-384; Br. J. Haematol. 2000 Sep; 110(3): 584-90; Blood 2000 Feb 15;95(4): 1283-92; and New England Journal of Medicine 2004 Sep; 351(14): 1409-1418).

[0098] Compounds having formula (II) maybe made by synthetic Chemical processes, examples of which are shown hereinbelow. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

[0099] Protecting groups for C(0)OH moieties inelude, but are not limited to, acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl and the like.

[0100] Protecting groups for C(O) and C(0)H moieties inelude, but are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal, 1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like.

[0101] Protecting groups for NH moieties include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl and the like.

[0102] Protecting groups for OH and SH moieties inelude, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl, triphenylmethyl, 2- (triphenylphosphonio)ethoxycarbonyl and the like.

[0103] The following abbreviations have the meanings indicated. ADDP means 1,T-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD^PHAL, K3Fe(CN)6, K2CO3 and K2SO4) AIBN means 2,2'-azobis(2-methylpropionitrile); 9-BBN means 9-borabicyclo[3.3.1]nonane; (DHQD)2PHAL means hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means Ν,Ν-dimethylaminopyridine; DME means 1,2-dimethoxyethane; DMF means Ν,Ν-dimethylformamide; dmpe means 1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)butane; dppe means 1,2-bis(diphenylphosphino)ethane; dppf means 1,1'-bis(diphenylphosphino)ferrorene; dppm means 1,1-bis(diphenylphosphino)methane; EDAC means 1-(3-dimethylaminopropyl)-3-ethylcarbadiimide; Fmoc means fluorenylmethoxycarbonyl; HATU means O-^-azabenzotriazoM-yO-N.N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis(hexamethyldisilylamide); MP-BH3 means macroporus triethylammonium methylpolystyrene cyanoborohydride; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TDA-1 means tris(2-(2-methoxyethoxy)ethyl)amine;

TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine.

[0104] As shown in SCHEME 1, compounds having formula (1) may be converted to compounds having formula (2) bv reacting the former, chlorosulfonic acid, and ammonia.

[0105] Compounds having formula (2) may be converted to compounds having formula (II) by reacting the former and compounds having formula (3) and a coupling agent, with or without a base. Examples of coupling agents inelude EDCI, CDI, and PyBop. Examples of bases include TEA, DIEA, DMAP, and mixtures thereof.

[0106] Compounds having formula (2) maybe converted to compounds having formula (II) by reacting the former and compounds having formula Z1-COCI and the base.

[0107] The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspeets of this invention.

EXAMPLE 1A

[0108] 3-(R)-((Carbabenzyloxy)amino)-y-b-atyrolactonf,-, prepared as described in J. Am. Chem. Soc. 1986, 108, 4943-4952, (62 g) and morpholine (46 ml_) in dioxane (700 ml_) at 65°C was stirred for 24 hours, cooled and concentrated. The concéntrate was chromatographed on silica gel with 10% methanol/ethyl acétate.

EXAMPLE 1B

[0109] EXAMPLE 1A(16.5 g), diphenyl disulfide (14.5 g) and tributylphosphine (16.6 mL) in toluene (250 mL) at 80°C was stirred for 24 hours, cooled and concentrated. The concéntrate was chromatographed on silica gel with 1:1 ethyl acetate/hexanes.

EXAMPLE 1C

[0110] EXAMPLE 1B (18 g) in 30% HBr in acetic acid (250 mL) at 25°C was stirred for 24 hours, concentrated, poured into 1M HCI and extracted with diethyl ether. The extract was extracted with 1M HCI, and this extract was cooled to 0°C, adjusted to pH 12 with KOH and extracted with dichloromethane. The extract was washed with brine and dried (Na2SÜ4), filtered and concentrated.

EXAMPLE 1D

[0111] EXAMPLE 1C (45.4 g) in THF (500 mL) at 55°C was treated with 1M BH3 THF (650 mL) over 2 hours, stirred for 24 hours, cooled to 0°C, treated with methanol (80 mL), poured into methanol (500 mL) and concentrated. A mixture of the concéntrate in methanol (400 mL) was treated with a HCI-saturated methanol (800 mL), refluxed for 24 hours, cooled, concentrated, poured into 2M NaOH and extracted with ethyl acétate. The extract was washed with 1M NaOH and brine and dried (Na2SÜ4), filtered and concentrated. The concéntrate was chromatographed on silica gel with ethyl acétate 10% methanol/ethyl acétate and 10% methanol/10% acetonitrile/5% TEA/75% ethyl acétate.

EXAMPLE 1E

[0112] Methyl viologen hydrochloride (1.17 g) in DMF (80 mL) at 25°C was saturated with trifluoromethyl iodide, treated with 2-fluorobenzenethiol (9.7 mL) and TEA (20 mL), stirred for 24 hours, diluted with water (240 mL) and extracted with diethyl ether. The extract was washed with 1M NaOH, saturated ammonium chloride and brine and concentrated.

EXAMPLE 1F

[0113] EXAMPLE 1E (17.346 g) in 1:1:2 carbón tetrachloride/acetonitrile/water (800 mL) at 25°C was treated with sodium periodate (56.8 g) and ruthenium(lll) chloride hydrate (183 mg), stirred for 18 hours, diluted with dichloromethane (100 mL) and filtered through diatomaceous earth (Celite®). The fíltrate was washed with saturated sodium bicarbonate and extracted with dichloromethane. The extract was washed with brine and dried (MgS04), filtered and concentrated. The concéntrate was filtered through silica gel.

EXAMPLE1G

[0114] EXAMPLE 1F (37.3 g) in chlorosulfonic acid (32.8 mL) at 120°C was stirred for 18 hours, cooled to 25°C and pipetted onto crushed ice. The mixture was extracted with ethyl acétate, and the extract was washed with water and brine and dried (MgSCU), filtered and concentrated.

EXAMPLE 1H

[0115] EXAMPLE 1G (23 g) in isopropanol (706 mL) at -78°C was treated with ammonium hydroxide (98 mL) over 1 hour, stirred for 1 hour, quenched with 6M HCI (353 mL), warmed to 25°C and concentrated. The concéntrate was mixed with water and extracted with ethyl acétate. The extract was dried (MgS04), filtered and concentrated. The concéntrate was recrystallized from ethyl acetate/hexane. EXAMPLE 11 [0116] EXAMPLE 1H (13.48 g) and EXAMPLE 1D (11.56 g) in THF (218 mL) was treated with DIEA(15.1 mL), stirred at 50°Cfor4 hours, cooled, treated with saturated sodium bicarbonate and extracted with ethyl acétate. The extract was dried (MgSC>4), filtered and concentrated. The concéntrate was recrystallized from hexanes/ethyl acétate.

EXAMPLE 1J

[0117] DMF (10 mL) and chloroform (80 mL) at 3°C was treated with PBr3 (12 mL), stirred for 20 minutes at 25°C, treated with 4,4-dimethylcyclohexanone (7.15 g) in chloroform (50 mL), stirred for 18 hours, poured onto ¡ce, neutralized with solid sodium bicarbonate and extracted with diethyl ether. The extract was washed with brine and dried (MgSÜ4), filtered and concentrated. The concéntrate was chromatographed on silica gel with 0-10% ethyl acetate/hexanes.

EXAMPLE 1K

[0118] EXAMPLE 1J (1.7 g) and 4-piperazin-1-ylbenzoic acid ethyl ester (1.9 g) in methanol (30 mL) was treated with sodium cyanoborohydride (0.6 g), adjusted to pH 5 with acetic acid, stirred for 18 hours and filtered through diatomaceous earth (Celite®). The fíltrate was concentrated, and the concéntrate was chromatographed on silica gel on silica gel with 10-30% ethyl acetate/hexanes.

EXAMPLE 1L

[0119] EXAMPLE 1K (1.1 g), 4-chlorophenylboronic acid (0.6 g), 2M Na2CÜ3 (2 mL) and PdCÍ2(PPh3)2 (0.1 g) in 7:3:2 DME/water/ethanol (20 mL) was stirred at 85°C for 18 hours, filtered through diatomaceous earth (Celite®) and concentrated. The concéntrate was chromatographed on silica gel with 10-30% ethyl acetate/hexanes.

EXAMPLE 1M

[0120] EXAMPLE 1L (4.59 g) and LiOH (1.25 g) in dioxane (75 mL) and water (10 mL) was stirred at 100°C for 18 hours, cooled to 25°C and concentrated. The concéntrate was disolved in water, heated to reflux, neutralized with 1M HCI (28.5 mL), cooled to 25°C, filtered and concentrated.

EXAMPLE 1N

[0121] EXAMPLE 1M (31.5 g), EXAMPLE 11 (39.93 g), EDACHCI (20.60 g) andDMAP (13.15 g) in dichloromethane (500 mL) at 25°C was stirred for 18 hours, diluted with dichloromethane, washed with saturated ammonium chloride and brine and dried (MgS04), filtered and concentrated, The concéntrate was chromatographed on silica gel with 0-10% methanol/ammonia-saturated dichloromethane. 1H NNM (300MHz, DMSO-de) δ 8.12 (d , 1H), 7.94 (dd, 1H), 7.71 (d, 2H), 7.38 (d, 2H 7.30 (m, 4H), 7.18 (m, 1H), 7.12 (d, 2H), 6.98 (d, 1H), 6.85 (d, 3H), 4.07 (m, 1H), 3.53 (br, 4H), 3.28 (m, 12H), 2.44 (m, 8H), 1.99 (m, 3H), 1.80 (m, 1H), 1.44 (t, 2H), 0.97 (s, 6H).

EXAMPLE 2A

[0122] Powdered NaOH (31.2 g), TDA-1 (5 mL) and 2-fluorobenzene thiol (33.6 mL) in benzene (400 mL) was saturated with chlorodifluoromethane, stirred at 80°C for 30 minutes and filtered through diatomaceous earth (Celite®). The fíltrate was washed with saturated NaHCOs and the water layer was extracted with diethyl ether. The extracts were combined and dried (MgS04), filtered and concentrated.

EXAMPLE 2B

[0123] EXAMPLE 2A (46 g) in 1:1:2 CC^CHsCN/water (1,2L) at 25°C was treated with NalÜ4 (165.6 g) and RUCI3 XH2O (534 mg), stirred for 18 hours, diluted with dichloromethane and filtered through diatomaceous earth (Celite®). The fíltrate was washed with saturated NaHC03 and dried (Na2S04), filtered and concentrated. The concéntrate was filtered through silica gel.

EXAMPLE 2C

[0124] EXAMPLE 2B (25 g) and NCS (17.55 g) in THF (700 mL) at -78 °C was treated with LHMDS (178.5 mL) over 1 hour, stirred for 1 hour and quenched with ammonium chloride. The mixture was extracted with ethyl acétate, and the extract was washed with brine and dried (MgSC>4), filtered and concentrated. The concéntrate was chromatographed on silica gel with 0-5% ethyl acetate/hexanes.

EXAMPLE 2D

[0125] EXAMPLE 2C (44 g) in chlorosulfonic acid (36.7 mL) at 120°C was stirred for 18 hours, cooled to 25°C, pipetted onto crushed ice and extracted with ethyl acétate. The extract was washed with water and brine and dried (MgSÜ4), filtered and concentrated.

EXAMPLE 2E

[0126] EXAMPLE 2D (22 g) in isopropanol (700 mL) at -78 °C was treated with aqueous ammonia (90 mL) over 1 hour, stirred for another hour, quenched with 6M HCI (300 mL), warmed to 25°C and concentrated. The concéntrate was mixed with water and extracted with ethyl acétate. The extract was dried (MgSCU), filtered and concentrated. The concéntrate was recrystallized from hexanes/ethyl acétate.

EXAMPLE 2F

[0127] EXAMPLE 2E (2.89 g) and EXAMPLE 1D (2.39 g) in THF (20 mL) was treated with diisopropylethylamine (3.2 mL), stirred at 60°C for 18 hours, cooled, treated with saturated sodium bicarbonate and extracted with ethyl acétate. The extract was dried (MgS04), filtered and concentrated. The concéntrate was chromatographed on silica gel with 1.5-5% 7M ammonia in methanol/dichloromethane.

EXAMPLE 2G

[0128] Hexane-washed 60% oily NaH (17 g) in dichloromethane (300 mL) at -5°C was treated with 4,4-dimethyl-2-oxo-cyclohexanecarboxylic acid methyl ester, prepared as described in Tetrahedron (1992), 48 (21), 4459-64, (53.89 g), stirred for 30 minutes, cooled to -78°C, treated with trifluoromethanesulfonic anhydride, warmed to 25°C, stirred for 18 hours, washed with brine and dried (MgS04), filtered and concentrated.

EXAMPLE 2H

[0129] EXAMPLE 2G (86 g), 4-chlorophenylboronic acid (50 g), CsF (104 g) and tetrakis(triphenylphosphine)palladium(0) (2.5 g) in 2:1 DME/methanol (600 mL) at 70°C was stirred for 18 hours and concentrated. The concéntrate was dissolved in diethyl ether, and the solution was dried (MgSC>4), filtered and concentrated. The concéntrate was filtered through silica gel with 20% ethyl acetate/hexanes.

EXAMPLE 2I

[0130] Lithium borohydride (18 g) was treated with EXAMPLE 2H (76 g) in diethyl ether (400 mL) and methanol (23 mL), stirred at reflux for 4 hours, cooled, quenched with 1M HCI, diluted with water and extracted with diethyl ether. The extract was dried (MgS04), filtered and concentrated. The concéntrate was chromatographed on silica gel with 0-30% ethyl acetate/hexanes.

EXAMPLE 2J

[0131] EXAMPLE 2I (17.5 g) in dichloromethane (100 mL) at 0°C was treated simultaneously with methanesulfonyl chloride (5.6 mL) and TEA (21 mL), stirred for 5 minutes, treated with 4-piperazin-1-ylbenzoic acid ethyl ester (17 g), stirred at 25°C for 18 hours, washed with ammonium chloride and dried (Na2SÜ4), filtered and concentrated. The concéntrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 2K

[0132] This example was prepared by substituting EXAMPLE 2J for EXAMPLE 1L in EXAMPLE 1 Μ.

EXAMPLE 2L

[0133] EXAMPLE 2K (16.9 g) and EXAMPLE 2F (22 g) in dichloromethane (200 mL) at 25°C was treated with EDAC HCI (11.06 g) and DMAP (7.06 g), stirred for 18 hours, diluted with dichloromethane (400 mL), washed with saturated ammonium chloride and brine and dried (MgSC>4), filtered and concentrated. The concéntrate was chromatographed on silica gel with 0-10% methanol/ammonia-saturated dichloromethane. 1H NMR (400MHz, DMSO-de) δ 8.07 (d, 1H), 7.90 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.29 (m, 2H), 7.20 (m, 1H), 7.09 (d, 2H), 6.86 (d, 1H), 6.80 (d, 2H), 6.76 (d, 1H), 4.02 (m, 1H), 3.50 (m, 4H), 3.33 (m, 2H), 3.16 (m, 4H), 2.81 (s, 2H), 2.29 (m, 12H), 1.99 (s, 2H), 1.94 (m, 1H), 1.71 (m, 1H), 1.42 (t, 2H), 0.96 (s, 6H).

EXAMPLE 3A

[0134] This example was prepared by substituting 2-bromo-cyclohex-1-enecarbaldehyde, prepared as described in Collect. Czech. Chem. Commun., 1961, 26, 3059.) for EXAMPLE 1J in EXAMPLE 1K.

EXAMPLE 3B

[0135] This example was prepared by substituting EXAMPLE 3A for EXAMPLE 1K in EXAMPLE 1L.

EXAMPLE 3C

[0136] This example was prepared by substituting EXAMPLE 3B for EXAMPLE 1L in EXAMPLE 1M.

EXAMPLE 3D

[0137] This example was prepared by substituting EXAMPLE 3C and EXAMPLE 2F for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE 1N. 1H NMR (400MHz, 17MSO-d6) δ 8.11 (d, 1H), 7.92 (dd, 1H), 7.71 (d, 2H), 7.37 (d, 2H), 7.34 (m, 2H), 7.27 (t, 2H), 7.18 (t, 1H), 7.12 (d, 2H), 6.94 (d, 1H), 6.84 (m, 3H), 4.04 (m, 1H), 3.51 (br, 4H), 3.27 (br, 10H), 2.84 (br, 2H), 2.33 (br, 6H), 2.18 (br, 4H), 1.97 (m, 1H), 1.76 (m, 1H), 1.66 (s, 4H).

EXAMPLE 4A

[0138] A solution of 3-(R)-((carbobenzyloxy)amino)-Y-butyrolactone (prepared according to the procedure described in J. Am. Chem. Soc. 1986, 108, 4943-4952, 7.72 g, 32.8 mmol) in THF (100mL) was saturated with gaseous dimethylamine, stirred at room temperature for 16 hours, and concentrated. The residue was filtered through a plug of silica gel eluting with 50% acetone in hexanes to give the desired product.

EXAMPLE 4B

[0139] A solution of EXAMPLE 4A (8.45 g, 30.14 mmol) in toluene (15 mL) was treated with tributylphosphine (9.76 mL, 39.20 mmol) and diphenyldisulfide (7.30 g, 39.20 mmol) and heated to 80 °C for 16 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel eluting with a gradient of 0-50% ethyl acétate in hexanes to give the desired product.

EXAMPLE 4C

[0140] EXAMPLE 4B (7.5g) and bis(cyclopentadienyl)zirconium(IV) chloride hydride (10.31 g) in THF (100 mL) at 25°C was stirred for 20 minutes and concentrated. The concéntrate was chromatographed on silica gel with with 50% ethyl acétate in hexane.

EXAMPLE 4D

[0141] EXAMPLE 4C (2.87 g) and N-isopropylrnethylamine (1.92 g) in 1,2-dichloroethane (50 mL) at 25°C was treated with sodium triacetoxyborohydride (3 g), stirred for 2 hours, diluted with ethyl acétate, washed with 2M NaOH, water and bríne and dried (Na2SÜ4), filtered and concentrated. The concéntrate was chromatographed on silica gel with with 1% methanol/dichloromethane.

EXAMPLE 4E

[0142] This example was prepared by substituting EXAMPLE 4D for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 4F

[0143] This example was prepared by substituting EXAMPLE 4E for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 4G

[0144] This example was prepared by substituting EXAMPLE 4F for EXAMPLE 11 in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.98 (d, 1H), 7.71 (d, 2H), 7.37 (m, 4H), 7.28 (t, 2H), 7.20 (t, 1H), 7.12 (d, 2H), 6.89 (d, 1H), 6.78 (d, 2H), 6.70 (d, 1H), 4.01 (m, 1H), 3.13 (m, 6H), 2.75 (m, 2H), 2.28 (m, 6H), 2.04 (m, 4H), 1.99 (m, 2H), 1.43 (m, 2H), 1.12 (m, 10H), 0.97 (s, 6H). EXAMPLE 5 [0145] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclo-1-enylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 4F for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (m, 1H), 8.09 (s, 1H), 7.98 (d, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.90 (d, 1H), 6.78 (d, 2H), 6.65 (d, 1H), 4.00 (m, 2H), 3.13 (m, 4H), 2.78 (m, 2H), 2.55 (m, 2H), 2.40 (m, 4H), 2.31 (m, 4H), 2.00 (m, 3H), 1.79 (m, 4H), 1.58 (m, 4H), 1.51 (m, 2H), 1.12 (m, 6H).

EXAMPLE 6A

[0146] This example was prepared by substituting EXAMPLE 4B for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 6B

[0147] EXAMPLE 6A (6.13 g) in THF (200 mL) at 25°C was treated with di-tert-butyldicarbonate (7 g), stirred for 4 hours and concentrated. The concéntrate was dissolved into ethyl acétate (500 mL), washed with 1M NaOH, water and brine and dried (Na2SC>4), filtered and concentrated. The concéntrate in THF (200 mL) at 25°C to was treated with 1M NaOH (200 mL), stirred for 5 hours and isolated. The water layer was extracted with ethyl acétate, and the THF and ethyl acétate extracts were combined, washed with water and brine and dried (Na2SÜ4), filtered and concentrated.

EXAMPLE 6C

[0148] This example was prepared by substituting EXAMPLE 6B for EXAMPLE 5B in EXAMPLE 4C.

EXAMPLE 6D

[0149] This example was prepared by substituting EXAMPLE 6C and 2-oxa-5-aza-bicyclo[2.2.1]heptane, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, for EXAMPLE 4C and N-isopropylmethyl amine in EXAMPLE 4D.

EXAMPLE 6E

[0150] EXAMPLE 6D (7.86 g) in dichloromethane (200 mL) at 25°C was treated with 2M HCI in diethyl ether (200 mL), stirred for 18 hours and concentrated. EXAMPLE 6F ; [0151] This example was prepared by substituting EXAMPLE 6E for EXAMPLE 1D in EXAMPLE 2F.

EXAMPLE 6G

[0152] This example was prepared by substituting EXAMPLE 6F and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M in EXAMPLE IN. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.92 (d, 1H), 7.70 (d, 2H), 7.37 (m, 4H), 7.30 (t, 2H), 7.21 (t, 1H), 7.12 (d, 2H), 6.84 (d, 1H), 6.79 (d, 2H), 4.21 (m, 1H), 4.09 (m, 1H), 4.01 (m, 2H), 3.82 (m, 2H), 3.46 (m, 1H), 3.18 (m, 6H), 2.86 (m, 4H), 2.75 (m, 4H), 2.28 (m, 2H), 2.18 (m, 4H), 1.88 (m, 4H), 1.66 (m, 4H). EXAMPLE 7 [0153] This example was prepared by substituting EXAMPLE 3C for EXAMPLE 1M in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 8.09 (d, 1H), 7.92 (dd, 1H), 7.71 (d, 2H), 7.31 (m 7H), 7.18 (tt, 1H), 7.12 (dt, 2H), 6.92 (d, 1H), 6.82 (m, 3H), 4.04 (m, 1H), 3.51 (m, 4H), 3.26 (m, 10H), 2.82 (m, 2H), 2.30 (m, 10H), 1.94 (m, 1H), 1.72 (m, 5H).

EXAMPLE 8A

[0154] A solution of 3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-phenylsulfanylbutyric acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 141988,338 and HATU in DMF was treated with 7-aza-bicyclo[2.2.1]heptane (prepared as described in Org. Lett., 2001, 3, 1371-1374; and N-methylmorpholine, stirred at ambient temperature for 30min, diluted with ethyl acatate, washed with 1.5% HCI, NaHC03(aq), H2O and brine, dried (Na2S04), filtered and concentrated to give the desired product.

EXAMPLE 8B

[0155] A solution of EXAMPLE 8A in THF was treated with diethyl amine, stirred at ambient temperature for 2 hours and concentrated. The residue was purified by silica gel chromatography eluting with CH2CI2 (saturated with NH3), followed by ethyl acétate to give the desired product.

EXAMPLE 8C

[0156] This example was prepared by substituting EXAMPLE 8B for EXAMPLE 1C in EXAMPLE 1D.

EXAMPLE 8D

[0157] This example was prepared by substituting EXAMPLE 8C for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 8E

[0158] This example was prepared by substituting EXAMPLE 8D and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE 1N. 1H NMR (300MHz, DMSO-d6) δ 9.19 (m, 1H), 8.07 (d, 1H), 7.97 (d, 1H), 7.71 (d, 2H), 7.31 (m 6H), 7.20 (tt, 1H), 7.12 (dt, 2H), 6.89 (d, 1H), 6.76 (d, 2H), 6.65 (d, 1H), 4.03 (m, 2H), 3.31 (m, 4H), 3.12 (m, 4H), 2.90 (br, 2H), 2.76 (m 2H), 1.96 (m, 21H).

EXAMPLE 9A

[0159] This example was prepared by substituting EXAMPLE 6E for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 9B

[0160] This example was prepared by substituting EXAMPLE 9A and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE 1N. 1H NMR (300MHz, DMSO-d6) δ 8.08 (d, 1H), 7.94 (d, 1H), 7.71 (d, 2H), 7.32 (m 7H), 7.20 (tt, 1H), 7.12 (dt, 2H), 6.87 (d, 1H), 6.78 (d, 3H), 4.40 (m, 1H), 4.03 (m, 2H), 3.83 (m, 2H), 3.54 (m, 2H), 3.26 (m, 2H), 3.14 (m, 4H), 2.80 (br, 2H), 2.78 (m, 4H), 1.97 (m, 14H). EXAMPLE 10 [0161] This example was prepared by substituting EXAMPLE 9A for EXAMPLE 11 in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 8.09 (d, 1H), 7.95 (d, 1H), 7.71 (d, 2H), 7.33 (m 7H), 7.20 (tt, 1H), 7.12 (dt, 2H), 6.90 (d, 1H), 6.79 (d, 3H), 4.44 (m, 1H), 4.03 (m, 1H), 3.84 (m, 1H), 3.57 (m, 1H), 3.02 (m, 13H), 2.25 (m, 6H), 1.99 (m, 6H), 1.43 (t, 2H), 0.97 (s, 6H). EXAMPLE 11 [0162] This example was prepared by substituting EXAMPLE 6F for EXAMPLE II in EXAMPLE 1N. 1H NMR (300MHz, DMSO-d6) δ 8.07 (d, 1H), 7.93 (d, 1H), 7.70 (d, 2H), 7.33 (m 7H), 7.20 (tt, 1H), 7.12 (dt, 2H), 6.81 (m, 4H), 4.41 (m, 1H), 4.06 (m, 1H), 3.83 (m, 1H), 3.47 (m, 1H), 3.02 (m, 13H), 2.25 (m, 6H), 1.99 (m, 6H), 1.43 (t, 2H), 0.97 (s, 6H). EXAMPLE 12 [0163] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclohept-1-enylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 9A for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 8.09 (d, 1H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.32 (m 7H), 7.19 (tt, 1H), 7.09 (dt, 2H), 6.90 (d, 1H), 6.79 (d, 3H), 4.45 (m, 1H), 4.03 (m, 2H), 3.85 (m, 2H), 3.55 (m, 2H), 3.04 (m, 8H), 2.34 (m, 8H), 1.85 (m, 7H), 1.54 (m, 5H). EXAMPLE 13 [0164] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclohept-1-enylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 6F for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 8.07 (d, 1H), 7.93 (dd, 1H), 7.71 (d, 2H), 7.32 (m 7H), 7.20 (tt, 1H), 7.09 (dt, 2H), 6.87 (d, 1H), 6.79 (d, 3H), 4.45 (m, 1H), 4.02 (m, 2H), 3.84 (m, 2H), 3.56 (m, 2H), 3.07 (m, 8H), 2.33 (m, 8H), 1.85 (m, 7H), 1.54 (m, 5H). EXAMPLE 14 [0165] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 4F for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 8.07 (d, 1H), 7.96 (dd, 1H), 7.71 (d, 2H), 7.33 (m 7H), 7.20, (tt, 1H), 7.09 (dt, 2H), 6.87 (d, 1H), 6.77 (d, 2H), 6.72 (d, 1H), 4.00 (m, 1H), 3.28 (m, 4H), 3.12 (m, 4H), 2.79 (m, 2H), 2.48 (m, 2H), 2.23 (m, 8H), 2.02 (m, 4H), 1.42 (t, 2H), 1.08 (m, 6H), 0.96 (s, 6H).

EXAMPLE 15A

[0166] This example was prepared by substituting EXAMPLE 6C and 1,4-oxazepane for EXAMPLE 4C and N-isopropyl-N-methylamine in EXAMPLE 4D.

EXAMPLE 15B

[0167] This example was prepared by substituting EXAMPLE 15A for EXAMPLE 6D in EXAMPLE 6E.

EXAMPLE 15C

[0168] This example was prepared by substituting EXAMPLE 15B for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 15D

[0169] This example was prepared by substituting EXAMPLE 15C and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE 1N. 1H NMR (400MHz, CDCI3) δ 8.32 (s, 1H), 8.01 (br, 1H), 7.67 (d, 2H), 7.34 (t, 4H), 7.24 (m, 3H), 6.99 (m, 3H), 6.67 (br, 3H), 3.97 (br, 1H), 3.88 (s, 2H), 3.79 (s, 2H), 3.73-3.23 (br m, 12H), 3.14 (m, 6H), 2.29 (s, 6H), 2.08 (m, 2H), 1.74 (s, 4H).

EXAMPLE 16A

[0170] This example was prepared by substituting azepane for N-isopropyl-N-methylamine in EXAMPLE 4D.

EXAMPLE 16B

[0171] This example was prepared by substituting EXAMPLE 16A for EXAMPLE 4D in EXAMPLE 4E.

EXAMPLE 16C

[0172] This example was prepared by substituting EXAMPLE 16A for EXAMPLE 1D in EXAMPLE II.

EXAMPLE 16D

[0173] This example was prepared by substituting EXAMPLE 16C and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE 1N. 1H NMR (400MHz, CDCI3) δ 8.33 (s, 1H), 8.01 (d, 1H), 7.67 (d, 2H), 7.34 (t, 4H), 7.23 (m, 3H), 6.98 (m, 3H), 6.67 (m, 3H), 3.99 (m, 1H), 3.82-3.19 (br m, 10H), 3.12 (s, 4H), 2.86 (m, 2H), 2.55 (br, 2H), 2.29 (s, 4H), 2.06 (m, 1H), 1.93 (m, 3H), 1.74 (s, 8H), 1.60 (m, 2H).

EXAMPLE 17A

[0174] This example was prepared by substituting EXAMPLE 6A for EXAMPLE 1C in EXAMPLE 1D.

EXAMPLE 17B

[0175] This example was prepared by substituting EXAMPLE 17B for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 17C

[0176] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclohept-1-enylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 17B for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE 1N. 1H NMR (400MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.46 (brs, 1H), 8.18 (d, 1H), 8.00 (dd, 1H), 7.77 (d, 2H), 7.41 (d, 2H), 7.29 (d, 2H), 7.24 (m, 2H), 7.13 (m, 4H), 6.96 (m, 3H), 4.12 (m, 1H), 3.87 (m, 1H), 3.63 (m, 1H), 3.38 (m, 4H), 3.15 (m, 4H), 3.02 (m, 2H), 2.74 (s, 6H), 2.46 (m, 4H), 2.09 (m, 2H), 1.81 (m, 2H), 1.57 (m, 4H).

EXAMPLE 18A

[0177] This example was prepared by substituting EXAMPLE 2E and EXAMPLE 17B for EXAMPLE 1H and EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 18B

[0178] This example was prepared by substituting EXAMPLE 18A and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE IN. 1H NMR (400MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.47 (brs, 1H), 8.18 (d, 1H), 7.99 (dd, 1H), 7.77 (d, 2H), 7.41 (d, 2H), 7.30 (d, 2H), 7.24 (m, 2H), 7.15 (m, 3H), 7.12 (d, 1H), 6.96 (m, 3H), 6.92 (d, 1H), 4.10 (m, 1H), 3.91 (m, 2H), 3.60 (m, 2H), 3.37 (m, 4H), 3.15 (m, 2H), 3.02 (m, 1H), 2.74 (s, 6H), 2.25 (d, 4H), 2.08 (m, 2H), 1.71 (m, 4H). EXAMPLE 19 [0179] This example was prepared by substituting EXAMPLE 2F for EXAMPLE 11 in EXAMPLE IN. 1H NMR (400MHz, DMSO-d6) δ 8.11 (d, 1H), 7.93 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.27 (m, 2H), 7.18 (m, 1H), 7.12 (d, 2H), 6.97 (d, 1H), 6.85 (m, 3H), 4.05 (m, 1H), 3.53 (m, 4H), 3.23 (m, 1H), 2.83 (m, 1H), 2.34 (m, 8H), 2.22 (m, 2H), 1.99 (m, 2H), 1.96 (m, 1H), 1.77 (m, 1H), 1.44 (t, 2H), 0.97 (s, 6H). EXAMPLE 20 [0180] This example was prepared by substituting EXAMPLE 17B for EXAMPLE 11 in EXAMPLE 1N. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (brs, 1H), 8.18 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.23 (t, 2H), 7.14 (s, 4H), 6.95 (m, 3H), 4.11 (m, 1H), 3.88 (m, 2H), 3.58 (m, 4H), 3.08 (m, 4H), 2.73 (s, 6H), 2.27 (m, 2H), 2.08 (m, 2H), 2.02 (s, 2H), 1.47 (t, 2H), 1.00 (s, 6H). EXAMPLE 21 [0181] This example was prepared by substituting 4-(4-(4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-ylmethyl)piperazin-1-yl)benzo¡c acid, prepared as described in commonly-owned U.S.

Patent Application Ser. No. 10/988,338, for EXAMPLE 1M in EXAMPLE IN. 1H NMR (400 MHz, DMSO-de) δ 8.27 (d, 1H), 8.11 (d, 1H), 7.89 (d, 2H), 7.59 (d, 2H), 7.48 (m, 4H), 7.37 (m, 3H), 7.13 (m, 1H), 7.01 (m, 3H), 4.35 (s, 2H), 4.24 (m, 1H), 3.97 (m, 2H), 3.68 (m, 4H), 3.36 (m, 6H), 3.07 (m, 3H), 2.68 (s, 2H), 2.59 (m, 4H), 2.14 (m, 2H), 1.93 (m, 2H).

EXAMPLE 22A

[0182] This example was prepared by substituting EXAMPLE 4E for EXAMPLE 2E in EXAMPLE 2F. EXAMPLE 22 [0183] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 22A for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) 5 9.21 (brs, 1H), 8.17 (m, 1H), 8.00 (dd, 1H), 7.77 (d, 2H), 7.42 (m, 2H), 7.31 (m, 2H), 7.24 (m, 2H), 7.14 (m, 4H), 6.97 (m, 3H), 4.11 (m, 1H), 3.90 (m, 1H), 3.12 (m, 6H), 2.84 (m, 3H), 2.63 (m, 3H), 2.25 (m, 2H), 2.07 (m, 4H), 1.49 (t, 2H), 1.16 (m, 6H), 0.97 (s, 6H). EXAMPLE 23 [0184] This example was prepared by substituting EXAMPLE 22A for EXAMPLE 11 in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (brs, 1H), 8.18 (m, 1H), 7.99 (dd, 1H), 7.78 (d, 2H), 7.40 (d, 2H), 7.30 (d, 2H), 7.24 (m, 2H), 7.15 (m, 4H), 6.97 (m, 3H), 4.11 (m, 1H), 3.89 (m, 1H), 3.13 (m, 6H), 2.84 (m, 2H), 2.63 (m, 3H), 2.28 (m, 2H), 2.07 (m, 4H), 1.48 (t, 2H), 1.17 (m, 6H), 1.00 (s, 6H). EXAMPLE 24 [0185] This example was prepared by substituting EXAMPLE 2K for EXAMPLE 1M in EXAMPLE 1N. 1H NMR (500 MHz, DMSO-d6) δ 12.14 (brs, 1 H), 9.89 (brs, 1H), 9.52 (s, 1H), 8.18 (d, 1H), 8.00 (dd, 1H), 7.77 (d, 2H), 7.41 (d, 2H), 7.30 (d, 2H), 7.24 (t, 2H), 7.14 (m, 4H), 6.96 (m, 3H), 4.12 (m, 1H), 3.93 (m, 3H), 3.63 (m, 4H), 2.93 (m, 10H), 2.24 (m, 2H), 2.09 (m, 4H), 1.48 (t, 2H), 0.97 (s, 6H). EXAMPLE 25 [0186] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 6F for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (500 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.39 (brs, 1H), 8.17 (s, 1H), 7.99 (dd, 1H), 7.77 (d, 2H, 7.41 (d, 2H), 7.30 (d, 2H), 7.24 (t, 2H), 7.14 (m, 4H), 6.97 (m, 3H), 4.63 (d, 1H), 4.43 (d, 1H), 4.13 (m, 1H), 3.92 (m, 2H), 3.69 (m, 2H), 3.52 (m, 2H), 3.01 (m, 6H), 2.25 (m, 2H), 2.04 (m, 6H), 1.49 (m, 2H), 0.98 (s, 6H). EXAMPLE 26 [0187] This example was prepared by substituting EXAMPLE 17B and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE 1N. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (brs, 1H), 8.08 (d, 1H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.20 (t, 1H), 7.12 (d, 2H), 6.84 (m, 2H), 6.78 (d, 2H), 3.98 (m, 1H), 3.28 (m, 2H), 3.12 (brs, 4H), 2.81 (brs, 1H), 2.77 (s, 1H), 2.46 (s, 6H), 2.28 (s, 4H), 2.19 (m, 4H), 2.00 (m, 1H), 1.90 (m, 1H), 1.65 (m, 4H).

EXAMPLE 27A

[0188] This example was prepared by substituting pyrrolidine for N-isopropylethylamine in EXAMPLE 4D.

EXAMPLE 27B

[0189] This example was prepared by substituting EXAMPLE 27A for EXAMPLE 4D in EXAMPLE 4E.

EXAMPLE 27C

[0190] This example was prepared by substituting EXAMPLE 27B for EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 27D

[0191] This example was prepared by substituting EXAMPLE 27C and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, 1H), 7.96 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.20 (t, 1 H), 7.12 (d, 2H), 6.87 (m, 1H), 6.77 (d, 2H), 6.72 (d, 1H), 4.00 (m, 1H), 3.26 (m, 2H), 3.12 (brs, 4H), 2.97 (m, 6H), 2.76 (s, 1H), 2.28 (brs, 4H), 2.19, (m, 4H), 2.05 (m, 1H), 1.95 (m, 1H), 1.82 (brs, 4H), 1.65 (m, 4H). EXAMPLE 28 [0192] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 17B for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (brs, 1H), 8.08 (d, 1H), 7.94 (dd, 1H), 7.70 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.21 (tt, 1H), 7.09 (d, 2H), 6.83 (d, 1H), 6.78 (d, 3H), 3.97 (m, 1H), 3.28 (m, 2H), 3.13 (brs, 4H), 2.90 (brs, 2H), 2.79 (s, 2H, 2.55 (s, 6H), 2.28 (brs, 4H), 2.20 (m, 2H), 1.99 (s, 2H), 1.90 (m, 2H), 1.42 (t, 2H), 0.96 (s, 6H). EXAMPLE 29 [0193] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclo-1-onylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 27C for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (brs, 1H), 8.08 (d, 1H), 7.94 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.83 (d, 1H), 6.77 (d, 3H), 3.99 (m, 1H), 3.26 (m, 2H), 3.12 (brs, 4H), 2.80 (m, 5H), 2.76 (s, 2H), 2.40 (m, 4H), 2.31 (brs, 4H), 1.99 (m, 1H), 1.89 (m, 1H), 1.77 (brs, 6H), 1.58 (m, 2H), 1.51 (m, 2H).

EXAMPLE 30A

[0194] This example was prepared by substituting EXAMPLE 2E and EXAMPLE 27B for EXAMPLE 1H and EXAMPLE 1D in EXAMPLE 11.

EXAMPLE 30B

[0195] This example was prepared by substituting EXAMPLE 30A for EXAMPLE 11 and EXAMPLE 1D in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (brs, 1H), 8.07 (d, 1H), 7.93 (dd, 1H), 7.70 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.21 (t, 1H), 7.12 (d, 2H), 6.81 (d, 1H), 6.77 (d, 3H), 3.99 (m, 1H), 3.26 (m, 2H), 3.12 (brs, 4H), 2.80 (m, 5H), 2.76 (s, 2H), 2.27 (m, 4H), 2.22 (m, 2H), 1.99 (m, 3H), 1.88 (m, 1H), 1.77 (brs, 4H), 1.43 (t, 2H), 0.97 (s, 6H). EXAMPLE 31 [0196] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 30A for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (brs, 1H), 8.06 (d, 1H), 7.92 (dd, 1H), 7.70 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.21 (t, 1H), 7.08 (d, 2H), 6.81 (d, 1H), 6.77 (d, 3H), 3.99 (m, 1H), 3.26 (m, 2H), 3.12 (brs, 4H), 2.76 (s, 2H), 2.75 (m, 5H), 2.26 (m, 4H), 2.20 (m, 2H), 1.99 (m, 3H), 1.86 (m, 1H), 1.76 (brs, 4H), 1.42 (t, 2H), 0.96 (s, 6H). EXAMPLE 32 [0197] This example was prepared by substituting 4-(4-(2-(4-chlorophenyl)cyclohept-1-enylmethyl)piperazin-1-yl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, and EXAMPLE 30A for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (brs, 1H), 8.08 (d, 1H), 7.94 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (t, 2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.83 (d, 1H), 6.77 (d, 3H), 3.99 (m, 1H), 3.26 (m, 2H), 3.12 (brs, 4H), 2.80 (m, 5H), 2.76 (s, 2H), 2.40 (m, 4H), 2.31 (brs, 4H), 1.98 (m, 1H), 1.87 (m, 1H), 1.76 (brs, 6H), 1.58 (m, 2H), 1.51 (m, 2H). EXAMPLE 33 [0198] This example was prepared by substituting EXAMPLE 4F and EXAMPLE 3C for EXAMPLE 11 and EXAMPLE 1M, respectively, in EXAMPLE IN. 1H NMR (300MHz, DMSO-d6) δ 9.03 (s, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.71 (d, 2H), 7.39-7.34 (m, 4H), 7.30 (t, 2H), 7.20 (tt, 1H), 7.13 (dt, 2H), 6.88 (m, 1H), 6.78 (d, 2H), 6.70 (m, 1H), 3.99 (m, 1H), 3.37-3.26 (m, 4H), 3.12 (s, 4H), 2.76 (s, 2H), 2.68-2.53 (m, 2H), 2.34-2.13 (m, 10H), 2.10-1.95 (m, 2H), 1.66 (s, 4H), 1.13 (m, 6H). EXAMPLE 34 [0199] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 27C for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE 1N. 1H NMR (304MHz, DMSO-d6) δ 9.53 (s, 1H), 8.08 (d, 1H), 7.97 (dd, 1H), 7.71 (d, 2H), 7.40-7.34 (m, 4H), 7.30 (t, 2H), 7.20 (tt, 1H), 7.09 (d, 2H), 6.89 (d, 1H), 6.78 (d, 2H), 6.71 (d, 1H), 4.01 (m, 1H), 3.38-3.27 (m, 4H), 3.20-2.84 (m, 10H), 2.79 (s, 2H), 2.27 (s, 4H), 2.20 (t, 2H), 2.03 (m, 2H), 1.85 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H). EXAMPLE 35 [0200] This example was prepared by substituting EXAMPLE 3C and EXAMPLE 30A for EXAMPLE 1M and EXAMPLE 11, respectively in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, 1H), 7.93 (dd, 1H), 7.71 (d, 2H), 7.36 (m, 4H), 7.30 (m, 2H), 7.21 (m, 1H), 7.12 (d, 2H), 6.81 (d, 1H), 6.77 (d, 3H), 3.97 (m, 1H), 3.26 (m, 4H), 3.12 (s, 4H), 2.78 (m, 6H), 2.27 (s, 4H), 2.18 (m, 4H), 1.99 (m, 1H), 1.87 (m, 1H), 1.76 (s, 4H), 1.66 (s, 4H). EXAMPLE 36 [0201] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 9A for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.97 (dd, 1 H), 7.71 (d, 2H), 7.33 (m, 6H), 7.21 (m, 1H), 7.08 (d, 2H), 6.87 (m, 1H), 6.78 (m, 3H), 3.99 (m, 1H), 3.14 (m, 4H), 2.95 (m, 1H), 2.80 (m, 3H), 2.58 (s, 6H), 2.28 (m, 4H), 2.20 (m, 2H), 1.99 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H). EXAMPLE 37 [0202] This example was prepared by substituting EXAMPLE 2K and EXAMPLE 17B for EXAMPLE 1M and EXAMPLE 11, respectively, in EXAMPLE 1N. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.97 (dd, 1 H), 7.71 (d, 2H), 7.33 (m, 6H), 7.21 (m, 1H), 7.08 (d, 2H), 6.87 (m, 1H), 6.78 (m, 3H), 3.99 (m, 1H), 3.14 (m, 4H), 2.95 (m, 1H), 2.80 (m, 3H), 2.58 (s, 6H), 2.28 (m, 4H), 2.20 (m, 2H), 1.99 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H). EXAMPLE 38 [0203] This example was prepared by substituting 4-(4-(1 ,T-biphenyl-2-ylmethyl)-1-piperazinyl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application Ser. No. 10/988,338, for EXAMPLE 1M and EXAMPLE 17B for EXAMPLE 11, respectively, in EXAMPLE IN. 1H NMR (400MHz, DMSO-d6) δ 8.19 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 3H), 7.52 (d, 4H), 7.40 (d, 2H), 7.35 (m, 1H), 7.30 (d, 2H), 7.24 (t, 2H), 7.16 (t, 2H), 6.96 (m, 3H), 4.25 (br, 2H), 4.12 (m, 1H), 3.37 (m, 2H), 3.14 (m, 1H), 3.10 (br, 8H), 2.74 (s, 6H), 2.10 (m, 2H). EXAMPLE 39 [0204] This example was prepared by substituting 4-(4-(1,1-biphenyl-2-ylmethyl)-1-piperazinyl)benzoic acid, prepared as described in commonly-owned U.S. Patent Application

Ser. No. 10/988,338, for EXAMPLE 1M in EXAMPLE 1N. 1H NMR (400MHz, DMSO-d6) δ 8.19 (d, 1H), 8.00 (dd, 1H), 7.76(d, 2H), 7.52 (m, 5H), 7.14 (m, 8H), 6.96 (m, 3H), 4.29 (m, 2H), 4.14 (m, 2H), 4.02 (m, 1H), 3.10 (m, 8H), 2.13 (m, 2H).

[0205] The foregoing is meant to ¡Ilústrate the invention but not to limit it. Variations and changes obvious to one skilled in the art are intended to be within the scope of the invention as defined in the claims.

[0206] The present invention further encompasses the following embodiments:

or a therapeutically acceptable salt thereof, wherein X3 is Cl or F; X4 is azepan-1-yl, morpholin-1-yl, pyrrolidin-1-yl, N(CH3)2, N(CH3)(CH(CH3)2), 7-azabicyclo[2.2.1]heptan-1-yl or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and R° is

wherein X5 is C(CH3)2, and X6 and X7 are both hydrogen; and X8isF, Cl, Br or I. 2. 2. A composition comprising an excipient and a therapeutically effective amount of a compound of item 1. 3. 3. A compound of ítem 1 for use in treating bladder cáncer, brain cáncer, breast cáncer, bone marrow cáncer, cervical cáncer, chronic lymphocytic leukemia, colorectal cáncer, esophageal cáncer, hepatocellular cáncer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cáncer, ovarían cáncer, non-small cell lung cáncer, prostate cáncer, small cell lung cáncer or spleen cáncer in a patient, by administering to the patient a therapeutically effective amount of a compound of item 1.

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description • WQ2005049594A [0002] [0087] [008S[ • US6720338BF06021 • US7030115B [0002] • USt 0988338B[00971 • US988338A Γ01451 Γ0149Ί f01831 Γ01841 Í01761 [0181] Γ01931 f01971 f02031 Í02041 • US141988338A [0154]

Non-patent literature cited in the description • Puré Appl. Chem., 1976, vol. 45, 13-10 [0028] . ZHANG, H. C.NIMMER, P.ROSENBERG, S. H.NG, S. C.JOSEPH, M.Development of a High-Throughput Fluorescence Polarization Assay for Bcl-x(L)Analytical Biochemistry, 2002, vol. 307, 70-75 [0077] • Science, 1997, vol. 275, 983-986 Í007S1 • PNAS, 2001, vol. 98, 3012-3017 10079] • Cáncer Res., 2000, vol. 60, 6101-10 Í00951 Í0G971 • MedicineJ.B. Lippincott Co. 19850000 [0095] • Current Allergy and Asthma Reporte, 2003, vol. 3, 378-384 [Q09B] [0097] • Br. J. Haematol., 2000, vol. 110, 3584-90 £0095] ITOZl • Bloori. 2000. vol. 95. 41283-92 Í00951 FQ0371 • New England Journal of Medicine, 2004, vol. 351, 141409-1418 [0095] [0097] • J. Am. Chem. Soc., 1986, vol. 108, 4943-4952 F01081 F01381 • Tetrahedron, 1992, vol. 48, 214459-64 Í61281 • Czech. Chem. Commun., 1961, vol. 26, 3059- [0134] . Org. Lett., 2001, vol. 3, 1371-1374 Γ61541

Claims (10)

A compound having formula (II) or a therapeutically acceptable salt thereof, wherein X 3 is chlorine or fluorine; X4 is azepan-1-yl, morpholin-1-yl, pyrrolidin-1-yl, N (CH3) 2, N (CH3) (CH (CH3) 2), 7-azabicyclo [2.2.1] heptane-1- yl or 2-oxa-5-azabicyclo [2.2.1] hept-5-yl; and R ° is wherein X8 is F, Cl, Brellerl. The compound of claim 1, wherein X 4 is morpholin-1-yl. 3. The compound 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 a therapeutically acceptable salt thereof . A composition suitable for oral administration, comprising a excipient and the compound of claims 1-3. The composition of claim 4 for use in the treatment of a patient with bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, lymphoblastic leukemia, lymphoblastic leukemia, origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or splenic cancer when administered to the patient by a therapeutically effective amount of the composition. The composition according to claim 5, wherein the composition is administered orally. The composition of claim 5 for use in treating a patient with lymphoid malignancy of B-cell origin. The composition of claim 7, wherein the lymphoid malignancy of B cell origin is a non-Hodgkin's lymphoma. The composition of claim 7, wherein the lymphoid malignancy of B-cell origin is a follicular lymphoma. The composition of claim 5 for use in the treatment of a patient with small cell lung cancer.