US007807672B2

(12) United States Patent (10) Patent No.: US 7,807,672 B2 Deng et al. (45) Date of Patent: Oct. 5, 2010

(54) COMPOUNDS THAT ARE ERK INHIBITORS (56) References Cited (75) Inventors: Yongqi Deng, Newton, MA (US); U.S. PATENT DOCUMENTS Gerald W. Shipps, Jr., Stoneham, MA 2. R 12: E. wa tal (US); Alan Cooper, West Caldwell, NJ 7,208,513w- B2 4/2007 BhagwatagWal et al. (US); Yang Nan, Malden, MA (US); 7.211,594 B2 5/2007 Bhagwat et al. Tong Wang, Cambridge, MA (US); M. 7,220,771 B2 5/2007 Bhagwat et al. Arshad Siddiqui, Newton, MA (US); 7,429,609 B2 9, 2008 Ohi et al. Robert Sun Berkeley Heights NJ (US); 2003/0055068 A1 3, 2003 Bebbington et al. Joseph M. Kell Parlin, NJ (US). s 2004/0127536 A1 7/2004 Bhagwat et al. pn V1. Kelly, s 2004/O127538 A1 7/2004 Oinuma et al. Ronald Doll, Convent Station, NJ (US); 2005/0009876 A1 1/2005 Bhagwat et al. Jagdish Desai, Monroe Township, NJ 2005, 0107386 A1 5.2005 Narla et al. (US); James J-S Wang, Westfield, NJ 2005/0107457 A1 5/2005 Bhagwat et al. (US); Youhao Dong, Cambridge, MA 2007/0060616 A1 3/2007 Bennett et al. (US); Vincent Madison, Mountain 38.9. A. 3. o et Fa Lakes, NJ (US); Li Xiao,w/ Cranbury, NJ 2007,0265333 A1 11/2007 Fuooper et al. et al. (US); Alan Hruza, Hackettstown, NJ 2008.0004287 A1 1/2008 Ma et al. (US); Neng-Yang Shih, Warren, NJ (US) 2008.0007509 A1 1/2008 Lankhorst et al. 2009 OO11284 A1 1/2009 Wang et al. (73) Assignee: Schering Corporation, Kenilworth, NJ 2009.0062355 A1 3, 2009 Izawa et al. (US) 2009.0118284 A1 5/2009 Cooper et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 GB 2 306 108 A 4f1997 U.S.C. 154(b) by 241 days. GB 2323 845. A 7, 1998 WO WO 97454.12 A1 12/1997 (21) Appl. No.: 11/705,709 WO WO9903498 A1 1/1999 WO WO991.0325 A1 3, 1999 (22) Filed: Feb. 13, 2007 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2007/O23261.0 A1 Oct. 4, 2007 PCT International Search Report dated Jul. 9, 2007, for correspond Related U.S. Application Data ing PCT Application No. PCT/US2007/003665. Primary Examiner Emily Bernhardt (60) Eyal application No. 60/774,043, filed on Feb. (74) Attorney, Agent, or Firm Henry C. Jeanette (57) ABSTRACT (51) Int. Cl. A6 IK3I/506 (2006.01) - - - - - A 6LX 3/5.377 (2006.01) Disclosed are the ERK inhibitors of formula 1.0: A6 IK 3/4025 (2006.01) A6 IK 3/496 (2006.01) (1.0) CO7D 40/06 (2006.01) 8 CO7D 40/12 (2006.01) R CO7D 40/4 (2006.01) 1- V2 O O CO7D 403/2 (2006.01) YY y 35 CO7D 405/2 (2006.01) HO X-1 2 N CO7D 413/12 (2006.01) \ 4 R C Q CO7D 417/06 (2006.01) R s C07D 417/12 (2006.01) R Re/ (52) U.S. Cl...... 514/235.5: 514/235.8: 514/248; 514/252.19; 514/254.01: 514/253.09: 514/254.02: and the pharmaceutically acceptable salts and Solvates 514/254.03: 514/254.05: 514/307: 514/321; thereof. Q is a piperidine or piperazine ring that can have a 514/326; 514/414: 514/423: 544/121; 544/142; bridge or a fused ring. The piperidine ring can have a double 544/235; 544/335; 544/357: 544/295; 544/366; bond in the ring. All other substituents are as defined herein. 544/367: 544/368; 544/369: 544/372; 546/146; Also disclosed are methods of treating cancer using the com 546/199: 546/226,546/279.1: 548/453 pounds of formula 1.0. (58) Field of Classification Search ...... None See application file for complete search history. 23 Claims, No Drawings US 7,807.672 B2 Page 2

FOREIGN PATENT DOCUMENTS WO WO 2004O26867 A2 4/2004 WO WO 2004083203 A1 9, 2004 WO WOO156557 A2 8, 2001 WO WO 2005OO2673 A1 1/2005 WO WOO157022 A2 8, 2001 WO WO 2005063.258 A1 T 2005 WO WOO168619 A1 9, 2001 WO WO 2005,100342 A1 10, 2005 WO WOO172721 A2 10, 2001 WO WO 200510O338 A1 10, 2005 W W. 3. A1 558. WO WO 2005,113541 A1 12/2005 WO WOO22261.0 A1 3f2002 WO WO 2005.113546 A1 12/2005 WO WOO250065 A2 6, 2002 WO WO 2006040569 A1 4, 2006 WO WO O2/O64586 A2 8, 2002 WO WO 2006O71644 A1 T 2006 WO WO 0208.8090 A2 11/2002 WO WO 2006136008 A1 12/2006 WO WO O2O88097 A1 11, 2002 WO WO 2007044401 A2 4/2007 WO WOO3O11854 A1 2, 2003 WO WO 2007044420 A1 4/2007 WO WOO3O 11855 A2 2, 2003 WO WO 2008121742 A2 10, 2008 WO WO O3035626 A2 5, 2003 WO WO 2008,156739 12/2008 WO WO 03/091246 A1 11, 2003 WO WO 2008154241 A1 12/2008 WO WOO3O992.12 A2 12/2003 WO WO 2009/105500 8, 2009 US 7,807,672 B2 1. 2 COMPOUNDS THAT ARE ERKINHIBITORS or the pharmaceutically acceptable salts thereof, wherein: Y', Y, and Y are each independently selected from the REFERENCE TO RELATED APPLICATION group consisting of C, N and substituted carbon; Q is selected from the group consisting of piperidinyl, This Application claims the benefit of U.S. Provisional piperazinyl, tetrahydropyridinyl (e.g., 1.2.3,6-tetrahydropy Application Ser. No. 60/774,043 filed Feb. 16, 2006. ridinyl), bridged piperazinyl, bridged piperidinyl, bridged tetrahydropyridinyl, substituted piperidinyl, substituted pip BACKGROUND erazinyl. Substituted tetrahydropyridinyl (e.g., a substituted 1.2.3,6-tetrahydro-pyridinyl), bridged substituted piperazi The processes involved in tumor growth, progression, and 10 nyl, bridged substituted piperidinyl, and bridged substituted metastasis are mediated by signaling pathways that are acti tetrahydropyridinyl: vated in cancer cells. The ERK pathway plays a central role in Z is 1 to 3 (and preferably 1); and regulating mammalian cell growth by relaying extracellular R", R. R. Rand Rare as defined below. signals from ligand-bound cell surface tyrosine kinase recep This invention provides compounds of formula 1.0 (for tors such as erbB family, PDGF, FGF, and VEGF receptor 15 example, as described in any one of Embodiment Nos. 1 to tyrosine kinase. Activation of the ERK pathway is via a cas 90) in pure or isolated form. cade of phosphorylation events that begins with activation of This invention also provides a pharmaceutical composition Ras. Activation of Ras leads to the recruitment and activation comprising an effective amount of at least one (e.g., 1, 2 or 3, of Raf, a serine-threonine kinase. Activated Raf then phos 1 or 2, and usually 1) compound of formula 1.0 (for example, phorylates and activates MEK1/2, which then phosphorylates as described in any one of Embodiment Nos. 1 to 90) and a and activates ERK1/2. When activated, ERK1/2 phosphory pharmaceutically acceptable carrier. lates several downstream targets involved in a multitude of This invention also provides a pharmaceutical composition cellular events including cytoskeletal changes and transcrip comprising an effective amount of at least one (e.g., 1, 2 or 3, tional activation. The ERK/MAPK pathway is one of the most 1 or 2, and usually 1) compound of formula 1.0 (for example, important for cell proliferation, and it is believed that the 25 as described in any one of Embodiment Nos. 1 to 90) and an ERK/MAPK pathway is frequently activated in many tumors. effective amount of at least one other (e.g., 1, 2 or 3, 1 or 2, and Ras genes, which are upstream of ERK 1/2, are mutated in usually 1) pharmaceutically active ingredient (such as, for Several cancers including colorectal, melanoma, breast and example, a chemotherapeutic agent), and a pharmaceutically pancreatic tumors. The high Ras activity is accompanied by acceptable carrier. elevated ERK activity in many human tumors. In addition, 30 This invention also provides a method of inhibiting ERK mutations of BRAF, a serine-threonine kinase of the Raf (i.e., inhibiting the activity of ERK) in a patient in need of family, are associated with increased kinase activity. Muta Such treatment comprising administering to said patient an tions in BRAF have been identified in melanomas (60%), effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and thyroid cancers (greater than 40%) and colorectal cancers. usually 1) compound of formula 1.0 (for example, as These observations indicate that the ERK 1/2 signalling path 35 described in any one of Embodiment Nos. 1 to 90). way is an attractive pathway for anticancer therapies in a This invention also provides a method of inhibiting ERK1 broad spectrum of human tumours. (i.e., inhibiting the activity of ERK1) in a patient in need of Therefore, a welcome contribution to the art would be Such treatment comprising administering to said patient an small-molecules (i.e., compounds) that inhibit ERK activity effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and (i.e., ERK1 and ERK2 activity), which small-molecules 40 usually 1) compound of formula 1.0 (for example, as would be useful for treating abroad spectrum of cancers, such described in any one of Embodiment Nos. 1 to 90). as, for example, melanoma, pancreatic cancer, thyroid cancer, This invention also provides a method of inhibiting ERK2 colorectal cancer, lung cancer, breast cancer, and ovarian (i.e., inhibiting the activity of ERK2) in a patient in need of cancer. Such a contribution is provided by this invention. Such treatment comprising administering to said patient an 45 effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and SUMMARY OF THE INVENTION usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90). This invention provides compounds that inhibit the activity This invention also provides a method of inhibiting ERK1 of ERK1 and/or the activity of ERK2. and ERK2 (i.e., inhibiting the activity of ERK1 and ERK2) in The compounds of this invention also inhibit the phospho 50 a patient in need of such treatment comprising administering rylation of ERK1 and ERK2. to said patient an effective amount of at least one (e.g., 1, 2 or Thus, this invention provides compounds that are ERK 3, 1 or 2, and usually 1) compound of formula 1.0 (for inhibitors (i.e., ERK1 inhibitors and/or ERK2 inhibitors), example, as described in any one of Embodiment Nos. 1 to said compounds being of the formula 1.0: 90). 55 This invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising (1.0) administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula R8 1.0 (for example, as described in any one of Embodiment O 60 Nos. 1 to 90). This invention also provides a method for treating cancer in 1 R35 HO N N a patient in need of such treatment, said method comprising \ ) R2 Q administering to said patient an effective amount of a phar Y3 R36 maceutical composition comprising an effective amount of at RI R35 65 least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodi ment Nos. 1 to 90). US 7,807,672 B2 3 4 This invention also provides a method for treating cancer in This invention also provides a method for treating lung a patient in need of Such treatment, said method comprising cancer, pancreatic cancer, colon cancer (e.g., colorectal can administering to said patient an effective amount of at least cer), myeloid leukemias (e.g., AML, CML, and CMML), one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula thyroid cancer, myelodysplastic syndrome (MDS), bladder 1.0 (for example, as described in any one of Embodiment carcinoma, epidermal carcinoma, melanoma, breast cancer, Nos. 1 to 90), in combination with an effective amount of at prostate cancer, head and neck cancers (e.g., squamous cell least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. cancer of the head and neck), ovarian cancer, brain cancers This invention also provides a method for treating cancer in (e.g., gliomas, Such as glioma blastoma multiforme), cancers a patient in need of Such treatment, said method comprising of mesenchymal origin (e.g., fibrosarcomas and rhabdomyo administering to said patient an effective amount of a phar 10 sarcomas), sarcomas, tetracarcinomas, nuroblastomas, kid maceutical composition comprising an effective amount of at ney carcinomas, hepatomas, non-Hodgkin’s lymphoma, mul least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of tiple myeloma, oranaplastic thyroid carcinoma in a patient in formula 1.0 (for example, as described in any one of Embodi need of Such treatment, said method comprising administer ment Nos. 1 to 90), in combination with an effective amount ing to said patient an effective amount of a pharmaceutical of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic 15 composition comprising an effective amount of at least one agent. (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 This invention also provides a method of treating cancer in (for example, as described in any one of Embodiment Nos. 1 a patient in need of Such treatment, said method comprising to 90). administering to said patient an effective amount of at least This invention also provides a method for treating lung one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula cancer, pancreatic cancer, colon cancer (e.g., colorectal can 1.0 (for example, as described in any one of Embodiment cer), myeloid leukemias (e.g., AML, CML, and CMML), Nos. 1 to 90) in combination with at least one (e.g., 1, 2 or 3, thyroid cancer, myelodysplastic syndrome (MDS), bladder 1 or 2, and usually 1) signal transduction inhibitor. carcinoma, epidermal carcinoma, melanoma, breast cancer, This invention also provides a method of treating cancer in prostate cancer, head and neck cancers (e.g., squamous cell a patient in need of Such treatment, said method comprising 25 cancer of the head and neck), ovarian cancer, brain cancers administering to said patient an effective amount of a phar (e.g., gliomas, Such as glioma blastoma multiforme), cancers maceutical composition comprising an effective amount of at of mesenchymal origin (e.g., fibrosarcomas and rhabdomyo least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of sarcomas), sarcomas, tetracarcinomas, nuroblastomas, kid formula 1.0 (for example, as described in any one of Embodi ney carcinomas, hepatomas, non-Hodgkin’s lymphoma, mul ment Nos. 1 to 90) in combination with at least one (e.g., 1, 2 30 tiple myeloma, oranaplastic thyroid carcinoma in a patient in or 3, 1 or 2, and usually 1) signal transduction inhibitor. need of Such treatment, said method comprising administer ing to said patient an effective amount of a pharmaceutical This invention also provides a method for treating lung composition comprising an effective amount of at least one cancer, pancreatic cancer, colon cancer (e.g., colorectal can (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 cer), myeloid leukemias (e.g., AML, CML, and CMML), 35 thyroid cancer, myelodysplastic syndrome (MDS), bladder (for example, as described in any one of Embodiment Nos. 1 carcinoma, epidermal carcinoma, melanoma, breast cancer, to 90), in combination with an effective amount of at least one prostate cancer, head and neck cancers (e.g., squamous cell (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. cancer of the head and neck), ovarian cancer, brain cancers This invention also provides a method for treating cancer in (e.g., gliomas, such as glioma blastoma multiforme), cancers 40 a patient in need of Such treatment, said method comprising of mesenchymal origin (e.g., fibrosarcomas and rhabdomyo administering to said patient an effective amount of at least sarcomas), sarcomas, tetracarcinomas, nuroblastomas, kid one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula ney carcinomas, hepatomas, non-Hodgkin’s lymphoma, mul 1.0 (for example, as described in any one of Embodiment tiple myeloma, oranaplastic thyroid carcinoma, in a patient in Nos. 1 to 90), wherein said cancer is selected from the group need of Such treatment, said method comprising administer 45 consisting of melanoma, pancreatic cancer, thyroid cancer, ing to said patient an effective amount of at least one (e.g., 1, colorectal cancer, lung cancer, breast cancer, and ovarian 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for CaCC. example, as described in any one of Embodiment Nos. 1 to This invention also provides a method for treating cancer in 90). a patient in need of Such treatment, said method comprising This invention also provides a method for treating lung 50 administering to said patient an effective amount of at least cancer, pancreatic cancer, colon cancer (e.g., colorectal can one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula cer), myeloid leukemias (e.g., AML, CML, and CMML), 1.0 (for example, as described in any one of Embodiment thyroid cancer, myelodysplastic syndrome (MDS), bladder Nos. 1 to 90), in combination with an effective amount of at carcinoma, epidermal carcinoma, melanoma, breast cancer, least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent prostate cancer, head and neck cancers (e.g., squamous cell 55 wherein said cancer is selected from the group consisting of cancer of the head and neck), ovarian cancer, brain cancers melanoma, pancreatic cancer, thyroid cancer, colorectal can (e.g., gliomas, such as glioma blastoma multiforme), cancers cer, lung cancer, breast cancer, and ovarian cancer. of mesenchymal origin (e.g., fibrosarcomas and rhabdomyo This invention also provides a method for treating cancer in sarcomas), sarcomas, tetracarcinomas, nuroblastomas, kid a patient in need of Such treatment, said method comprising ney carcinomas, hepatomas, non-Hodgkin’s lymphoma, mul 60 administering to said patient an effective amount of a phar tiple myeloma, oranaplastic thyroid carcinoma in a patient in maceutical composition comprising an effective amount of at need of Such treatment, said method comprising administer least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of ing to said patient an effective amount of at least one (e.g., 1, formula 1.0 (for example, as described in any one of Embodi 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for ment Nos. 1 to 90), wherein said cancer is selected from the example, as described in any one of Embodiment Nos. 1 to 65 group consisting of melanoma, pancreatic cancer, thyroid 90), in combination with an effective amount of at least one cancer, colorectal cancer, lung cancer, breast cancer, and ova (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. rian cancer. US 7,807,672 B2 5 6 This invention also provides a method for treating cancer in compound of formula 1.0 (for example, as described in any a patient in need of Such treatment, said method comprising one of Embodiment Nos. 1 to 90), in combination with an administering to said patient an effective amount of a phar effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) maceutical composition comprising an effective amount of at chemotherapeutic agent. least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of 5 This invention also provides a method for treating thyroid formula 1.0 (for example, as described in any one of Embodi cancer in a patient in need of Such treatment, said method ment Nos. 1 to 90), in combination with an effective amount comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound agent wherein said cancer is selected from the group consist of formula 1.0 (for example, as described in any one of ing of melanoma, pancreatic cancer, thyroid cancer, colorec 10 Embodiment Nos. 1 to 90). tal cancer, lung cancer, breast cancer, and ovarian cancer. This invention also provides a method for treating thyroid This invention also provides a method for treating mela cancer in a patient in need of Such treatment, said method noma in a patient in need of Such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound 15 of formula 1.0 (for example, as described in any one of of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective Embodiment Nos. 1 to 90). amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo This invention also provides a method for treating mela therapeutic agent. noma in a patient in need of Such treatment, said method This invention also provides a method for treating thyroid comprising administering to said patient an effective amount cancer in a patient in need of Such treatment, said method of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound comprising administering to said patient an effective amount of formula 1.0 (for example, as described in any one of of a pharmaceutical composition comprising an effective Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo compound of formula 1.0 (for example, as described in any therapeutic agent. 25 one of Embodiment Nos. 1 to 90). This invention also provides a method for treating mela This invention also provides a method for treating thyroid noma in a patient in need of Such treatment, said method cancer in a patient in need of Such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) 30 amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90). one of Embodiment Nos. 1 to 90), in combination with an This invention also provides a method for treating mela effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) noma in a patient in need of Such treatment, said method chemotherapeutic agent. comprising administering to said patient an effective amount 35 This invention also provides a method for treating colorec of a pharmaceutical composition comprising an effective tal cancer in a patient in need of such treatment, said method amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) comprising administering to said patient an effective amount compound of formula 1.0 (for example, as described in any of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound one of Embodiment Nos. 1 to 90), in combination with an of formula 1.0 (for example, as described in any one of effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) 40 Embodiment Nos. 1 to 90). chemotherapeutic agent. This invention also provides a method for treating colorec This invention also provides a method for treating pancre tal cancer in a patient in need of such treatment, said method atic cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound 45 of formula 1.0 (for example, as described in any one of of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective Embodiment Nos. 1 to 90). amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo This invention also provides a method for treating pancre therapeutic agent. atic cancer in a patient in need of such treatment, said method This invention also provides a method for treating colorec comprising administering to said patient an effective amount 50 tal cancer in a patient in need of such treatment, said method of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound comprising administering to said patient an effective amount of formula 1.0 (for example, as described in any one of of a pharmaceutical composition comprising an effective Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo compound of formula 1.0 (for example, as described in any therapeutic agent. 55 one of Embodiment Nos. 1 to 90). This invention also provides a method for treating pancre This invention also provides a method for treating colorec atic cancer in a patient in need of such treatment, said method tal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) 60 amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90). one of Embodiment Nos. 1 to 90), in combination with an This invention also provides a method for treating pancre effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) atic cancer in a patient in need of such treatment, said method chemotherapeutic agent. comprising administering to said patient an effective amount 65 This invention also provides a method for treating lung of a pharmaceutical composition comprising an effective cancer in a patient in need of Such treatment, said method amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) comprising administering to said patient an effective amount US 7,807,672 B2 7 8 of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective Embodiment Nos. 1 to 90). amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo This invention also provides a method for treating lung therapeutic agent. cancer in a patient in need of Such treatment, said method 5 This invention also provides a method for treating ovarian comprising administering to said patient an effective amount cancer in a patient in need of Such treatment, said method of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound comprising administering to said patient an effective amount of formula 1.0 (for example, as described in any one of of a pharmaceutical composition comprising an effective Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo 10 compound of formula 1.0 (for example, as described in any therapeutic agent. one of Embodiment Nos. 1 to 90). This invention also provides a method for treating lung This invention also provides a method for treating ovarian cancer in a patient in need of Such treatment, said method cancer in a patient in need of Such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 15 of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90). one of Embodiment Nos. 1 to 90), in combination with an This invention also provides a method for treating lung effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) cancer in a patient in need of Such treatment, said method chemotherapeutic agent. comprising administering to said patient an effective amount This invention also provides methods of treating breast of a pharmaceutical composition comprising an effective cancer (i.e., post-menopausal and premenopausal breast can amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) cer, e.g., hormone-dependent breast cancer) in a patient in compound of formula 1.0 (for example, as described in any need of such treatment, said treatment comprising the admin one of Embodiment Nos. 1 to 90), in combination with an 25 istration of an effective amount of at least one (e.g., 1, 2 or 3. effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) 1 or 2, and usually 1) compound of formula 1.0 (for example, chemotherapeutic agent. as described in any one of Embodiment Nos. 1 to 90) in This invention also provides a method for treating breast combination with hormonal therapies (i.e., antihormonal cancer in a patient in need of Such treatment, said method agents). comprising administering to said patient an effective amount 30 This invention also provides methods of treating breast of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound cancer (i.e., post-menopausal and premenopausal breast can of formula 1.0 (for example, as described in any one of cer, e.g., hormone-dependent breast cancer) in a patient in Embodiment Nos. 1 to 90). need of such treatment, said treatment comprising the admin This invention also provides a method for treating breast istration of an effective amount of a pharmaceutical compo cancer in a patient in need of Such treatment, said method 35 sition comprising an effective amount of at least one (e.g., 1, comprising administering to said patient an effective amount 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound example, as described in any one of Embodiment Nos. 1 to of formula 1.0 (for example, as described in any one of 90) in combination with hormonal therapies (i.e., antihor Embodiment Nos. 1 to 90), in combination with an effective monal agents). amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo 40 This invention also provides methods of treating breast therapeutic agent. cancer (i.e., post-menopausal and premenopausal breast can This invention also provides a method for treating breast cer, e.g., hormone-dependent breast cancer) in a patient in cancer in a patient in need of Such treatment, said method need of such treatment, said treatment comprising the admin comprising administering to said patient an effective amount istration of an effective amount of at least one (e.g., 1, 2 or 3. of a pharmaceutical composition comprising an effective 45 1 or 2, and usually 1) compound of formula 1.0 (for example, amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) as described in any one of Embodiment Nos. 1 to 90) in compound of formula 1.0 (for example, as described in any combination with hormonal therapies (i.e., antihormonal one of Embodiment Nos. 1 to 90). agents), and in combination with an effective amount of at This invention also provides a method for treating breast least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. cancer in a patient in need of Such treatment, said method 50 This invention also provides methods of treating breast comprising administering to said patient an effective amount cancer (i.e., post-menopausal and premenopausal breast can of a pharmaceutical composition comprising an effective cer, e.g., hormone-dependent breast cancer) in a patient in amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) need of such treatment, said treatment comprising the admin compound of formula 1.0 (for example, as described in any istration of an effective amount of a pharmaceutical compo one of Embodiment Nos. 1 to 90), in combination with an 55 sition comprising an effective amount of at least one (e.g., 1, effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for chemotherapeutic agent. example, as described in any one of Embodiment Nos. 1 to This invention also provides a method for treating ovarian 90) in combination with hormonal therapies (i.e., antihor cancer in a patient in need of Such treatment, said method monal agents), and in combination with an effective amount comprising administering to said patient an effective amount 60 of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound agent. of formula 1.0 (for example, as described in any one of The methods of treating breast cancer described herein Embodiment Nos. 1 to 90). include the treatment of hormone-dependent metastatic and This invention also provides a method for treating ovarian advanced breast cancer, adjuvant therapy for hormone-de cancer in a patient in need of Such treatment, said method 65 pendent primary and early breast cancer, the treatment of comprising administering to said patient an effective amount ductal carcinoma in situ, and the treatment of inflammatory of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound breast cancer in situ. US 7,807,672 B2 10 The methods of treating hormone-dependent breast cancer This invention also provides a method for treating brain can also be used to prevent breast cancer in patients having a cancer (e.g., glioma, such as glioma blastoma multiforme) in high risk of developing breast cancer. a patient in need of Such treatment, said method comprising Thus, this invention also provides methods of preventing administering to said patient an effective amount of a phar breast cancer (i.e., post-menopausal and premenopausal 5 maceutical composition comprising an effective amount of at breast cancer, e.g., hormone-dependent breast cancer) in a least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of patient in need of Such treatment, said treatment comprising formula 1.0 (for example, as described in any one of Embodi the administration of an effective amount of at least one (e.g., ment Nos. 1 to 90), in combination with an effective amount 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic example, as described in any one of Embodiment Nos. 1 to 10 agent. 90) in combination with hormonal therapies (i.e., antihor This invention also provides a method for treating brain monal agents). cancer (e.g., glioma, such as glioma blastoma multiforme) in This invention also provides methods of preventing breast a patient in need of Such treatment, said method comprising cancer (i.e., post-menopausal and premenopausal breast can administering to said patient an effective amount of at least cer, e.g., hormone-dependent breast cancer) in a patient in 15 one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula need of such treatment, said treatment comprising the admin 1.0 (for example, as described in any one of Embodiment istration of an effective amount of a pharmaceutical compo Nos. 1 to 90), in combination with an effective amount of a sition comprising an effective amount of at least one (e.g., 1, chemotherapeutic agent wherein said chemotherapeutic 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for agent is temozolomide. example, as described in any one of Embodiment Nos. 1 to This invention also provides a method for treating brain 90) in combination with hormonal therapies (i.e., antihor cancer (e.g., glioma, such as glioma blastoma multiforme) in monal agents). a patient in need of Such treatment, said method comprising This invention also provides methods of preventing breast administering to said patient an effective amount of a phar cancer (i.e., post-menopausal and premenopausal breast can maceutical composition comprising an effective amount of at cer, e.g., hormone-dependent breast cancer) in a patient in 25 least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of need of such treatment, said treatment comprising the admin formula 1.0 (for example, as described in any one of Embodi istration of an effective amount of at least one (e.g., 1, 2 or 3. ment Nos. 1 to 90), in combination with an effective amount 1 or 2, and usually 1) compound of formula 1.0 (for example, of a chemotherapeutic agent, wherein said chemotherapeutic as described in any one of Embodiment Nos. 1 to 90) in agent is temozolomide. combination with hormonal therapies (i.e., antihormonal 30 This invention also provides a method for treating prostate agents), and in combination with an effective amount of at cancer in a patient in need of Such treatment, said method least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. comprising administering to said patient an effective amount This invention also provides methods of preventing breast of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound cancer (i.e., post-menopausal and premenopausal breast can of formula 1.0 (for example, as described in any one of cer, e.g., hormone-dependent breast cancer) in a patient in 35 Embodiment Nos. 1 to 90). need of such treatment, said treatment comprising the admin This invention also provides a method for treating prostate istration of an effective amount of a pharmaceutical compo cancer in a patient in need of Such treatment, said method sition comprising an effective amount of at least one (e.g., 1, comprising administering to said patient an effective amount 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound example, as described in any one of Embodiment Nos. 1 to 40 of formula 1.0 (for example, as described in any one of 90) in combination with hormonal therapies (i.e., antihor Embodiment Nos. 1 to 90), in combination with an effective monal agents), and in combination with an effective amount amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic therapeutic agent. agent. This invention also provides a method for treating prostate This invention also provides a method for treating brain 45 cancer in a patient in need of Such treatment, said method cancer (e.g., glioma, such as glioma blastoma multiforme) in comprising administering to said patient an effective amount a patient in need of Such treatment, said method comprising of a pharmaceutical composition comprising an effective administering to said patient an effective amount of at least amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula compound of formula 1.0 (for example, as described in any 1.0 (for example, as described in any one of Embodiment 50 one of Embodiment Nos. 1 to 90). Nos. 1 to 90). This invention also provides a method for treating prostate This invention also provides a method for treating brain cancer in a patient in need of Such treatment, said method cancer (e.g., glioma, such as glioma blastoma multiforme) in comprising administering to said patient an effective amount a patient in need of Such treatment, said method comprising of a pharmaceutical composition comprising an effective administering to said patient an effective amount of at least 55 amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula compound of formula 1.0 (for example, as described in any 1.0 (for example, as described in any one of Embodiment one of Embodiment Nos. 1 to 90), in combination with an Nos. 1 to 90), in combination with an effective amount of at effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. chemotherapeutic agent. This invention also provides a method for treating brain 60 This invention also provides a method for treating myelo cancer (e.g., glioma, such as glioma blastoma multiforme) a dysplastic syndrome in a patient in need of Such treatment, in a patient in need of such treatment, said method comprising said method comprising administering to said patient an administering to said patient an effective amount of a phar effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and maceutical composition comprising an effective amount of at usually 1) compound of formula 1.0 (for example, as least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of 65 described in any one of Embodiment Nos. 1 to 90). formula 1.0 (for example, as described in any one of Embodi This invention also provides a method for treating myelo ment Nos. 1 to 90). dysplastic syndrome in a patient in need of Such treatment, US 7,807,672 B2 11 12 said method comprising administering to said patient an This invention also provides a method for treating acute effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and myelogenous leukemia (AML) in a patient in need of Such usually 1) compound of formula 1.0 (for example, as treatment, said method comprising administering to said described in any one of Embodiment Nos. 1 to 90), in com patient an effective amount of a pharmaceutical composition bination with an effective amount of at least one (e.g., 1, 2 or comprising an effective amount of at least one (e.g., 1, 2 or 3. 3, 1 or 2, or 1) chemotherapeutic agent. 1 or 2, and usually 1) compound of formula 1.0 (for example, This invention also provides a method for treating myelo as described in any one of Embodiment Nos. 1 to 90). dysplastic syndrome in a patient in need of Such treatment, This invention also provides a method for treating acute said method comprising administering to said patient an myelogenous leukemia (AML) in a patient in need of Such effective amount of a pharmaceutical composition compris 10 treatment, said method comprising administering to said ing an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, patient an effective amount of a pharmaceutical composition and usually 1) compound of formula 1.0 (for example, as comprising an effective amount of at least one (e.g., 1, 2 or 3. described in any one of Embodiment Nos. 1 to 90). 1 or 2, and usually 1) compound of formula 1.0 (for example, This invention also provides a method for treating myelo as described in any one of Embodiment Nos. 1 to 90), in dysplastic syndrome in a patient in need of Such treatment, 15 combination with an effective amount of at least one (e.g., 1, said method comprising administering to said patient an 2 or 3, 1 or 2, or 1) chemotherapeutic agent. effective amount of a pharmaceutical composition compris This invention also provides a method for treating chronic ing an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, myelomonocytic leukemia (CMML) in a patient in need of and usually 1) compound of formula 1.0 (for example, as Such treatment, said method comprising administering to said described in any one of Embodiment Nos. 1 to 90), in com patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or bination with an effective amount of at least one (e.g., 1, 2 or 2, and usually 1) compound of formula 1.0 (for example, as 3, 1 or 2, or 1) chemotherapeutic agent. described in any one of Embodiment Nos. 1 to 90). This invention also provides a method for treating myeloid This invention also provides a method for treating chronic leukemias in a patient in need of Such treatment, said method myelomonocytic leukemia (CMML) in a patient in need of comprising administering to said patient an effective amount 25 Such treatment, said method comprising administering to said of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or of formula 1.0 (for example, as described in any one of 2, and usually 1) compound of formula 1.0 (for example, as Embodiment Nos. 1 to 90). described in any one of Embodiment Nos. 1 to 90), in com This invention also provides a method for treating myeloid bination with an effective amount of at least one (e.g., 1, 2 or leukemias in a patient in need of Such treatment, said method 30 3, 1 or 2, or 1) chemotherapeutic agent. comprising administering to said patient an effective amount This invention also provides a method for treating chronic of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound myelomonocytic leukemia (CMML) in a patient in need of of formula 1.0 (for example, as described in any one of Such treatment, said method comprising administering to said Embodiment Nos. 1 to 909), in combination with an effective patient an effective amount of a pharmaceutical composition amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo 35 comprising an effective amount of at least one (e.g., 1, 2 or 3. therapeutic agent. 1 or 2, and usually 1) compound of formula 1.0 (for example, This invention also provides a method for treating myeloid as described in any one of Embodiment Nos. 1 to 90). leukemias in a patient in need of Such treatment, said method This invention also provides a method for treating chronic comprising administering to said patient an effective amount myelomonocytic leukemia (CMML) in a patient in need of of a pharmaceutical composition comprising an effective 40 Such treatment, said method comprising administering to said amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) patient an effective amount of a pharmaceutical composition compound of formula 1.0 (for example, as described in any comprising an effective amount of at least one (e.g., 1, 2 or 3. one of Embodiment Nos. 1 to 90). 1 or 2, and usually 1) compound of formula 1.0 (for example, This invention also provides a method for treating myeloid 45 as described in any one of Embodiment Nos. 1 to 90), in leukemias in a patient in need of Such treatment, said method combination with an effective amount of at least one (e.g., 1, comprising administering to said patient an effective amount 2 or 3, 1 or 2, or 1) chemotherapeutic agent. of a pharmaceutical composition comprising an effective This invention also provides a method for treating chronic amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) myelogenous leukemia (chronic myeloid leukemia, CML) in compound of formula 1.0 (for example, as described in any 50 a patient in need of Such treatment, said method comprising one of Embodiment Nos. 1 to 90), in combination with an administering to said patient an effective amount of at least effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula chemotherapeutic agent. 1.0 (for example, as described in any one of Embodiment This invention also provides a method for treating acute Nos. 1 to 90). myelogenous leukemia (AML) in a patient in need of Such 55 This invention also provides a method for treating chronic treatment, said method comprising administering to said myelogenous leukemia (chronic myeloid leukemia, CML) in patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or a patient in need of Such treatment, said method comprising 2, and usually 1) compound of formula 1.0 (for example, as administering to said patient an effective amount of at least described in any one of Embodiment Nos. 1 to 90). one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula This invention also provides a method for treating acute 60 1.0 (for example, as described in any one of Embodiment myelogenous leukemia (AML) in a patient in need of Such Nos. 1 to 90), in combination with an effective amount of at treatment, said method comprising administering to said least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or This invention also provides a method for treating chronic 2, and usually 1) compound of formula 1.0 (for example, as myelogenous leukemia (chronic myeloid leukemia, CML) in described in any one of Embodiment Nos. 1 to 90), in com 65 a patient in need of Such treatment, said method comprising bination with an effective amount of at least one (e.g., 1, 2 or administering to said patient an effective amount of a phar 3, 1 or 2, or 1) chemotherapeutic agent. maceutical composition comprising an effective amount of at US 7,807,672 B2 13 14 least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of of a pharmaceutical composition comprising an effective formula 1.0 (for example, as described in any one of Embodi amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) ment Nos. 1 to 90). compound of formula 1.0 (for example, as described in any This invention also provides a method for treating chronic one of Embodiment Nos. 1 to 90), in combination with an myelogenous leukemia (chronic myeloid leukemia, CML) in 5 effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) a patient in need of Such treatment, said method comprising chemotherapeutic agent. administering to said patient an effective amount of a phar This invention also provides a method for treating non maceutical composition comprising an effective amount of at Hodgkin’s lymphoma in a patient in need of Such treatment, least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of said method comprising administering to said patient an formula 1.0 (for example, as described in any one of Embodi 10 effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and ment Nos. 1 to 90), in combination with an effective amount usually 1) compound of formula 1.0 (for example, as of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic described in any one of Embodiment Nos. 1 to 90). agent. This invention also provides a method for treating non This invention also provides a method for treating myeloid Hodgkin’s lymphoma in a patient in need of Such treatment, leukemias in a patient in need of Such treatment, said method 15 said method comprising administering to said patient an comprising administering to said patient an effective amount effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound usually 1) compound of formula 1.0 (for example, as of formula 1.0 (for example, as described in any one of described in any one of Embodiment Nos. 1 to 90), in com Embodiment Nos. 1 to 90). bination with an effective amount of at least one (e.g., 1, 2 or This invention also provides a method for treating myeloid 3, 1 or 2, or 1) chemotherapeutic agent. leukemias in a patient in need of Such treatment, said method This invention also provides a method for treating non comprising administering to said patient an effective amount Hodgkin’s lymphoma in a patient in need of Such treatment, of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound said method comprising administering to said patient an of formula 1.0 (for example, as described in any one of effective amount of a pharmaceutical composition compris Embodiment Nos. 1 to 90), in combination with an effective 25 ing an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo and usually 1) compound of formula 1.0 (for example, as therapeutic agent. described in any one of Embodiment Nos. 1 to 90). This invention also provides a method for treating myeloid This invention also provides a method for treating non leukemias in a patient in need of Such treatment, said method Hodgkin’s lymphoma in a patient in need of Such treatment, comprising administering to said patient an effective amount 30 said method comprising administering to said patient an of a pharmaceutical composition comprising an effective effective amount of a pharmaceutical composition compris amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) ing an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, compound of formula 1.0 (for example, as described in any and usually 1) compound of formula 1.0 (for example, as one of Embodiment Nos. 1 to 90). described in any one of Embodiment Nos. 1 to 90), in com This invention also provides a method for treating myeloid 35 bination with an effective amount of at least one (e.g., 1, 2 or leukemias in a patient in need of Such treatment, said method 3, 1 or 2, or 1) chemotherapeutic agent. comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective This invention also provides a method for treating multiple myeloma in a patient in need of Such treatment, said method amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) comprising administering to said patient an effective amount compound of formula 1.0 (for example, as described in any 40 one of Embodiment Nos. 1 to 90), in combination with an of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) of formula 1.0 (for example, as described in any one of chemotherapeutic agent. Embodiment Nos. 1 to 90). This invention also provides a method for treating bladder This invention also provides a method for treating multiple cancer in a patient in need of Such treatment, said method 45 myeloma in a patient in need of Such treatment, said method comprising administering to said patient an effective amount comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90). Embodiment Nos. 1 to 90), in combination with an effective This invention also provides a method for treating bladder 50 amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo cancer in a patient in need of Such treatment, said method therapeutic agent. comprising administering to said patient an effective amount This invention also provides a method for treating multiple of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound myeloma in a patient in need of Such treatment, said method of formula 1.0 (for example, as described in any one of comprising administering to said patient an effective amount Embodiment Nos. 1 to 90), in combination with an effective 55 of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemo amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) therapeutic agent. compound of formula 1.0 (for example, as described in any This invention also provides a method for treating bladder one of Embodiment Nos. 1 to 90). cancer in a patient in need of Such treatment, said method This invention also provides a method for treating multiple comprising administering to said patient an effective amount 60 myeloma in a patient in need of Such treatment, said method of a pharmaceutical composition comprising an effective comprising administering to said patient an effective amount amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) of a pharmaceutical composition comprising an effective compound of formula 1.0 (for example, as described in any amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) one of Embodiment Nos. 1 to 90). compound of formula 1.0 (for example, as described in any This invention also provides a method for treating bladder 65 one of Embodiment Nos. 1 to 90), in combination with an cancer in a patient in need of Such treatment, said method effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) comprising administering to said patient an effective amount chemotherapeutic agent. US 7,807,672 B2 15 16 In the methods of this invention the compounds of this 'antineoplastic agent’ means a drug (medicament or phar invention can be administered concurrently or sequentially maceutically active ingredient) for treating cancer (i.e., a (i.e., consecutively) with the chemotherapeutic agents or the chemotherapeutic agent); signal transduction inhibitor. “at least one', as used in reference to the number of com The methods of treating cancers described herein can pounds of this invention means for example 1-6, gener optionally include the administration of an effective amount ally 1-4, more generally 1, 2 or 3, and usually one or two, of radiation (i.e., the methods of treating cancers described and more usually one; herein optionally include the administration of radiation “at least one', as used in reference to the number of che therapy). motherapeutic agents used, means for example 1-6, gen 10 DETAILED DESCRIPTION OF THE INVENTION erally 14, more generally 1, 2 or 3, and usually one or two, or one; “chemotherapeutic agent’ means a drug (medicament or As described herein, unless otherwise indicated, the use of pharmaceutically active ingredient) for treating cancer a drug or compound in a specified period is per treatment (i.e., and antineeoplastic agent); cycle. For example, once a day means once per day of each 15 day of the treatment cycle. Twice a day means twice per day “compound with reference to the antineoplastic agents, each day of the treatment cycle. Once a week means one time includes the agents that are antibodies; per week during the treatment cycle. Once every three weeks “concurrently means (1) simultaneously in time (e.g., at means once per three weeks during the treatment cycle. the same time); or (2) at different times during the course The following abbreviations have the following meanings of a common treatment schedule; unless defined otherwise: “consecutively’ means one following the other; ACN Acetonitrile “different as used in the phrase “different antineoplastic AcOHAcetic acid agents' means that the agents are not the same com DAST (diethylamino)sulfur trifluoride pound or structure; preferably, “different as used in the DCC Dicyclohexylcarbodiimide 25 phrase “different antineoplastic agents' means not from DCU Dicyclohexylurea the same class of antineoplastic agents; for example, one DCM Dichloromethane antineoplastic agent is a taxane, and another antine DIAD Diisopropylazodicarboxylate oplastic agent is a platinum coordinator compound; DIEA Diisopropylethylamine “effective amount’ or “therapeutically effective amount” is DMAP 4-Dimethylaminopyridine 30 DME Dimethoxyethane meant to describe an amount of compound or a compo DMF Dimethylformamide sition of the present invention, oranamount of radiation, dimethylacetal effective in treating or inhibiting the diseases or condi DMFDMA N,N-Dimethylformamide tions described herein, and thus producing the desired DMSO Dimethylsulfoxide therapeutic, ameliorative, inhibitory or preventative DTT Dithiothreitol 35 EDC1 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide effect; thus, for example, in the methods of treating hydrochloride cancer described herein “effective amount” (or “thera peutically effective amount') means, for example, the EtOAc Ethyl acetate amount of the compound (or drug), or radiation, that EtOH Ethanol results in: (a) the reduction, alleviation or disappearance HATU N.N.N',N'-Tetramethyl-O-(7-AZabenzotriazol-1- 40 yl)Uronium hexafluorophosphate of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, Hex hexanes and/or (d) long-term disease stabilization (growth HOBt 1-Hydroxylbenzotriazole arrest) of the tumor, for example, in the treatment of lung HPLC High pressure liquid chromatography cancer (e.g., non Small cell lung cancer) a therapeuti LCMS Liquid chromatography mass spectrometry 45 LDA Lithium diisopropylamide cally effective amount is that amount that alleviates or mCPBA meta-Chloroperoxybenzoic acid eliminates cough, shortness of breath and/or pain; also, MeOH Methanol for example, an effective amount, or a therapeutically MTT (3-4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazo effective amount of the ERK inhibitor (i.e., a compound of this invention) is that amount which results in the lium bromide. Thiazolyl blue) 50 NMR Nuclear magnetic resonance reduction in ERK (ERK1 and/or ERK2) activity and PFP Pentafluorophenol phosphorylation; the reduction in ERK activity may be PMB p-methoxybenzyl determined by the analysis of pharmacodynamic mark Pyr Pyridine ers such as phosphorylated RSK1.2 and phosphorylated ERK1,2, using techniques well known in the art; RT Room temperature 55 SEMC12-(Trimethylsily)ethoxy methyl chloride “one or more' has the same meaning as “at least one': TEA Triethylamine "patient’ means an animal. Such as a mammal (e.g., a TrTriphenyl methane human being, and preferably a human being); TrC1 Triphenyl methane chloride “prodrug means compounds that are rapidly transformed, TFA Trifluoroacetic acid 60 for example, by hydrolysis in blood, in vivo to the parent THF Tetrahydrofuran compound, i.e., to the compounds of formula 1.0 or to a TLC Thin layer chromatography salt and/or to a Solvate thereof a thorough discussion is TMS Trimethylsilyl provided in T. Higuchi and V. Stella, Pro-drugs as Novel As used herein, unless otherwise specified, the following Delivery Systems, Vol. 14 of the A.C.S. Symposium terms have the following meanings: 65 Series, and in Edward B. Roche, ed., Bioreversible Car 'anti-cancer agent’ means a drug (medicament or pharma riers in Drug Design, American Pharmaceutical Asso ceutically active ingredient) for treating cancer, ciation and Pergamon Press, 1987, both of which are US 7,807,672 B2 17 18 incorporated herein by reference; the scope of this alkyl group is unsubstituted or substituted as described invention includes Prodrugs of the novel compounds of below; non-limiting examples of Suitable alkoxy groups this invention; include methoxy, ethoxy, n-propoxy, isopropoxy, n-bu sequentially-represents (1) administration of one compo toxy and heptoxy, nent of the method ((a) compound of the invention, or (b) 5 “alkoxycarbonyl means an alkyl-O CO— group (i.e., chemotherapeutic agent, signal transduction inhibitor the bond to the parent moiety is through the carbonyl) and/or radiation therapy) followed by administration of wherein the alkyl group is unsubstituted or substituted as the other component or components; after administra previously defined; non-limiting examples of Suitable tion of one component, the next component can be alkoxycarbonyl groups include methoxycarbonyl and administered substantially immediately after the first 10 ethoxycarbonyl: component, or the next component can be administered “alkyl (including the alkyl portions of other moieties, after an effective time period after the first component; Such as trifluoroalkyl and alkyloxy) means an aliphatic the effective time period is the amount of time given for hydrocarbon group (chain) that can be straight or realization of maximum benefit from the administration branched wherein said group comprises about 1 to about of the first component; and 15 20 carbon atoms in the chain; preferred alkyl groups 'solvate” means a physical association of a compound of comprise about 1 to about 12 carbon atoms in the chain; this invention with one or more solvent molecules; this more preferred alkyl groups comprise about 1 to about 6 physical association involves varying degrees of ionic carbon atoms in the chain; branched means that one or and covalent bonding, including hydrogen bonding; in more lower alkyl groups, such as methyl, ethyl or propyl. certain instances the solvate will be capable of isolation, are attached to a linear alkyl chain; “lower alkyl means for example when one or more solvent molecules are a group comprising about 1 to about 6 carbon atoms in incorporated in the crystal lattice of the crystalline solid; the chain, and said chain can be straight or branched; the 'solvate” encompasses both solution-phase and isolat term “substituted alkyl means that the alkyl group is able solvates; non-limiting examples of suitable Solvates substituted by one or more independently selected sub include ethanolates, methanolates, and the like; 25 stituents, and wherein each Substituent is independently “hydrate' is a solvate wherein the solvent molecule is Selected from the group consisting of halo, aryl, H.O. cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, As used herein, unless otherwise specified, the following —NH(alkyl). - NH(cycloalkyl), N(alkyl), carboxy, terms have the following meanings, and unless otherwise —C(O)O-alkyl and —S(alkyl); non-limiting examples specified, the definitions of each term (i.e., moiety or Sub 30 of Suitable alkyl groups include methyl, ethyl, n-propyl. stituent) apply when that term is used individually or as a isopropyl. n-butyl, t-butyl, n-pentyl, heptyl, nonyl, component of another term (e.g., the definition of aryl is the decyl, fluoromethyl, trifluoromethyl and cyclopropylm same for aryland for the aryl portion of arylalkyl, alkylaryl, ethyl: arylalkynyl, and the like): “alkylaryl’ (oralkaryl) means an alkyl-aryl-group (i.e., the “acyl means an H C(O)—, alkyl-C(O)—, alkenyl-C 35 bond to the parent moiety is through the aryl group) (O)—, Alkynyl-C(O)—, cycloalkyl-C(O)—, cycloalk wherein the alkyl group is unsubstituted or substituted as enyl-C(O)—, or cycloalkynyl-C(O)— group in which defined above, and the aryl group is unsubstituted or the various groups are as defined below (and as defined substituted as defined below; preferred alkylaryls com below, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalk prise a lower alkyl group; non-limiting examples of suit enyl and cycloalkynyl moieties can be substituted); the 40 able alkylaryl groups include o-tolyl, p-tolyl and Xylyl; bond to the parent moiety is through the carbonyl; pre “alkylheteroaryl' means an alkyl-heteroaryl- group (i.e., ferred acyls contain a lower alkyl: Non-limiting the bond to the parent moiety is through the heteroaryl examples of suitable acyl groups include formyl, acetyl, group) wherein the alkyl is unsubstituted or substituted propanoyl, 2-methylpropanoyl, butanoyl and cyclohex as defined above and the heteroaryl group is unsubsti anoyl; 45 tuted or substituted as defined below: 'alkenyl' means an aliphatic hydrocarbon group (chain) “alkylsulfinyl' means an alkyl-S(O)— group (i.e., the comprising at least one carbon to carbon double bond, bond to the parent moiety is through the sulfinyl) wherein the chain can be straight or branched, and wherein the alkyl group is unsubstituted or substituted as wherein said group comprises about 2 to about 15 car previously defined; preferred groups are those in which bonatoms; Preferred alkenyl groups comprise about 2 to 50 the alkyl group is lower alkyl; about 12 carbonatoms in the chain; and more preferably “alkylsulfonyl' means an alkyl-S(O)— group (i.e., the about 2 to about 6 carbon atoms in the chain; branched bond to the parent moiety is through the sulfonyl) means that one or more lower alkyl groups, such as wherein the alkyl group is unsubstituted or substituted as methyl, ethyl or propyl, or alkenyl groups are attached to previously defined; preferred groups are those in which a linear alkenyl chain; “lower alkenyl' means an alkenyl 55 the alkyl group is lower alkyl; group comprising about 2 to about 6 carbonatoms in the “alkylthio’ means an alkyl-S group (i.e., the bond to the chain, and the chain can be straight or branched; the term parent moiety is through the sulfur) wherein the alkyl “substituted alkenyl' means that the alkenyl group is group is unsubstituted or Substituted as previously substituted by one or more independently selected sub described; non-limiting examples of Suitable alkylthio stituents, and each substituent is independently selected 60 groups include methylthio, ethylthio, i-propylthio and from the group consisting of halo, alkyl, aryl, heptylthio; cycloalkyl, cyano, alkoxy and —S(alkyl); non-limiting “alkynyl' means an aliphatic hydrocarbon group (chain) examples of Suitable alkenyl groups include ethenyl, comprising at least one carbon to carbon triple bond, propenyl. n-butenyl, 3-methylbut-2-enyl, n-pentenyl, wherein the chain can be straight or branched, and octenyl and decenyl: 65 wherein the group comprises about 2 to about 15 carbon 'alkoxy' means an alkyl-O-group (i.e., the bond to the atoms in the; preferred alkynyl groups comprise about 2 parent moiety is through the ether oxygen) in which the to about 12 carbon atoms in the chain; and more prefer US 7,807,672 B2 19 20 ably about 2 to about 4 carbon atoms in the chain; heteroaryl group) wherein the aryl group is unsubsti Branched means that one or more lower alkyl groups, tuted or Substituted as defined above, the amino group is Such as methyl, ethyl or propyl, are attached to a linear as defined above (i.e., a —NH here), and the het alkynyl chain; “lower alkynyl' means an alkynyl group eroaryl group is unsubstituted or Substituted as defined comprising about 2 to about 6 carbonatoms in the chain, below: and the chain can be straight or branched; non-limiting “arylheteroaryl means an aryl-heteroaryl group—(i.e., examples of Suitable alkynyl groups include ethynyl, the bond to the parent moiety is through the heteroaryl propynyl, 2-butynyl, 3-methylbutynyl. n-pentynyl, and group) wherein the aryl group is unsubstituted or Sub decynyl; the term “substituted alkynyl' means that the stituted as defined above, and the heteroaryl group is alkynyl group is Substituted by one or more indepen 10 unsubstituted or substituted as defined below: dently selected, and each Substituent is independently “aryloxy' means an aryl-O-group (i.e., the bond to the Selected from the group consisting of alkyl, aryl and parent moiety is through the ether oxygen) wherein the cycloalkyl; aryl group is unsubstituted or Substituted as defined 'amino means a —NH group; above; non-limiting examples of Suitable aryloxy 'aralkenyl' (or arylalkenyl) means an aryl-alkenyl-group 15 groups include phenoxy and naphthoxy; (i.e., the bond to the parent moiety is through the alkenyl “aryloxycarbonyl means an aryl-O-C(O)—group (i.e., group) wherein the aryl group is unsubstituted or Sub the bond to the parent moiety is through the carbonyl) stituted as defined below, and the alkenyl group is unsub wherein the aryl group is unsubstituted or Substituted as stituted or substituted as defined above; preferred aralk previously defined; non-limiting examples of Suitable enyls contain a lower alkenyl group; non-limiting 20 aryloxycarbonyl groups include phenoxycarbonyl and examples of Suitable aralkenyl groups include naphthoxycarbonyl: 2-phenethenyl and 2-maphthylethenyl: “arylsulfinyl' means an aryl-S(O)—group (i.e., the bond 'aralkyl (orarylalkyl) means an aryl-alkyl-group (i.e., the to the parent moiety is through the sulfinyl) wherein aryl bond to the parent moiety is through the alkyl group) is unsubstituted or substituted as previously defined; wherein the aryl is unsubstituted or substituted as 25 “arylsulfonyl' means an aryl-S(O)—group (i.e., the bond defined below and the alkyl is unsubstituted or substi- to the parent moiety is through the sulfonyl) whereinaryl tuted as defined above; preferred aralkyls comprise a is unsubstituted or substituted as previously defined; lower alkyl group; non-limiting examples of Suitable “arylthio’ means an aryl-S— group (i.e., the bond to the aralkyl groups include benzyl, 2-phenethyl and naphtha- parent moiety is through the sulfur) wherein the aryl lenylmethyl; 30 group is unsubstituted or Substituted as previously “aralkyloxy” (or arylalkyloxy) means an aralkyl-O- described; non-limiting examples of Suitable arylthio group (i.e., the bond to the parent moiety is through the groups include phenylthio and naphthylthio: ether oxygen) wherein the aralkyl group is unsubstituted “cycloalkenyl' means a non-aromatic mono or multicyclic or Substituted as previously described; non-limiting ring system comprising about 3 to about 10 carbon examples of Suitable aralkyloxy groups include benzy- 35 atoms, preferably about 5 to about 10 carbon atoms that loxy and 1- or 2-naphthalenemethoxy; contains at least one carbon-carbon double bond; pre 'aralkoxycarbonyl' means an aralkyl-O C(O)— group ferred cycloalkenyl rings contain about 5 to about 7 ring (i.e., the bond to the parent moiety is through the carbo- atoms; the cycloalkenyl can be optionally substituted nyl) wherein the aralkyl group is unsubstituted or Sub- with one or more independently selected “ring system stituted as previously defined; a non-limiting example of 40 substituents” (defined below); Non-limiting examples a Suitable aralkoxycarbonyl group is benzyloxycarbo- of suitable monocyclic cycloalkenyls include cyclopen nyl: tenyl, cyclohexenyl, cycloheptenyl, and the like; a non 'aralkylthio’ means an aralkyl-S— group (i.e., the bond to limiting example of a suitable multicyclic cycloalkenyl the parent moiety is through the sulfur) wherein the is norbornylenyl: aralkyl group is unsubstituted or Substituted as previ- 45 “cycloalkyl means a non-aromatic mono- or multicyclic ously described; a non-limiting example of a Suitable ring system comprising about 3 to about 7 carbonatoms, aralkylthio group is benzylthio; preferably about 3 to about 6 carbon atoms; the “aroyl means an aryl-C(O)—group (i.e., the bond to the cycloalkyl can be optionally substituted with one or parent moiety is through the carbonyl) wherein the aryl more independently selected “ring system substituents' group is unsubstituted or substituted as defined below: 50 (defined below); non-limiting examples of suitable non-limiting examples of Suitable groups include ben- monocyclic cycloalkyls include cyclopropyl, cyclopen Zoyland 1- and 2-maphthoyl; tyl, cyclohexyl, cycloheptyl and the like; non-limiting “aryl' (sometimes abbreviated “ar) means an aromatic examples of Suitable multicyclic cycloalkyls include monocyclic or multicyclic ring system comprising about 1-decalin, norbornyl, adamanty1 and the like; 6 to about 14 carbon atoms, preferably about 6 to about 55 “cycloalkylalkyl means a cycloalkyl-alkyl-group (i.e., the 10 carbon atoms; the aryl group can be optionally Sub bond to the parent moiety is through the alkyl group) stituted with one or more independently selected “ring wherein the cycloalkyl moiety is unsubstituted or sub system substituents” (defined below). Non-limiting stituted as defined above, and the alkyl moiety is unsub examples of Suitable aryl groups include phenyl and stituted or substituted as defined above; naphthyl; 60 "halo' means fluoro, chloro, bromo, or iodo groups; pre 'arylalkynyl' means an aryl-alkynyl-group (i.e., the bond ferred halos are fluoro, chloro or bromo, and more pre to the parent moiety is through the alkynyl group) ferred are fluoro and chloro; wherein the aryl group is unsubstituted or Substituted as "halogen' means fluorine, chlorine, bromine, or iodine; defined above, and the alkynyl group is unsubstituted or preferred halogens are fluorine, chlorine and bromine; Substituted as defined above; 65 “haloalkyl means an alkyl, as defined above, wherein one 'arylaminoheteroaryl' means an aryl-amino-heteroaryl or more hydrogen atoms on the alkyl is replaced by a group (i.e., the bond to the parent moiety is through the halo group, as defined above; US 7,807,672 B2 21 22 "heteroaralkenyl' means a heteroaryl-alkenyl-group (i.e., "heterocyclenyl' (or heterocycloalkenyl) means a non-aro the bond to the parent moiety is through the alkenyl matic monocyclic or multicyclic ring system comprising group) wherein the heteroaryl group is unsubstituted or about 3 to about 10 ring atoms, preferably about 5 to substituted as defined below, and the alkenyl group is about 10 ring atoms, in which one or more of the atoms unsubstituted or substituted as defined above; in the ring system is an element other than carbon (for "heteroaralkyl (or heteroarylalkyl) means a heteroaryl example one or more heteroatoms independently alkyl- group (i.e., the bond to the parent moiety is Selected from the group consisting of nitrogen, oxygen through the alkyl group) in which the heteroaryl is and Sulfur atom), and which contains at least one carbon unsubstituted or substituted as defined below, and the carbon double bond or carbon-nitrogen double bond; alkyl group is unsubstituted or Substituted as defined 10 there are no adjacent oxygen and/or Sulfur atoms present above; preferred heteroaralkyls comprise an alkyl group in the ring system; Preferred heterocyclenyl rings con that is a lower alkyl group; non-limiting examples of tain about 5 to about 6 ring atoms; the prefix aza, oxa or Suitable aralkyl groups include pyridylmethyl, 2-(furan thia before the heterocyclenyl root name means that at 3-yl)ethyl and quinolin-3-ylmethyl; least a nitrogen, oxygen or Sulfur atom, respectively, is "heteroaralkylthio’ means a heteroaralkyl-S group 15 present as a ring atom; the heterocyclenyl can be option wherein the heteroaralkyl group is unsubstituted or sub ally substituted by one or more independently selected stituted as defined above; “Ring system substituents” (defined below); the nitro "heteroaryl means an aromatic monocyclic or multicyclic gen or Sulfur atom of the heterocyclenyl can be option ring system comprising about 5 to about 14 ring atoms, ally oxidized to the corresponding N-oxide, S-oxide or preferably about 5 to about 10 ring atoms, in which one S.S.-dioxide; non-limiting examples of Suitable mono or more of the ring atoms is an element other than car cyclic azaheterocyclenyl groups include 1.2.3,4-tet bon, for example nitrogen, oxygen or Sulfur, alone or in rahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropy combination; preferred heteroaryls comprise about 5 to ridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6- about 6 ring atoms; the "heteroaryl can be optionally tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, substituted by one or more independently selected “ring 25 2-imidazolinyl, 2-pyrazolinyl, and the like: Non-limit system substituents' (defined below); the prefix aza, oxa ing examples of Suitable oxaheterocyclenyl groups or thia before the heteroaryl root name means that at include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluo least a nitrogen, oxygen or Sulfur atom, respectively, is rodihydrofuranyl, and the like: A non-limiting example present as a ring atom; a nitrogen atom of a heteroaryl of a Suitable multicyclic oxaheterocyclenyl group is can be optionally oxidized to the corresponding N-ox 30 7-Oxabicyclo2.2.1]heptenyl; non-limiting examples of ide; non-limiting examples of Suitable heteroaryls Suitable monocyclic thiaheterocyclenyl rings include include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, dihydrothiophenyl, dihydrothiopyranyl, and the like: isoxazolyl, isothiazolyl, oxazolyl, thiazolyl pyrazolyl, "heterocycloalkylalkyl (or heterocyclylalkyl) means a furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiaz heterocycloalkyl-alkyl-group (i.e., the bond to the par olyl pyrazinyl, pyridaZinyl, quinoxalinyl, phthalazinyl, 35 ent moiety is through the alkyl group) wherein the het imidazol-2-alpyridinyl, imidazo[2.1-bithiazolyl, ben erocycloalkyl group (i.e., the heterocyclyl group) is Zofurazanyl, indolyl azaindolyl, benzimidazolyl, ben unsubstituted or substituted as defined below, and the Zothienyl, quinolinyl, imidazolyl, thienopyridyl, alkyl group is unsubstituted or Substituted as defined quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imida above; Zopyridyl, isoquinolinyl, benzoaZaindolyl, 1,2,4-triazi 40 nyl, benzothiazolyl and the like: "heterocyclyl (or heterocycloalkyl) means a non-aro "heteroarylalkynyl' (or heteroaralkynyl) means a het matic saturated monocyclic or multicyclic ring system eroaryl-alkynyl-group (i.e., the bond to the parent moi comprising about 3 to about 10 ring atoms, preferably ety is through the alkynyl group) wherein the heteroaryl about 5 to about 10 ring atoms, in which one or more of 45 the atoms in the ring system is an element other than group is unsubstituted or Substituted as defined above, carbon, for example nitrogen, oxygen or Sulfur, alone or and the alkynyl group is unsubstituted or Substituted as in combination; there are no adjacent oxygen and/or defined above; Sulfur atoms present in the ring system; preferred het "heteroarylaryl’ (or heteroararyl) means a heteroaryl-aryl erocyclyls contain about 5 to about 6 ring atoms; the group (i.e., the bond to the parent moiety is through the 50 prefix aza, oxa or thia before the heterocyclyl root name aryl group) wherein the heteroaryl group is unsubsti means that at least a nitrogen, oxygen or Sulfur atom tuted or substituted as defined above, and the aryl group respectively is present as a ring atom; the heterocyclyl is unsubstituted or substituted as defined above; can be optionally Substituted by one or more indepen "heteroarylheteroarylaryl means a heteroaryl-heteroaryl dently selected “ring system substituents' (defined group (i.e., the bond to the parent moiety is through the 55 below); the nitrogen or sulfur atom of the heterocyclyl last heteroaryl group) wherein each heteroaryl group is can be optionally oxidized to the corresponding N-ox independently unsubstituted or substituted as defined ide, S-oxide or S.S.-dioxide; non-limiting examples of above; Suitable monocyclic heterocyclyl rings include pip "heteroarylsulfinyl' means a heteroaryl-SO group eridyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomor wherein the heteroaryl group is unsubstituted or substi 60 pholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tuted as defined above; tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothi "heteroarylsulfonyl' means a heteroaryl-SO group opyranyl, and the like; wherein the heteroaryl group is unsubstituted or substi “hydroxyalkyl means a HO-alkyl- group wherein the tuted as defined above; alkyl group is substituted or unsubstituted as defined "heteroarylthio’ means a heteroaryl-S group wherein 65 above; preferred hydroxyalkyls comprise a lower alkyl; the heteroaryl group is unsubstituted or Substituted as Non-limiting examples of suitable hydroxyalkyl groups defined above; include hydroxymethyl and 2-hydroxyethyl; and US 7,807,672 B2 23 24 “ring system substituent’ means a Substituent attached to agents'. The bulk composition is material that has not yet an aromatic or non-aromatic ring system that, for been formed into individual dosage units. An illustrative dos example, replaces an available hydrogen on the ring age unit is an oral dosage unit such as tablets, capsules, pills system; ring system Substituents are each independently and the like. Similarly, the herein-described methods of treat Selected from the group consisting of alkyl, aryl, het ing a patient by administering a pharmaceutical composition eroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, of the present invention is also intended to encompass the alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxy administration of the afore-said bulk composition and indi alkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, vidual dosage units. cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, Prodrugs of the compounds of the invention are also con aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroar 10 templated herein. The term “prodrug, as employed herein, ylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfi denotes a compound that is a drug precursor which, upon nyl, alkylthio, arylthio, heteroarylthio, aralkylthio, het administration to a subject, undergoes chemical conversion eroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, by metabolic or chemical processes to yield a compound of heterocyclenyl, R60R65N RRN-alkyl-, formula 1.0 or a salt and/or solvate thereof. A discussion of R'R''NC(O) and RRNSO, , wherein R and 15 prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Rare each independently selected from the group con Novel Delivery Systems (1987) 14 of the A.C.S. Symposium sisting of hydrogen, alkyl, aryl, and aralkyl: "Ring sys Series, and in Bioreversible Carriers in Drug Design, (1987) tem. Substituent also means a cyclic ring of 3 to 7 ring Edward B. Roche, ed., American Pharmaceutical Association atoms, wherein 1-2 ring atoms can be heteroatoms, and Pergamon Press, both of which are incorporated herein attached to an aryl, heteroaryl, heterocyclyl or hetero by reference thereto. cyclenyl ring by simultaneously substituting two ring For example, if a compound of formula 1.0, or a pharma hydrogenatoms on said aryl, heteroaryl, heterocyclyl or ceutically acceptable salt, hydrate or Solvate of the com heterocyclenyl ring; Non-limiting examples include: pound, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the 25 hydrogen atom of the acid group with a group Such as, for example, (C-Cs)alkyl, (C-C)alkanoyloxy-methyl, 1-(al kanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl 1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 30 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxy-carbonyl)amino) and the like ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-cro 35 tonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C-C) Lines drawn into a ring mean that the indicated bond may alkylamino(C-C)alkyl (Such as B-dimethylaminoethyl), be attached to any of the substitutable ring carbon atoms. carbamoyl-(C-C)alkyl, N,N-di (C-C)alkylcarbamoyl Any carbon or heteroatom with unsatisfied valences in the (C-C)alkyl and piperidino-, pyrrolidino- or morpholino text, schemes, examples, structural formulae, and any Tables (C-C)alkyl, and the like. herein is assumed to have the hydrogen atom or atoms to 40 Similarly, ifa compound of formula 1.0 contains an alcohol satisfy the Valences. functional group, a prodrug can beformed by the replacement One or more compounds of the invention may also exist as, of the hydrogenatom of the alcohol group with a group Such or optionally converted to, a solvate. Preparation of solvates is as, for example, (C-C)alkanoyloxymethyl, 1-((C-C)al generally known. Thus, for example, M. Caira et al., J. Phar kanoyl-oxy)ethyl, 1-methyl-1-((C-C)alkanoyloxy)ethyl, maceutical Sci., 93(3), 601-611 (2004) describe the prepara 45 (C-C)alkoxycarbonyloxymethyl, N-(C-C)alkoxycarbo tion of the solvates of the antifungal fluconazole in ethyl nylaminomethyl. Succinoyl, (C-C)alkanoyl, C.-amino(C- acetate as well as from water. Similar preparations of Sol C.)alkanyl, arylacyl and C-aminoacyl, or O-aminoacyl-C- vates, hemisolvate, hydrates and the like are described by E. aminoacyl, where each C-aminoacyl group is independently C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 selected from the naturally occurring L-amino acids, P(O) (2004); and A. L. Bingham et al. Chem. Commun., 603-604 50 (OH), —P(O)(O(C-C)alkyl) or glycosyl (the radical (2001). A typical, non-limiting, process involves dissolving resulting from the removal of a hydroxyl group of the hemi the inventive compound in desired amounts of the desired acetal form of a carbohydrate), and the like. Solvent (organic or water or mixtures thereof) at a higher than If a compound of formula 1.0 incorporates an amine func ambient temperature, and cooling the Solution at a rate Suffi tional group, a prodrug can be formed by the replacement of cient to form crystals which are then isolated by standard 55 a hydrogen atom in the amine group with a group Such as, for methods. Analytical techniques such as, for example I.R. example, R7-carbonyl, R'O-carbonyl, NR'R'-carbonyl spectroscopy, show the presence of the solvent (or water) in where R'' and R' are each independently (C-Co.)alkyl, the crystals as a Solvate (or hydrate). (C-C) cycloalkyl, benzyl, or R'-carbonyl is a natural The term “pharmaceutical composition' is also intended to C.-aminoacyl or natural O-aminoacyl, -C(OH)C(O)OY encompass both the bulk composition and individual dosage 60 wherein Y is H, (C-C)alkyl or benzyl, C(OY)Y units comprised of more than one (e.g., two) pharmaceuti whereinY is (C-C) alkyl and Y is (C-C)alkyl, carboxy cally active agents such as, for example, a compound of the (C-C)alkyl, amino(C-C)alkyl or mono-N- or di-N,N- present invention and an additional agent selected from the (C-C)alkylaminoalkyl, -C(Y)Y wherein Y is H or lists of the additional agents described herein, along with any methyl and Y is mono-N- or di-N,N-(C-C)alkylamino pharmaceutically inactive excipients. The bulk composition 65 morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. and each individual dosage unit can contain fixed amounts of This invention also includes the compounds of this inven the afore-said “more than one pharmaceutically active tion in isolated and purified form. US 7,807,672 B2 25 26 Polymorphic forms of the compounds of formula 1.0, and website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), of the salts, Solvates and prodrugs of the compounds of for Handbook of Pharmaceutical Salts. Properties, Selection, mula 1.0, are intended to be included in the present invention. and Use, (2002) Intl. Union of Pure and Applied Chemistry, Certain compounds of the invention may exist in different pp. 330-331. These disclosures are incorporated herein by isomeric (e.g., enantiomers, diastereoisomers, atropisomers) reference thereto. forms. The invention contemplates all such isomers both in Exemplary acid addition salts include acetates, adipates, pure form and in admixture, including racemic mixtures. alginates, ascorbates, aspartates, benzoates, benzene Enol forms are also included. Sulfonates, bisulfates, borates, butyrates, citrates, camphor All Stereoisomers (for example, geometric isomers, optical ates, camphorsulfonates, cyclopentanepropionates, diglu isomers and the like) of the present compounds (including 10 conates, dodecylsulfates, ethanesulfonates, fumarates, those of the salts, Solvates and prodrugs of the compounds as glucoheptanoates, glycerophosphates, hemisulfates, hep well as the salts and Solvates of the prodrugs), such as those tanoates, hexanoates, hydrochlorides, hydrobromides, which may exist due to asymmetric carbons on various Sub hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, stituents, including enantiomeric forms (which may exist methanesulfonates, methyl sulfates, 2-naphthalene even in the absence of asymmetric carbons), rotameric forms, 15 Sulfonates, nicotinates, nitrates, oxalates, pamoates, pecti atropisomers, and diastereomeric forms, are contemplated nates, persulfates, 3-phenylpropionates, phosphates, picrates, within the scope of this invention. Individual stereoisomers of pivalates, propionates, salicylates, succinates, Sulfates, Sul the compounds of the invention may, for example, be Sub stantially free of other isomers, or may be admixed, for fonates (such as those mentioned herein), tartarates, thiocy example, as racemates or with all other, or other selected, anates, toluenesulfonates (also known as tosylates) unde Stereoisomers. The chiral centers of the present invention can canoates, and the like. have the S or R configuration as defined by the IUPAC 1974 Exemplary basic salts include ammonium salts, alkali Recommendations. The use of the terms 'salt”, “solvate’ metal salts such as sodium, lithium, and potassium salts, “prodrug and the like, is intended to equally apply to the salt, alkaline earth metal salts such as calcium and magnesium Solvate and prodrug of enantiomers, Stereoisomers, rotamers, 25 salts, aluminum salts, Zinc salts, salts with organic bases (for tautomers, racemates or prodrugs of the inventive com example, organic amines) Such as benzathines, diethylamine, pounds. dicyclohexylamines, hydrabamines (formed with N,N-bis Diasteromeric mixtures can be separated into their indi (dehydroabietyl)ethylenediamine), N-methyl-D-glucam vidual diastereomers on the basis of their physical chemical ines, N-methyl-D-glucamides, t-butyl amines, piperazine, differences by methods well known to those skilled in the art, 30 phenylcyclohexyl-amine, choline, tromethamine, and salts Such as, for example, by chromatography and/or fractional with amino acids such as arginine, lysine and the like. Basic crystallization. Enantiomers can be separated by converting nitrogen-containing groups may be quarternized with agents the enantiomeric mixture into a diasteromeric mixture by Such as lower alkyl halides (e.g. methyl, ethyl, propyl, and reaction with an appropriate optically active compound (e.g., butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid 35 dimethyl, diethyl, dibutyl, and diamyl Sulfates), long chain chloride), separating the diastereomers and converting (e.g., halides (e.g. decyl, lauryl, myristyl and Stearyl chlorides, hydrolyzing) the individual diastereomers to the correspond bromides and iodides), aralkylhalides (e.g. benzyl and phen ing pure enantiomers. Also, some of the compounds of For ethyl bromides), and others. mula (I) may be atropisomers (e.g., Substituted biaryls) and All Such acid and base salts are intended to be pharmaceu are considered as part of this invention. Enantiomers can also 40 tically acceptable salts within the scope of the invention and be separated by use of chiral HPLC column. all acid and base salts are considered equivalent to the free The compounds of formula 1.0 form salts that are also forms of the corresponding compounds for purposes of the within the scope of this invention. Reference to a compound invention. of formula 1.0 herein is understood to include reference to Compounds of formula 1.0, and salts, Solvates and pro salts thereof, unless otherwise indicated. The term “salt(s)'. 45 drugs thereof, may exist in their tautomeric form (for as employed herein, denotes acidic salts formed with inor example, as an amide or imino ether). All Such tautomeric ganic and/or organic acids, as well as basic salts formed with forms are contemplated herein as part of the present inven inorganic and/or organic bases. In addition, when a com tion. pound of formula 1.0 contains both a basic moiety, Such as, In hetero-atom containing ring systems of this invention, but not limited to a pyridine or imidazole, and an acidic 50 there are no hydroxyl groups on carbonatoms adjacent to a N. moiety, Such as, but not limited to a carboxylic acid, Zwitte O or S, and there are no N or S groups on carbon adjacent to rions (“inner salts') may be formed and are included within another heteroatom. Thus, for example, in the ring: the term "salt(s) as used herein. Pharmaceutically accept able (i.e., non-toxic, physiologically acceptable salts) are pre ferred. Salts of the compounds of the formula 1.0 may be 55 formed, for example, by reacting a compound of formula 1.0 with an amount of acid or base. Such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the forma 60 tion of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. there is no —OH attached directly to carbons marked 2 and 5. Berge etal, Journal of Pharmaceutical Sciences (1977) 66(1) The compounds of formula 1.0 may exist in different tau 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 tomeric forms, and all such forms are embraced within the 201-217; Anderson et al. The Practice of Medicinal Chemis 65 Scope of the invention. Also, for example, all keto-enol and try (1996), Academic Press, New York; in The Orange Book imine-enamine forms of the compounds are included in the (Food & Drug Administration, Washington, D.C. on their invention. US 7,807,672 B2 27 28 Tautomeric forms such as, for example, the moieties: and carbon-14 (i.e., "C) isotopes are particularly preferred for their ease of preparation and detectability. Further, sub stitution with heavier isotopes such as deuterium (i.e., H) N N may afford certain therapeutic advantages resulting from and greater metabolic stability (e.g., increased in Vivo half-life or 2 reduced dosage requirements) and hence may be preferred in O N OH Some circumstances. Isotopically labelled compounds of for H mula 1.0 can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the 10 Examples hereinbelow, by Substituting an appropriate isoto are considered equivalent in certain embodiments of this pically labelled reagent for a non-isotopically labelled invention. reagent. The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the This invention provides compounds of formula 1.0: indicated group, provided that the designated atoms normal 15 Valency under the existing circumstances is not exceeded, and (1.0) that the substitution results in a stable compound. Combina tions of substituents and/or variables are permissible only if R8 such combinations result in stable compounds. By “stable O compound' or “stable structure' is meant a compound that is 1. R35 sufficiently robust to survive isolation to a useful degree of HO N N purity from a reaction mixture, and formulation into an effi \ 2 R? Q cacious therapeutic agent. y3 R36 The term “optionally substituted” means optional substi RI R35 tution with the specified groups, radicals or moieties. 25 The term “purified, “in purified form' or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or the pharmaceutically acceptable salts thereof, wherein: or natural source or combination thereof. Thus, the term Y', Y, and Y are each independently selected from the “purified, “in purified form' or “in isolated and purified 30 group consisting of: -CH=, N= and —CR = (prefer form” for a compound refers to the physical state of said ably Y', Y, and Y are each-CH=); compound after being obtained from a purification process or Z is 1 to 3 (i.e., 1, 2 or 3, and preferably 1); processes described herein or well known to the skilled arti Q is a Substituent selected from the group consisting of: san, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the 35 skilled artisan. (2.1) When a functional group in a compound is termed "pro R7 R7 tected’, this means that the group is in modified form to R6 preclude undesired side reactions at the protected site when N the compound is subjected to a reaction. Suitable protecting 40 R3 R6 groups will be recognized by those with ordinary skill in the R3 R5, art as well as by reference to standard textbooks such as, for R4 R4 example, T. W. Greene et al. Protective Groups in organic (2.2) Synthesis (1991), Wiley, New York. 45 R7 R7 When any variable (e.g., aryl, heterocycle, R, etc.) occurs R6 more than one time in any moiety or in any compound of N formula 1.0, its definition on each occurrence is independent R3 of its definition at every other occurrence. R3 R5, As used herein, the term “composition' is intended to 50 encompass a product comprising the specified ingredients in R4 R4 the specified amounts, as well as any product which results, (2.3) directly or indirectly, from combination of the specified R7 ingredients in the specified amounts. R6 N The present invention also embraces isotopically-labelled 55 compounds of the present invention which are identical to R3 Zl R6 those recited herein, but for the fact that one or more atoms are R3 R5, replaced by an atom having an atomic mass or mass number R4 different from the atomic mass or mass number usually found (2.4) in nature. Examples of isotopes that can be incorporated into 60 R7 compounds of the invention include isotopes of hydrogen, R6 carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, N such as 2H, H, C, 14C, 15 N, 18O, 17O, P, P 35S, F, and R3 Zl Cl, respectively. R3 R5 Certain isotopically-labelled compounds of formula 1.0 65 (e.g., those labeled with Hand ''C) are useful in compound R4 and/or substrate tissue distribution assays. Tritiated (i.e., H) US 7,807,672 B2 29 30

-continued -continued (2.13) R7 R7 (2.5) R6 N R3 Zl R5, R4 R4 10 (2.14)

(2.6)

15

(2.15) (2,7)

25 (2.16) (2.8)

30

35 Each Q' represents a ring independently selected from the (2.9) group consisting of cycloalkyl, Substituted cycloalkyl, het erocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said sub stituted rings are substituted with 1 to 3 substituents indepen 40 dently selected from the group consisting of the R' moi eties; provided that when Q is aryl, heteroaryl, substituted aryl or substituted heteroaryl then the carbonatoms at the ring junction (i.e., the two carbon atoms common to the fused (2.10) rings) are not Substituted; 45 Q represents a ring selected from the group consisting of: cycloalkyl, Substituted cycloalkyl, heterocycloalkyl, and Sub stituted heterocycloalkyl, wherein said Substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of the R' moieties; 50 Z' represents —(C(R).), wherein each R is inde pendently selected from the group consisting of H, alkyl (2.11) (e.g., C to C alkyl, for example methyl) and F, and wherein w is 1, 2 or 3, and generally w is 1 or 2, and usually w is 1, and whereinin one example each R" is H, and in anotherexample 55 w is 1, and in another example each R is H and w is 1, preferably w is 1 and each R is H (i.e., preferably Z' is —CH2—); Z is selected from the group consisting of N(R) , (2.12) —O— and C(R) - (e.g., Z is NH-, - O - or 60 —CH2—): m is 1 to 6: n is 1 to 6: p is 0 to 6: t is 0, 1, or 2; 65 R" is selected from the group consisting of: (2) —NO, US 7,807,672 B2 31 32 (3) OR', (14) (4) - SR', (5) N(R'), (6) R', (7) halo (e.g., Cl, Br, and F), (C(R30))-N Z2 (8) —CF; (9) alkenyl (e.g., —CH=CHCH): H2 v M (10) - C(O)N(R'), wherein each R' is independently C.9. (CH)-N Z’’ such as C -N Z2, selected, and preferably each R" is independently 10 Selected from the group consisting of: (a) H., (b) alkyl (e.g., methyl, butyl, and i-propyl), (c) heteroaryl (e.g., pyridyl), (d) aryl (e.g., phenyl), and (e) cycloalkyl (e.g., cyclopropyl), wherein for example, each R" is selected wherein: from the group consisting of H. methyl, butyl, i-propyl. (a) in one example said (12) moiety is pyridyl, phenyl and cyclopropyl, wherein, for example, 15 said —C(O)N(R') moiety is selected from the group consisting of —C(O)NH2, —C(O)NH(CH), —C(O) NH(CH)(CH), (i.e., C(O)NH(i-propyl)), C(O) (C(R30))-N Z2 NH(CH), C(O)NH(CH) (i.e., C(O)NH(phe nyl)), —C(O)NH(CHS) (i.e., —C(O)NH(cyclopropyl), and –C(O)NH(CHN) (i.e., C(O)NH(pyridyl), Such as and n is 1. (b) in another example said (12) moiety is 25

– cost-K)/ CH-N Z2 30 (11) arylalkenyl- (aralkenyl-), for example, aryl(C. to C.)alkenyl-, such as for example, —CH=CH-phenyl: (i.e., n is 1, and each R' is H), R is selected from the group consisting of: (c) in another example Z is NH-in (a), (1) H, (d) in another example Z is NH-in (b). 35 (e) in another example Z is —O— in (a), (f) in another example Z is —O—in (b). (3) halo (e.g., F), (g) in another example Z is —CH2— in (a), (4) alkyl (e.g., C to C alkyl, such as, for example, methyl, (h) in another example Z is —CH2—in (b), ethyl and propyl, and in another example, methyl and (i) in another example R is —(CH.) R' and m is 1, ethyl), 40 (j) in another example R is N(R), (5) substituted alkyl (e.g., substituted C to C6 alkyl, such (k) in another example R is N(R), and each R is H as, for example, substituted methyl and substituted (i.e., R is NH), ethyl) wherein said substituted alkyl is substituted with (l) in another example R is —OR, and 1 to 3 substituents (e.g., 1 substituent) selected from the (m) in another example R is -OH (i.e., R is H): group consisting of: (a) —OH, (b) —O-alkyl (e.g., 45 each R. R. R. Rand R7 is independently selected from —O—(C-C alkyl), (c) —O-alkyl (e.g., —O—(C- the group consisting of Calkyl)) substituted with 1 to 3 F atoms, and (d) (1) H, - N(R'), wherein each R" is independently selected (2) alkenyl (e.g., —CH2CH=CH-), from the group consisting of: (i) H., (ii) C-C alkyl (e.g., (3) substituted alkenyl, methyl) and (iii) —CF (examples of said Substituted 50 (4) alkyl (e.g., methyl and ethyl), alkyl groups described in (5) include but are not limited (5) substituted alkyl, to —CHOCH), (6) cycloalkyl (e.g., cyclohexyl), (6) alkynyl (e.g., ethynyl), (7) substituted cycloalkyl, (7) alkenyl (e.g., -CH-CH=CH-), (8) cycloalkylalkyl-, 55 (9) substituted cycloalkylalkyl-, (8) —(CH),R'', (10) heterocycloalkyl, (9) - N(R), (11) substituted heterocycloalkyl, (10) —OR (e.g., -OH, OCH and —O-phenyl), (12) heterocycloalkylalkyl-, (11)-N(R)C(O)R' wherein in one example Riis Hor (13) substituted heterocycloalkylalkyl-, C. to C alkyl (e.g., methyl) and R is alkyl (e.g., 60 (14) —C(O)R' wherein in one example R' is selected methyl), and in another example - N(R)C(O)R’ is from the group consisting of alkyl (e.g., C to C, e.g., NHC(O)CH, methyl), in another example R' is aryl (e.g., phenyl), in (12) cycloalkyl (e.g., C to C cycloalkyl, such as, for another example R' is substituted aryl (e.g., substituted example, cyclopropyl and cyclohexyl), phenyl, Such as, for example, fluorophenyl-), in another (13) cycloalkylalkyl (e.g., C to Ce cycloalkyl-(C to 65 example R' is heteroaryl (e.g., furanyl), and in another C.)alkyl-, such as, for example, cyclopropyl-CH2—and example R' is heterocycloalkyl (e.g., tetrahydrofura cyclohexyl-CH2—), US 7,807,672 B2 33 34 (15) arylheteroaryl- (e.g., phenylthiadiazolyl-, and phe (40) substituted heterocycloalkyl (e.g., N CHC(O)-pip nylthienyl-), eridinyl-, N CHC(O)-methyl substituted piperidinyl, (16) substituted arylheteroaryl- (e.g., substituted phe N-(t-butylC(O)O)-methyl substituted piperidinyl, and nylthiadiazolyl-), N-benzyl-piperidinyl), and (17) heteroarylaryl-, such as, for example, pyrimidinylphe (41) heterocycloalkyl-C(O)-alkyl- (e.g., morpholinyl-C nyl-, pyrazinylphenyl-, pyridinylphenyl- (i.e., (O)—CH2—). pyridylphenyl-), furanylphenyl-, thienylphenyl-, thiaz (42) benzo. 1.3dioxolyl, olylphenyl-, benzofuranylphenyl-, oxazolylphenyl-, wherein said R. R. R. Rand R7 substituted groups (7), pyrazolylphenyl-, pyrrolylphenyl, and triazolylphenyl, (9), (11), (13), (16), (18), (20), (22), (24), (26), (28), (30), (18) substituted heteroarylaryl-, such as, for example, sub 10 (33), (36), (39) and (40), are substituted with 1 to 3 substitu stituted pyrimidinylphenyl-, Substituted pyrazinylphe ents independently selected from the group consisting of nyl-, Substituted pyridinylphenyl- (i.e., Substituted —CHOH, CN, -OH, -NH, alkyl (e.g., C to C alkyl, pyridylphenyl-), substituted furanylphenyl-, substituted e.g., methyl, ethyl, and i-propyl), alkenyl (e.g., C to Calk thienylphenyl-, substituted thiazolylphenyl-, substituted enyl, Such as, for example —CH=CH-), halo (e.g., I, F, Cl pyrimidinylphenyl, Substituted pyridazinylphenyl, and 15 and Br, and in one example said halo is selected from the substituted pyrrolylphenyl-, group consisting of F. Cland Br, and in another example said (19) aryl (e.g., phenyl and naphthyl), halo is F, and in another example said halo is Br, and in (20) substituted aryl (e.g., substituted phenyl and substi another example said halo is Cl), —C(O) NH R (e.g., tuted naphthyl), C(O) NH-CH), C(O) NH, C(O)CR (e.g., (21) heteroaryl (e.g., thiazolyl, thienyl, pyridyl, pyrimidi —C(O)OCHs), C(O)R’ (e.g., C(O)CH), C(alkyl)= nyl, bonZoimidazolyl, benzotriazolyl, benzooxazolyl, NOH (e.g., —C(CH)—NOH), —C(alkyl)-NO(alkyl)(e.g., benzothiazolyl, benzofuranyl, and pyrazinyl), —C(CH)—NOCH), alkoxy (e.g., methoxy and t-butoxy), (22) substituted heteroaryl (e.g., substituted thiazolyl, sub hydroxyl substituted alkyl (e.g., —CH(CH)OH), dialky stituted pyridyl, substituted pyrimidinyl, substituted lamine wherein each alkyl group is independently selected benzoimidazolyl, and Substituted pyrazinyl), examples 25 (e.g., - N(CH3)2), —CF, -SO-alkyl (e.g., -SOCH), of Substituted heteroaryl groups include, for example and NHC(O)H, bromothiazolyl-, bromopyrimidinyl-, fluoropyrimidi wherein said R. R. R. Rand R7 substituted groups (3) nyl-, ethenylpyrimidinyl-, chloropyrazinyl-, cyanoben and (5) are substituted with 1 to 3 substituents independently Zoimidazolyl, cyanopyridyl-, nitropyridyl-, methylpy selected from the group consisting of —NH, halo (e.g., F. Cl ridyl-, CHC(O)-pyrimidyl-, and N-cyclopropylmethyl 30 and Br, and in another example F), —C(O) NH R (e.g., benzoimidazolyl-, —C(O) NH-CH), C(O)OR (e.g., C(O)CCHs), (23) heteroarylheteroaryl- (e.g., pyrimidinylpyridyl-, and and C(O)R’ (e.g., —C(O)CH), and pyrimidinylthiazolyl-), wherein: (24) substituted heteroarylheteroaryl- (e.g., substituted in one example said substituted heteroarylaryl (moiety (18) pyrimidinyl-pyridyl-) 35 above) is substituted with 1 to 3 substituents indepen (25) arylaminoheteroaryl- (e.g., phenyl-NH-oxadiazolyl-), dently selected from the group consisting of: -NH2, (26) Substituted arylaminoheteroaryl- (e.g., Substituted alkyl (e.g., C to Calkyl, e.g., methyl), halo (e.g., F. Cl phenyl-NH-oxadiazolyl-), and Br. Such as, for example F). (27) arylalkynyl- (e.g., aryl(C. to C.)alkynyl such as, for in another example said substituted aryl (moiety (20) example phenylethynyl-), 40 above) is substituted with 1 to 3 substituents indepen (28) substituted arylalkynyl- (e.g., Substituted aryl(C. to dently selected from the group consisting of halo (e.g., F. C.)alkynyl-, such as, for example, Substituted phenyl C1 and Br), C(O) NH R (e.g., C(O) NH ethynyl-), CH), —C(O)OR (e.g., —C(O)O CHs), and (29) heteroarylalkynyl-(e.g., heteroaryl(C. to C.)alkynyl-, 45 —C(O)R’ (e.g., —C(O)CH), and Such as, for example, pyrimidinylethynyl-), in another example said substituted heteroaryl (moiety (22) (30) substituted heteroarylalkynyl- (e.g., substituted het above) is substituted with 1 to 3 substituents selected eroaryl(C. to C.)alkynyl-, such as, for example Substi from the group consisting of halo (e.g., Br, F, and Cl), tuted pyrimidinylethynyl-), alkenyl (e.g., C to C alkenyl. Such as, for example, (31) - C(O)NHR' (e.g., C(O)NHCH), 50 -CH=CH-); (32) cycloalkylheteroarylaryl- (e.g., cyclopropylpyrim R is selected from the group consisting of H, -OH, alkyl idylphenyl-). (e.g., methyl), aryl (e.g., phenyl), -N (R'), (e.g., -NH2) (33) substituted arylaryl- (e.g., HOCH-phenyl-phenyl-, and NRC(O)R' (e.g., -NHC(O)CH): Cl-phenyl-phenyl-, F-phenyl-phenyl-, and CH-O-phe each R is independently selected from the group consist 55 ing of halogen, CN, NO, OR', SR', N(R'), nyl-phenyl-), and R'': (34) arylalkenylaryl- (e.g., aryl(C-C)alkenylaryl, such each R" is independently selected from the group consist as, for example, phenylethenylphenyl-), ing of H, alkyl (e.g., i-propyl, t-butyl, and methyl), aryl (e.g., (35) arylaryl- (e.g., phenyl-phenyl-), phenyl), arylalkyl, heteroaryl (e.g., pyridyl. Such as o-pyridyl, (36) substituted arylalkyl- (e.g., Br-phenyl-CH(CH) , 60 and pyrazolyl), heteroarylalkyl, cycloalkyl (e.g., cyclopro and 1-phenyl-CH(CH)—), pyl), cycloalkylalkyl, heterocycloalkyl, heterocycloalkyla (37) arylalkyl-(e.g., benzyl), lkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substi (38) —SOaryl (e.g., -SO-phenyl), tuted aryl, substituted arylalkyl, substituted heteroaryl, (39) benzoheteroaryl-C(O)-(substituted heterocy substituted heteroarylalkyl, substituted cycloalkyl, substi cloalkyl)- (e.g., benzopyridazinyl-C(O)-(substituted 65 tuted cycloalkylalkyl, substituted heterocycloalkyl, substi piperidinyl)-. Such as, for example, benzopyridazinyl-C tuted heterocycloalkylalkyl, substituted alkylheteroaryl- and (O)-(methyl substituted piperidinyl)-), substituted alkylaryl-, and wherein: US 7,807,672 B2 35 36 said R'substituted alkyl is substituted with 1 to 3 substitu ents independently selected from the group consisting of NH, -NHR, NO, CN, OR, halo (e.g., F. Cl and Br, and in another example F), —C(O) NH R (e.g., —C(O) NH-CH, i.e., R is alkyl, such as methyl), —C(O)CR (e.g., —C(O)CCHs, i.e., R is alkyl, such as ethyl), and —C(O)R’ (e.g., —C(O)CH, i.e., R is alkyl, Such as methyl), and said R' substituted aryl, substituted arylalkyl, substituted 10 R" is selected from the group consisting of: alkyl, aryl, heteroaryl, substituted heteroarylalkyl, substituted heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and cycloalkyl, substituted cycloalkylalkyl, substituted heterocy heterocycloalkylalkyl: cloalkyl, substituted heterocycloalkylalkyl, substituted alky R'' is selected from the group consisting of: alkyl, aryl, lheteroaryl- and substituted alkylaryl- are substituted with 1 heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, to 3 Substituents independently selected from the group con 15 alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylhet sisting of: (1) - NH. (2) —NO, (3) —CN, (4) —OH, (5) eroaryl- and alkylaryl-, OR, (6) OCF (7) CF (8) C(O)R (e.g., R is H R" is selected from the group consisting of H. —OH, or alkyl (e.g., C to C alkyl, Such as, for example, methyl or alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocy ethyl), for example, R is alkyl (e.g., methyl), thus, an cloalkyl and heterocycloalkylalkyl-, alkylheteroaryl- and example of C(O)R’ is —C(O)CH), (9) alkyl (e.g., C to alkylaryl-, Calkyl, e.g., methyl, ethyl, and i-propyl), (10) alkenyl (e.g., R" represents alkyl (e.g., C to C alkyl, such as, for C. to C alkenyl. Such as, for example —CH=CH-), (11) example, methyl or ethyl); halo (e.g., F. Cl and Br, and in another example F), (12) R’ is selected from the group consisting of H, alkyl (e.g., 25 C to Calkyl, Such as, for example, methylandi-propyl), aryl —C(O) NH R (e.g., C(O) NH-CH), (13)—C(O) (e.g., phenyl), cycloalkyl (e.g., C. to C cycloalkyl, Such as, OR (e.g., R is Horalkyl (e.g., C to Calkyl, such as, for for example, cyclopropyl and cyclohexyl), and cycloalkyla example, methyl or ethyl), for example, R is alkyl (e.g., lkyl- (e.g., C to C cycloalkylalkyl-, such as —(CH)-cy methyl or ethyl), thus, for example, —C(O)OR is C(O) cloalkyl. Such as —(CH), (C. to C.)cycloalkyl, wherein OCH), (14) –C(O) NRP (C(R)), N(R), (e.g., 30 each H of each —(CH), moiety can independently be —C(O) NH-(CH2), N(R)) (wherein (a) in one Substituted with an alkyl group (e.g., C to C alkyl, such as, example R is H. (b) in another example each R' is H. (c) in for example, methyl), and wherein in one example n is 1 and another example n is 2, (d) in another example each R is the —CH2— moiety is not Substituted, that is, —CH2-cy independently selected, (e) in another example each R is cloalkyl. Such as, —CH2-cyclopropyl, is an example of said independently selected from the group consisting of H and 35 cycloalkylalkyl-moiety); alkyl (e.g., methyl), (f) in another example R is H, each R' each R’ is independently selected from the group consist ing of H and alkyl (e.g., C to C alkyl. Such as, for example, is H, and each R is independently selected, (g) in another methyl and ethyl); example R is H, each R is H, and each R is indepen R is alkyl (e.g., C to C alkyl, such as, for example, dently selected from the group consisting of H and alkyl 40 methyl or ethyl); (e.g., methyl), (15)—S(O).R (wherein in one exampletis 2, each R' is independently selected from the group consist and in another example R is alkyl (e.g., methyl), and in ing of H, alkyl (e.g., C to C alkyl, such as, for example another example t is 2 and R is alkyl (e.g., methyl)), (16) methyl, ethyl and i-propyl), and F, and wherein in one C(O) NR R (e.g., C(O) NR R) (wherein example each R' is H: one example R is H, in another example R is alkyl (e.g., 45 each R is independently selected from the group consist propyl), and in another example R’ is HandR is alkyl (e.g., ing of H and alkyl (e.g., C to C alkyl, such as, for example propyl)), (17) - NR° C(O)—R (e.g., -NH C(O)— methyl, ethyl and propyl), and wherein each R’ is generally R) (wherein in one example R is H, in another example H; R is alkyl (e.g., methyl), and in another example R’ is H each R is independently selected from the group consist and R is alkyl (e.g., methyl)), 50 ing of H and C to C alkyl (e.g., methyl, ethyl, i-propyl, and propyl), and whereinin one example both R substituents are the same or different alkyl groups (e.g., both R groups are the same alkyl group, Such as methyl), and in another example (18) one R group is Hand the other R group is alkyl, such as N. R.32 N 55 methyl), and in another example each R is preferably H: C-N-R38 C.S., C-NH-R38 R is selected from the group consisting of H and alkyl (e.g., C to C alkyl, such as, for example, methyl, ethyl and propyl), and preferably R is selected from the group con 60 sisting of H and methyl, and more preferably R is H: each R is independently selected from the group consist (wherein in one example R is H, in another example R is ing of H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, H, and in another example R is H and R is H); and (19) cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy NHR20; cloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, R'' is selected from the group consisting of F. -OH, 65 substituted aryl, substituted arylalkyl, substituted heteroaryl, —CN, OR', -NHNR'R''. —SR'' and heteroaryl (e.g., substituted heteroarylalkyl, substituted cycloalkyl, substi triazolyl. Such as, for example, tuted cycloalkylalkyl, substituted heterocycloalkyl, substi US 7,807,672 B2 37 38 tuted heterocycloalkylalkyl, substituted alkylheteroaryl- and Such as, for example, cyclopropyl-methyl- and cyclohexyl substituted alkylaryl-, and wherein: methyl-), and in one example, R is H; and said Rsubstituted alkyl is substituted with 1 to 3 substitu Each R" is independently selected from the group consist ents independently selected from the group consisting of ing of H, alkyl (e.g., C to C alkyl, Such as, for example, C —NH, NO, CN, OR, halo (e.g., F. Cland Br, and to C alkyl, such as, for example, methyl, ethyl and i-propyl), in another example F), —C(O) NH R (e.g., —C(O)— cycloalkyl (e.g., C to Ce cycloalkyl. Such as, for example, NH-CH), C(O)CR (e.g., C(O)CCH), and C(O) cyclopropyl and cyclohexyl), and cycloalkylalkyl (e.g., (C. to R (e.g., —C(O)CH), and C.)cycloalkyl (C. to C.)alkyl, Such as, for example, (C. to said R substituted aryl, substituted arylalkyl, substituted C)cycloalkyl (C. to C.)alkyl, such as, for example, (C. to heteroaryl, substituted heteroarylalkyl, substituted 10 C.)cycloalkyl-methyl-, such as, for example, cyclopropyl cycloalkyl, substituted cycloalkylalkyl, substituted heterocy methyl- and cyclohexyl-methyl-), and in one example, each cloalkyl, substituted heterocycloalkylalkyl, substituted alky R is H. lheteroaryl- and substituted alkylaryl- are substituted with 1 When R is a cycloalkyl group (i.e., R is R' wherein R' to 3 Substituents independently selected from the group con is cycloalkyl), examples of said cycloalkyl group include, but sisting of: (1) —NH. (2) —NO, (3) —CN, (4) —OH, (5) 15 are limited to, cyclopropyl and cyclobutyl. -OR), (6)–OCF, (7) CF, (8)-C(O)R’ (e.g., R is When R' is a heterocycloalkyl group (i.e., R is R' H or C to C alkyl, such as, for example, methyl or ethyl, for wherein R' is heterocycloalkyl), examples of said heterocy example, R is alkyl (e.g., methyl), thus, an example of cloalkyl group include, but are limited to, morpholinyl, pyr —C(O)R’ is C(O)CH), (9) alkyl (e.g., C to Calkyl, e.g., rolidinyl, piperidinyl and piperazinyl. methyl, ethyl, and i-propyl), (10) alkenyl (e.g., C to Calk When R' is a heteroaryl group (i.e., R is R'' and R' is enyl, such as, for example —CH=CH-), (11) halo (e.g., F. Cl heteroaryl), examples of said heteroaryl group include, but and Br, and in another example F), (12) —C(O) NH R' are not limited to, (e.g., -C(O) NH-CH), (13) - C(O)CR (e.g., R is H (a) unsubstituted heteroaryl, or e.g., C to C alkyl, Such as, for example, methyl or ethyl, (b) heteroaryl substituted with 1 to 3 substituents indepen for example, R is alkyl (e.g., methyl or ethyl), thus, for 25 dently selected from the group consisting of: C(O)R’ example, –C(O)OR is C(O)OCHs); (14) - C(O)– (e.g., R is alkyl such as methyl), -NHR' (e.g., NR°(C(R).), N(R), (e.g., -C(O) NH-(CH), N NHCH), OR' (e.g., OCH), and halo (e.g., Cl), (R)) (wherein (a) in one example R is H., (b) in another (c) heteroaryl selected from the group consisting of pyr example each R" is H. (c) in another example n is 2, (d) in rolyl pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, another example each R is independently selected, (e) in 30 pyridyl, pyridyl N-O, and pyrimidinyl, another example each R is independently selected from the (d) heteroaryl selected from the group consisting of pyr group consisting of H and methyl), (f) in another example rolyl pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, R’ is H, each R is H, and each R is independently pyridyl, pyridyl N-O, and pyrimidinyl, wherein said selected, (g) in another example R is H, each R" is H, and heteroaryl is substituted with 1 to 3 substituents inde each R is independently selected from the group consisting 35 pendently selected from the group consisting of —C(O) of Hand methyl), (15)—S(O)R’ (wherein in one example R (e.g., R is alkyl such as methyl), -NHR' (e.g., t is 2, and in another example R is methyl, and in another NHCH), OR' (e.g., OCH), and halo (e.g., Cl), example t is 2 and R is methyl), (16) –C(O)N(R)(R) and (wherein in one example R is H, in another example R is (e) heteroaryl selected from the group consisting of thie alkyl (e.g., propyl), and in another example R’ is Hand R' 40 nyl substituted with —C(O)R (such as, for example, is alkyl (e.g., propyl)), (17) - NR°C(O)R’ (e.g., -NHC thienyl substituted with —C(O)CH), thiazolyl substi (O)R’) (wherein in one example R° is H. in another tuted with NHR' such as, for example (thazolyl sub example R is alkyl (e.g., methyl), and in another example stituted with —NHCH), pyridyl substituted with halo R is Hand R is alkyl (e.g., methyl)), (such as, for example, pyridyl Substituted with —Cl). 45 pyridyl substituted with —OR' (such as, for example, pyridyl substituted with methyl), and pyrimidinyl sub (18) stituted with —OR' (such as, for example, pyrimidinyl N R32 substituted with —OCH). C-N-R26 C.S., -NH-R26 When R' is a heteroarylalkyl group (i.e., R is R'' and R' 50 is heteroarylalkyl), examples of said heteroarylalkyl group include, but are not limited to, (a) unsubstituted heteroarylalkyl (b) heteroarylalkyl-substituted with 1 to 3 substituents (wherein in one example R is H, in another example R is independently selected from the group consisting of: H, and in another example R is H and R is H); and (19) 55 —C(O)R (e.g., R is alkyl such as methyl), -NHR' NHR20; (e.g., NHCH), —OR' (e.g., OCH), and halo R" is selected from the group consisting of: alkyl (e.g., C. (e.g., Cl). to C alkyl, such as, for example —CH), aryl (e.g., phenyl). (c) heteroarylalkyl-selected from the group consisting of heteroaryl (e.g., thiazolyl and pyridyl), and cycloalkyl (e.g., pyrrolylalkyl- (e.g., pyrrolylCH ), pyrazolylalkyl C. to Ce cycloalkyl, Such as, for example, cyclopropyl); 60 (e.g., pyrazolylCH2—), imidazolylalkyl- (e.g., imda R" is selected from the group consisting of H, alkyl (e.g., Zolyl-CH ), furanylalkyl- (e.g., furanylCH ), thie C to Calkyl, Such as, for example, C to C alkyl, such as, for nylalkyl- (e.g., thienylCH2—), thiazolylalkyl- (e.g., example, methyl, ethyl and i-propyl), cycloalkyl (e.g., C to thiazolylcH ), pyridylalkyl- (e.g., pyridylCH ), C cycloalkyl. Such as, for example, cyclopropyl and cyclo pyridyl N O alkyl- (e.g., pyridyl(N—O)CH ), and hexyl), and cycloalkylalkyl (e.g., (C. to C.)cycloalkyl (C. to 65 pyrimidinylalkyl- (e.g., pyrimidinylCH2—), C.)alkyl, Such as, for example, (C. to C.)cycloalkyl(C to (d) heteroarylalkyl-selected from the group consisting of C.)alkyl, Such as, for example, (C. to C.)cycloalkyl-methyl-, pyrrolylalkyl- (e.g., pyrrolylCH ), pyrazolylalkyl US 7,807,672 B2 39 40 (e.g., pyrazolylCH2—), imidazolylalkyl- (e.g., imda There is no Rand no R' groups in 2.15 when Q' fused to the ZolylcH ), furanylalkyl- (e.g., furanylCH ), thie R and R' positions is aryl, substituted aryl, heteroaryl or nylalkyl- (e.g., thienylCH2—), thiazolylalkyl- (e.g., substituted heteroaryl. There is no R and no R7 groups in thiazolylcH ), pyridylalkyl- (e.g., pyridylcH ), pyridyl N-O alkyl- (e.g., pyridyl(N—O)CH ), and 2.15 when Q' fused to the RandR'positions is aryl, substi pyrimidinylalkyl- (e.g., pyrimidinylCH2—), wherein tuted aryl, heteroaryl or substituted heteroaryl. said heteroaryl is substituted with 1 to 3 substituents In one embodiment of the compounds of formula 1.0, Z is independently selected from the group consisting of: 1. Thus, in this embodiment the compounds of formula 1.0 - C(O)R (e.g., R is alkyl such as methyl), -NHR have the formula 1.0A1: (e.g., -NHCH), —OR” (e.g., OCH), and halo 10 (e.g., Cl), and (e) heteroarylalkyl-selected from the group consisting of (1.0A1) thienylalkyl-substituted with a —C(O)R’ group (such R8 O as, for example, thienylCH substituted with —C(O) O CH), thiazolylalkyl-substituted with NHR" such as, 15 for example (thazolylCH-substituted with NHCH), N pyridylalkyl-substituted with halo (such as, for example, HO -, N) R2 n ill pyridylCH-substituted with —Cl), pyridylalkyl-substi \ 4 ( Q tuted with —OR' (such as, for example, pyridylCH Y R36 R35 substituted with methyl), and pyrimidinylalkyl-substi tuted with —OR' (such as, for example, pyrimidi nylcH substituted with —OCH). In another embodiment of the compounds of formula 1.0, Z When R is an aryl group (i.e., R is R'' and R' is aryl), is 1 and R is H. Thus, in this embodiment the compounds of examples of said aryl group include, but are not limited to, formula 1.0 have the formula 1.0A: phenyl and naphthyl, and preferably phenyl. 25 When R' is an arylalkyl group (i.e., R is R'' and R' is arylalkyl), examples of said arylalkyl group include, but are (1.0A) not limited to, -(C(R).)phenyl (e.g., -(CH2), phenyl), R8 wherein in one example said arylalkyl- is —(C(R).)phenyl O wherein n is 1, and in another example said arylalkyl- is 30 —(CH2)phenyl whereinn is 1 (i.e., said arylalkyl- is benzyl). 1=Y2 \ 35 O When R is a substituted arylalkyl group (i.e., R is R'' and HO X- / R2 N n JlsQ R" is a substituted arylalkyl), examples of said substituted N 4 arylalkyl group include, but are not limited to, -(C(R).) Y H R35 substituted phenyl (e.g., -(CH), substituted phenyl). 35 wherein in one example said Substituted arylalkyl- is —(C (R')), substituted phenyl wherein n is 1, and in another example said Substituted arylalkyl- is —(CH2). Substituted In another embodiment of the compounds of formula 1.0, Z phenyl wherein n is 1 (i.e., said substituted arylalkyl- is sub is 1, and each R is independently selected from the group stituted benzyl), wherein the aryl moiety of said substituted 40 consisting of H. methyl, ethyl, i-propyl and propyl (e.g., one arylalkyl is substituted with 1 to 3 substituents independently R is Hand the other is methyl, or both R substituents are selected from the group consisting of halo (e.g., F. Cland Br), methyl, or preferably both R substituents are H). —CF, and —OR” (e.g., OCH). In another embodiment of the compounds of formula 1.0, Z In one embodiment the invention R' is selected from the is 1, each R is independently selected from the group con group consisting of H, alkyl (e.g., methyl, i-propyl, and 45 t-butyl), cycloalkyl (e.g., cyclopropyl), aryl (e.g., phenyl), sisting of H. methyl, ethyl, i-propyland propyl (e.g., one R Substituted aryl (e.g., halo Substituted aryl. Such as for is H and the other is methyl, or both R substituents are example, fluorophenyl), halo (e.g., Cl, Br, and F), heteroaryl methyl, or preferably both R substituents are H), and R is (e.g., pyridyl and pyrazolyl), —CF. —C(O)NH2, and selected from the group consisting of H. methyl, ethyl and —CH2OH. 50 propyl. Those skilled in the art will appreciate that when Q' is aryl, In another embodiment of the compounds of formula 1.0, Z substituted aryl, heteroaryl or substituted heteroaryl the two is 1, each R is independently selected from the group con carbon atoms common to the two fused rings are not substi sisting of H. methyl, ethyl, i-propyland propyl (e.g., one R tuted. Thus, there is no Rand no R' groups in 2.9 when Q is aryl, substituted aryl, heteroaryl or substituted heteroaryl. 55 is H and the other is methyl, or both R substituents are There is no Rand no R' groups in 2.10 when Q' fused to the methyl, or preferably both R substituents are H), and R is R and R' positions is aryl, substituted aryl, heteroaryl or selected from the group consisting of H and methyl. substituted heteroaryl. There is no R' and no R' groups in In another embodiment of the compounds of formula 1.0, Z 2.10 when Q', fused to the R and R7 positions is aryl, sub is 1, each R is independently selected from the group con stituted aryl, heteroaryl or substituted heteroaryl. There is no 60 sisting of H. methyl, ethyl, i-propyland propyl (e.g., one R Rand no R groups in 2.11 when Q' fused to the Rand R' positions is aryl, substituted aryl, heteroaryl or substituted is H and the other is methyl, or both R substituents are heteroaryl. There is no Rand no R' groups in 2.13 when Q methyl, or preferably both R substituents are H), and R is: fused to the R and R' positions is aryl, substituted aryl, H. heteroaryl or substituted heteroaryl. There is no Rand no R' 65 In another embodiment of the compounds of formula 1.0, groups in 2.14 when Q' fused to the R and R positions is each R is H. Thus, in this embodiment the compounds of aryl, substituted aryl, heteroaryl or substituted heteroaryl. formula 1.0 have the formula 1.0B1: US 7,807,672 B2 41 42

8 (1.0B1) (1.1A) R O Yl-Y2 \ O HO \ 4X-y R2 ---z Q. Y R36 10

In another embodiment of the compounds of formula 1.0, Another embodiment of this invention is directed to com each R is H and R is H. Thus, in this embodiment the 15 pounds of formula 1.0 having the formula 1.1: compounds of formula 1.0 have the formula 1.0B:

(1.1) R8 R8 (1.0B) O O Yli-Y2 Yu. O

Yl-Y2 \ O HO \ X- W R2 Nulls Q HO \ X- / R2 s z Q. 25 y3 y3 R1

30 wherein all substituents are as defined for formula 1.0. Another embodiment of this invention is directed to com In another embodiment of the compounds of formula 1.0, Z pounds of formulas 1.0 and 1.1A whereinY', Y, and Y are is preferably 1 and each R is preferably H. Thus, in this —CH=. Thus, one embodiment of this invention is directed embodiment the compounds of formula 1.0 have the formula to compounds of formula 1.2A: 1.OC1: 35

R8 (1.2A)

(1.0C1) O 40 \ O O / 4 N Yl=Y2 \ O HO R Q. HO X-Y R2 Nulls R36 \ 4 Q 45 Y R36

Another embodiment of this invention is directed to com pounds of formulas 1.0 and 1.1 wherein Y', Y, and Y are In another embodiment of the compounds of formula 1.0, Z 50 —CH=. Thus, one embodiment of this invention is directed is preferably 1, each R is preferably H, and Riis H. Thus, to compounds of formula 1.2: preferably the compounds of formula 1.0 have the formula 1.OC: (1.2) 55 R8 (1.0C)

O O Yl-Y2 \ HO HO \ X- / R2 NullsQ 60 y3 R1 wherein all substituents are as defined for formula 1.0. 65 Another embodiment of this invention is directed to com Another embodiment of this invention is directed to com pounds of formula 1.0 having the formula 1.1A: pounds of formula 1.0 having the formula 1.3A: US 7,807,672 B2 44 In another example of Q, Q is moiety 2.3 wherein each R, R, R, and R7 is H. (1.3A) In another example of Q, Q is moiety 2.4 wherein each R, R. R. and R is independently selected from the group consisting of H and alkyl (e.g., C to C alkyl. Such as, for example methyl). In another example of Q, Q is moiety 2.4 wherein each R, HO R. R. and R is independently selected from the group consisting of H and methyl. 10 In another example of Q, Q is moiety 2.4 wherein each R, R1 R, R, and R7 is H. In another example of Q, Q is moiety 2.5 wherein each R, Another embodiment of this invention is directed to com R. R. and R is independently selected from the group pounds of formula 1.0 having the formula 1.3: consisting of H and alkyl (e.g., C to C alkyl, such as, for 15 example methyl). In another example of Q, Q is moiety 2.5 wherein each R, (1.3) R. R. and R is independently selected from the group consisting of H and methyl. In another example of Q, Q is moiety 2.5 wherein each R, R, R, and R7 is H. In another example of Q, Q is moiety 2.6 wherein each R, HO R. R. and R is independently selected from the group consisting of H and alkyl (e.g., C to C alkyl, such as, for RI example methyl). 25 In another example of Q, Q is moiety 2.6 wherein each R, R. R. and R7 is independently selected from the group wherein all substituents are as defined for formula 1.0. consisting of H and methyl. Examples of Q include, but are not limited to: moieties 2.1, In another example of Q, Q is moiety 2.7 wherein each R, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.14, or 2.15 R. R. and R is independently selected from the group 30 consisting of H and alkyl (e.g., C to C alkyl, such as, for wherein each R. R. R. and R7 is independently selected example methyl). from the group consisting of Hand alkyl (e.g., C to C alkyl, In another example of Q, Q is moiety 2.7 wherein each R, Such as, for example methyl). R. R. and R7 is independently selected from the group Examples of Qalso include, but are not limited to: moieties consisting of H and methyl. 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.14, or 35 In another example of Q, Q is moiety 2.7 wherein each 2.15 wherein each R. R. R. and R7 is H. RR, R, and R7 is H. Examples of Q include, but are not limited to: moieties In another example of Q, Q is moiety 2.8 wherein each R, 2.12, 2.13, or 2.16 wherein each R. R. and R7 is indepen R. R. and R is independently selected from the group dently selected from the group consisting of H and alkyl E. i. yond alkyl (e.g., C to C alkyl, Such as, for (e.g., C to C alkyl, such as, for example methyl). 40 example methyl). Examples of Qalso include, but are not limited to: moieties In another example of Q, Q is moiety 2.8 wherein each R, 2.12, 2.13, or 2.16 wherein each R, R', and R7 is H. R. R. and R7 is independently selected from the group Thus, in one example of Q, Q is moiety 2.1 wherein each consisting of H and methyl. R. R. R. and R is independently selected from the group In another example of Q, Q is moiety 2.8 wherein each R, consisting of H and alkyl (e.g., C to C alkyl, such as, for 45 R, R and R7 is H. example methyl). In another example of Q, Q is moiety 2.9 or 2.10 wherein In another example of Q, Q is moiety 2.1 wherein each R, each R. R. R. and R7 is independently selected from the R. R. and R7 is independently selected from the group group consisting of Hand alkyl (e.g., C to C alkyl, Such as, consisting of H and methyl. for example methyl). In another example of Q, Q is moiety 2.1 wherein each R, 50 In another example of Q, Q is moiety 2.9 or 2.10 wherein R, R, and R7 is H. each R. R. R. and R is independently selected from the In another example of Q, Q is moiety 2.2 wherein each R, group consisting of H and methyl. R. R. and R7 is independently selected from the group In another example of Q, Q is moiety 2.9 or 2.10 wherein consisting of H and alkyl (e.g., C to C alkyl, such as, for each R,R,R, and R7 is H. example methyl). 55 In anotherexample of Q, Q is moiety 2.11 wherein each R, In another example of Q, Q is moiety 2.2 wherein each R. R. R. and R7 is independently selected from the group R. R. and R is independently selected from the group consisting of H and alkyl (e.g., C to C alkyl. Such as, for consisting of H and methyl. example methyl). In another example of Q, Q is moiety 2.2 wherein each R, In another example of Q, Q is moiety 2.11 wherein each R, R, R, and R7 is H. 60 R. R. and R is independently selected from the group In another example of Q, Q is moiety 2.3 wherein each R. consisting of H and methyl. R. R. and R is independently selected from the group In anotherexample of Q, Q is moiety 2.11 wherein each R, consisting of H and alkyl (e.g., C to C alkyl, such as, for R, R, and R7 is H. example methyl). In another example of Q, Q is moiety 2.12 or 2.13 wherein In another example of Q, Q is moiety 2.3 wherein each R, 65 each R, R', and R is independently selected from the group R. R. and R7 is independently selected from the group consisting of H and alkyl (e.g., C to C alkyl. Such as, for consisting of H and methyl. example methyl). US 7,807,672 B2 45 46 In another example of Q, Q is moiety 2.12 or 2.13 wherein An example of the Q substituent 2.4 is: each R, R', and R is independently selected from the group consisting of H and methyl. In another example of Q, Q is moiety 2.12 or 2.13 wherein (2.4A) each R, R, and R7 is H. In another example of Q, Q is moiety 2.14 or 2.15 wherein each R. R. R. and R’ is independently selected from the group consisting of: Handalkyl (e.g., C to C alkyl, such as, for example methyl). 10 In another example of Q, Q is moiety 2.14 or 2.15 wherein each R. R. R. and R7 is independently selected from the (i.e., each R is H and w is 1). group consisting of H and methyl. Another example of the Q substituent 2.4 is: In another example of Q, Q is moiety 2.14 or 2.15 wherein 15 each R. R. R. and 7 is H. In another example of Q, Q is moiety 2.16 wherein each R, (2.4B) R, and R7 is H. Another example of the Q substituent 2.3 is:

(2.3A) R7 25 (i.e., each R is H and w is 1). AnkN Another example of the Q substituent 2.4 is: R3 R6

R3 R5 30

(2.4C) R4

(i.e., each R is Hand w is 1). 35 Another example of the Q substituent 2.3 is:

40 (i.e., each R is Hand w is 1). (2.3B) An example of the Q substituent 2.5 is: R7 R6 N (2.5A) R3 R6 45 R3 R5 R4

50 (i.e., each R is Hand w is 1). Another example of the Q substituent 2.3 is: (i.e., each R is Hand w is 1). 55 Another example of the Q substituent 2.5 is:

(2.3C) (2.5B)

60

65 (i.e., each R is Hand w is 1). (i.e., each R is Hand w is 1). US 7,807,672 B2 47 48 Another example of the Q substituent 2.5 is: An example of the Q substituent 2.8 is:

(2.5C) (2.8A)

10

(i.e., each R is Hand w is 1). (i.e., each R is Hand w is 1). An example of the Q substituent 2.6 is: 15 Another example of the Q substituent 2.8 is:

(2.6A) (2.8B)

25

(2.7A) (i.e., each R is H and w is 1). 30 Another example of the Q substituent 2.8 is:

(2.8C)

35

(i.e., each R is Hand w is 1). An example of the Q substituent 2.7 is: 40

(2.7B) (i.e., each R is H and w is 1).

45 Another example of the Q substituent 2.3 is:

(2.3A1)

50 (i.e., each R is Hand w is 1). /O An example of the Q substituent 2.7 is: 55 Another example of the Q substituent 2.3 is:

(2.7C) (2.3B1) 60

65 /O. (i.e., each R is Hand w is 1). US 7,807,672 B2 49 50 Another example of the Q substituent 2.3 is: Another example of the Q substituent 2.5 is:

(2.3C1) (2.5C1) 5

10 Another example of the Q substituent 2.4 is: Another example of the Q substituent 2.7 is:

15 (2.4A1) A. (2.7A1) Nin /O R5. Another example of the Q substituent 2.4 is: Another example of the Q substituent 2.7 is: 25 (2.4B1) (2.7B1)

30 A. N ^ C. R5.

Another example of the Q substituent 2.4 is: 35 Another example of the Q substituent 2.7 is:

(2.4C1) (2.7C1)

40

wS 2.a. Nn R5.

45 Another example of the Q substituent 2.5 is: Another example of the Q substituent 2.8 is:

(2.5A1) (2.8A1) 50

55 Another example of the Q substituent 2.5 is: Another example of the Q substituent 2.8 is:

(2.5B1) (2.8B1) 60

“2. 65 ^2. US 7,807,672 B2 51 52 Another example of the Q substituent 2.8 is: In one example of the Q substituent 2.16

(2.8C1) (2.16)

10 Another example of the Q substituent is the piperazine ring: Q is heteroaryl. In another example of the Q substituent 2.16 Q' is aryl. 15 Thus, one example of the Q substituent 2.16 is 2.16A:

(2.16A)

Sa /CON 25 substituted with one or two substituents independently (i.e., Q' is pyridyl, and each R, RandR is H). selected from the group consisting of R groups, provided that Another example of the Q substituent 2.16 is 2.16B: said one or two substituents are not H. In one embodiment said Substituents are selected from the group consisting of alkyl groups (e.g., C to C alkyl, e.g., methyl). In another (2.16B) embodiment there is one substituent on said piperazine ring. In another embodiment there is one Substituent on said pip erazine ring and said substituent is methyl. Another example of the Q substituent is the piperazine 35 /CO ring: (i.e., Q' is phenyl, and each R, R and R is H). When the Q substituent comprises two Q' rings, each Q' 40 ring is independently selected. Generally, the Q' cycloalkyl rings and the Q' substituted cycloalkyl rings comprise 5 to 7 ring carbons. In general, the heterocycloalkyl Q" rings and the substituted heterocycloalkyl Q" rings comprise 5 to 7 ring carbons and comprise 1 to 3 (generally 1 or 2, or generally 1) 45 ring heteroatoms selected from the group consisting of O. N and S. In general, the heteroaryl Q" rings and the substituted heteroaryl Q" rings comprise 5 to 7 ring carbons and comprise 1 to 3 (generally 1 or 2, or generally 1) ring heteroatoms Another example of the Q substituent is the piperidine ring: selected from the group consisting of O, N and S. Examples 50 of the Q" rings include, but are not limited to: piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, morpholinyl, thiomor pholinyl, pyridyl, pyrimidinyl, pyrrolyl pyrazolyl, furanyl. thienyl, thiazolyl, imidazolyl, cyclopentyl, cyclohexyl and A. cycloheptyl. Examples of the Q" rings also include, but are 55 not limited to: substituted piperidinyl, substituted piperazi nyl, substituted pyranyl, substituted pyrrolidinyl, substituted morpholinyl, substituted thiomorpholinyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolyl, substi tuted pyrazolyl, substituted furanyl, substituted thienyl, sub substituted with one or two substituents independently O stituted thiazolyl, substituted imidazolyl, substituted cyclo selected from the group consisting of R groups, provided that pentyl, substituted cyclohexyl and substituted cycloheptyl said one or two substituents are not H. In one embodiment wherein said substituted Q' rings are substituted with 1 to 3 said Substituents are selected from the group consisting of substituents selected from the R' moieties. alkyl groups (e.g., C to C alkyl, e.g., methyl). In another Generally, the Q’ cycloalkyl rings and the Q' substituted embodiment there is one substituent on said piperidine ring. 65 cycloalkyl rings comprise 5 to 7 ring carbons. In general, the In another embodiment there is one Substituent on said pip heterocycloalkyl Q rings and the substituted heterocy eridine ring and said Substituent is methyl. cloalkyl Q" rings comprise 5 to 7 ring carbons and comprise US 7,807,672 B2 53 54 1 to 3 (generally 1 or 2, or generally 1) ring heteroatoms selected from the group consisting of O, N and S. -continued Examples of the Q rings include, but are not limited to: piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the Q’ rings also include, but are not limited to: substituted piperidinyl, substi O NH NH tuted piperazinyl. Substituted pyranyl. Substituted pyrrolidi | H nyl, substituted morpholinyl, substituted thiomorpholinyl, N-S-CH, C-N-OH, C-OH, substituted cyclopentyl, substituted cyclohexyl and substi O tuted cyclohepty1 wherein said substituted Q' rings are sub 10 stituted with 1 to 3 substituents selected from the R' moi eties. C-O-CH, C-NH2, Examples of R' for the compounds of this invention (e.g., compounds of formulas 1.0, 1.0A1, 1.0B1, 1.0C1, 1.1, 1.1A, O O 1.2, 1.2A, 1.3 and 1.3A) include, but are not limited to: 15 methyl, i-propyl, t-butyl, cyclopropyl, o-F-phenyl, m-F-phe nyl, p-F-phenyl, Cl, Br, F, phenyl, -CF, —C(O)NH2. O -N-(cis-o-ch. O -Si-Cho-o. —CH2OH. H. pyridyl (e.g., o-pyridyl), and pyrazolyl (Such O O as, for example, ---- H || i N-C i NH2, c---e-Nil,

O O CH(CH3)2

25 O -n-ch. Oi-N-cal. F

Other Examples of R' for the compounds of this invention H H (e.g., compounds of formulas 1.0, 1.0A1, 1.0B1, 1.0C1, 1.1, 30 1.1A, 1.2, 1.2A, 1.3 and 1.3A) include, but are not limited to: O --inch H---O ) \ C-N-CH / \ H H 35 ci-n- s CH-N-S(O)CH, O

H H CH-N-C-N-CH(CH3), CH2CH3, 40 O O

45

H H cit-s--chich C -N s O 50 -- -i. -oil -n. CH2OH, 55 S=C-CH,H is

H H 60 N-C-CH, N-C-CH, O O H-i (). n-i-Ni.H O O US 7,807,672 B2 55 56

-continued -continued i NH-CH-CH-O-CH, C-NH-CH-CH-OH, O

-OH, ZI

OCH,

=/

30

35 N

N

OCH

Cl,

55 OH

60 NCH, /Cl

N US 7,807,672 B2 57 58

-continued -continued O CH s OCH, 3. C YCH, 5

C 10 212 NN1

F, s

NO, s 15 22 C no1 CH3 HNN-CH3C F, s | 2O

Cl, s

F ON 25 NO /C /C CH3 , s 1. CH3, s CHCH3, CF, 30

F O / 35 H3COS FC F

40 F

s OCF,

(H3C)HC)HC 45 OCH C l C l 50 CH(CH3)2, OCH3, F F, s s OCH, CI , F , CF OCH

s s s 55

F CF O O s sc.1\ch 60 CEC H. H. CH3 , and HN 65 R", in one embodiment of this invention, is —CF. 3 R", in another embodiment of this invention is substituted aryl. Such as, US 7,807,672 B2 59 60

-continued

5

F, and F

10 s

15 R", in another embodiment of this invention, is heteroaryl (e.g., pyridyl, Such as lsD 2O NS

25 NH2, R", in another embodiment of this invention, is i-propyl. co R", in another embodiment of this invention, is t-butyl. R", in another embodiment of this invention, is methyl. 30 R", in another embodiment of this invention, is cyclopro pyl. R", in another embodiment of this invention, is i-propyl. R", in another embodiment of this invention, is C1. 35 R", in another embodiment of this invention, is —CF. R", in another embodiment of this invention, is H. R", in another embodiment of this invention, is —CH2OH. R", in another embodiment of this invention, is —C(O) 40 NH. R", in another embodiment of this invention, is pyrazolyl. R", in another embodiment of this invention, is phenyl. Examples of R for the compounds of this invention (e.g., 45 compounds of formulas 1.0, 1.0A1, 1.0B1, 1.0C1, 1.1, 1.1A, 1.2, 1.2A, 1.3 and 1.3A) include but are not limited to:

50 “O, N “O, N 55 Na2 N4N

60

Na2Cl CH3, 65

US 7,807,672 B2 63 64

-continued -continued

21 OCH, 10

n 15 /o Na2 OH,

HC

25

30

N OCH3, 35

40 Co.N N(CH3), CF3, OCH3, . C s 45 N1 N NSU 50 C(O)OCH

s

55

C YC(O)OCH, 60

OH,

65

US 7,807,672 B2 68

-continued -continued CN CH CH3,3 s 5

CH3 CH N CH3 CEO 10 N SCOOC(CH3), Cl, s

N 1- N N HC 15 HC CH3 CH3 N YC(O)CH, N YC(O)CH, Xo Br, X C. I, 2O A N /c N s O s

/C 25 C - C-N O, C s s C(O)CH3, *-i-I ), ()), ()-CIO /cy 30 / C / 35 C Choo N N 40 N 2 N C(O)CH3, N ,

N

45 N CN, S1

N N CH3 -CO-CO 50 n n

21 NC(O)H, 2 s

O N 2. 21

N NO2, N-N and

vo/ 60

65 ACH-O In another embodiment of this invention, R is selected from the group consisting of

US 7,807,672 B2 77 78 R, in another embodiment of this invention, is —(CH), R", in one embodiment of this invention, is H. R'' wherein R'' is OR', and R' is Horalkyl. R, in one embodiment of this invention, is H. R, in another embodiment of this invention, is —(CH), Y', in one embodiment of this invention, is carbon. R'', wherein R'' is —OR', and R'' alkyl (e.g., methyl). Y, in one embodiment of this invention, is carbon. R, in another embodiment of this invention, is —(CH), Y in one embodiment of this invention, is carbon. R'', wherein m is 1 and R'' is OR'. Y in one embodiment of this invention, is carbon. R, in another embodiment of this invention, is —(CH), Y', Y and Y, in one embodiment of this invention, are R'', wherein m is 1, R'' is —OR', and R' is Horalkyl. carbon. R, in another embodiment of this invention, is —(CH), One embodiment of this invention is directed to a com R'', wherein m is 1, R' is OR', and R'' alkyl. 10 pound of formula 1.0, preferably a compound of formula R, in another embodiment of this invention, is —(CH), 1.0C1 and more preferably a compound of formula 1.0C, R'', wherein m is 1, R'' is —OR', and R' methyl (i.e., R. (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is —CHOCH). is 2.16, and each R. R. and R7 is independently selected R, in another embodiment of this invention, is —OR from the group consisting of H and methyl. wherein R is alkyl, and said alkyl is methyl (i.e., R is 15 One embodiment of this invention is directed to a com —OCH). pound of formula 1.0, preferably a compound of formula R, in another embodiment of this invention, is alkynyl. An 1.0C1 and more preferably a compound of formula 1.0C, example of an alkynyl group is ethynyl: (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16A, and each R, R', and R is independently selected from the group consisting of H and methyl. One embodiment of this invention is directed to a com CECH. pound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q 25 is 2.16B, and each R. R. and R7 is independently selected Another example of an alkynyl group is propynyl: from the group consisting of H and methyl. One embodiment of this invention is directed to a com pound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, 30 (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q C - CECH. is 2.16, and each R. R. and R7 is H. One embodiment of this invention is directed to a com pound of formula 1.0, preferably a compound of formula R, in another embodiment of this invention, is alkenyl. An 1.0C and more preferably a compound of formula 1.0C, (e.g., example of an alkenyl group is —CH2—CH=CH2. 35 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is In one embodiment, R is selected from the group consist 2.16A, and each R. R. and R7 is H. ing of ethynyl, —OCH, and —CHOCH. One embodiment of this invention is directed to a com In another embodiment, R is selected from the group pound of formula 1.0, preferably a compound of formula consisting of H, ethyl, —CH2OH. —CHOCH, —CHF, 40 1.0C1 and more preferably a compound of formula 1.0C, —CF, —CH-NH —CH2—C=CH, -NH2, and —CH. (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q Additional examples of the R (CH) R' group include, is 2.16B, and each R, R, and R7 is H. but are not limited to —CH2OH. —CHCN, —CHOCHs. The compounds of this invention inhibit the activity of —(CH2)5OCH, —CHF and —CH2-triazolyl. Such as, ERK1 and ERK2 Thus, this invention further provides a 45 method of inhibiting ERK in mammals, especially humans, by the administration of an effective amount (e.g., a therapeu tically effective amount) of one or more (e.g., one) com pounds of this invention. The administration of the com "- pounds of this invention to patients, to inhibit ERK1 and/or N N / N. N 50 ERK2, is useful in the treatment of cancer. In any of the methods of treating cancer described herein, unless stated otherwise, the methods can optionally include R, in one embodiment of this invention, is independently the administration of an effective amount of one or more (e.g., selected from the group consisting of H and alkyl. 1, 2 or 3, or 1 or 2, or 1) chemotherapeutic agents. The R, in another embodiment of this invention, is indepen 55 chemotherapeutic agents can be administered currently or dently selected from the group consisting of H and methyl. sequentially with the compounds of this invention. R, in another embodiment of this invention, is H. The methods of treating cancer described herein include R", in one embodiment of this invention, R.H. methods wherein a combination of drugs (i.e., compounds, or R", in another embodiment of this invention, is selected pharmaceutically active ingredients, or pharmaceutical com from the group consisting of H and alkyl. 60 positions) are used (i.e., the methods of treating cancer of this R", in another embodiment of this invention, is selected invention include combination therapies). Those skilled in the from the group consisting of H and methyl. art will appreciate that the drugs are generally administered R, in one embodiment of this invention, is RH. individually as a pharmaceutical composition. The use of a R", in one embodiment of this invention, is independently pharmaceutical composition comprising more than one drug selected from the group consisting of H and alkyl. 65 is within the scope of this invention. R", in another embodiment of this invention, is indepen In any of the methods of treating cancer described herein, dently selected from the group consisting of H and methyl. unless stated otherwise, the methods can optionally include US 7,807,672 B2 79 80 the administration of an effective amount of radiation therapy. anti-mitotic effect, by affecting microtubule formation and/or For radiation therapy, Y-radiation is preferred. action. Such agents can be, for instance, microtubule stabi Examples of cancers which may be treated by the methods lizing agents or agents which disrupt microtubule formation. of this invention include, but are not limited to: (A) lung Microtubule affecting agents, useful in the methods of this cancer (e.g., lung adenocarcinoma and non Small cell lung invention, are well known to those skilled in the art and cancer), (B) pancreatic cancers (e.g., pancreatic carcinoma include, but are not limited to: Allocolchicine (NSC 406042), Such as, for example, exocrine pancreatic carcinoma), (C) Halichondrin B (NSC 609395), Colchicine (NSC 757), colon cancers (e.g., colorectal carcinomas, Such as, for Colchicine derivatives (e.g., NSC 33410), Dolastatin 10 example, colon adenocarcinoma and colon adenoma), (D) (NSC 376128), Maytansine (NSC 153858), Rhizoxin (NSC myeloid leukemias (for example, acute myelogenous leuke 10 332598), Paclitaxel (Taxol R, NSC 125973), Paclitaxel mia (AML), CML, and CMML), (E) thyroid cancer, (F) derivatives (e.g., Taxotere, NSC 608832), Thiocolchicine myelodysplastic syndrome (MDS), (G) bladder carcinoma, (NSC 361792), Trityl (H) epidermal carcinoma, (I) melanoma, (J) breast cancer, Cysteine (NSC 83265), Vinblastine Sulfate (NSC 49842), (K) prostate cancer, (L) head and neck cancers (e.g., squa Vincristine Sulfate (NSC 67574), Epothilone A, Epothilone, mous cell cancer of the head and neck), (M) ovarian cancer, 15 Discodermolide (see Service, (1996) Science, 274:2009), (N) brain cancers (e.g., gliomas, such as glioma blastoma Estramustine, Nocodazole, MAP4, and the like. Examples of multiforme), (O) cancers of mesenchymal origin (e.g., fibro such agents are described in, for example, Bulinski (1997) J. sarcomas and rhabdomyosarcomas), (P) sarcomas, (Q) tetra Cell Sci. 110:3055-3064, Panda (1997) Proc. Natl. Acad. Sci. carcinomas, (R) nuroblastomas, (S) kidney carcinomas, (T) USA 94.10560-10564, Muhlradt (1997) Cancer Res. hepatomas, (U) non-Hodgkin’s lymphoma, (V) multiple 57:3344-3346, Nicolaou (1997) Nature 387:268-272, myeloma, and (W) anaplastic thyroid carcinoma. Vasquez (1997) Mol. Biol. Cell. 8:973-985, and Panda (1996) Chemotherapeutic agents (antineoplastic agent) include J. Biol. Chem. 271:29807-29812. but are not limited to: microtubule affecting agents, alkylating Chemotherapeutic agents with paclitaxel-like activity agents, antimetabolites, natural products and their deriva include, but are not limited to, paclitaxel and paclitaxel tives, hormones and steroids (including synthetic analogs), 25 derivatives (paclitaxel-like compounds) and analogues. and synthetics. Paclitaxel and its derivatives (e.g. Taxol and Taxotere) are Examples of alkylating agents (including nitrogen mus available commercially. In addition, methods of making tards, ethylenimine derivatives, alkylsulfonates, nitrosoureas paclitaxel and paclitaxel derivatives and analogues are well and triaZenes) include: Uracil mustard, Chlormethine, Cyclo known to those of skill in the art (see, e.g., U.S. Pat. Nos. phosphamide (Cytoxan R), Ifosfamide, Melphalan, Chloram 30 5,569,729; 5,565,478; 5,530,020; 5,527,924: 5,508.447; bucil, Pipobroman, Triethylene-melamine, Triethylenethio 5,489,589: 5,488,116; 5,484.809; 5,478,854; 5,478,736; phosphoramine, Busulfan, Carmustine, Lomustine, 5,475,120; 5,468,769; 5.461,169; 5,440,057; 5,422,364: Streptozocin, Dacarbazine, and Temozolomide. 5,411,984; 5,405,972; and 5,296,506). Examples of antimetabolites (including folic acid antago More specifically, the term “paclitaxel as used herein nists, pyrimidine analogs, purine analogs and adenosine 35 refers to the drug commercially available as Taxol.R (NSC deaminase inhibitors) include: Methotrexate, 5-Fluorouracil, number: 125973). Taxol.R inhibits eukaryotic cell replication Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, by enhancing polymerization of tubulin moieties into stabi Fludarabine phosphate, Pentostatine, and Gemcitabine. lized microtubule bundles that are unable to reorganize into Examples of natural products and their derivatives (includ the proper structures for mitosis. Of the many available che ing Vinca alkaloids, antitumor antibiotics, enzymes, lym 40 motherapeutic drugs, paclitaxel has generated interest phokines and epipodophyllotoxins) include: Vinblastine, because of its efficacy in clinical trials against drug-refractory Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunoru tumors, including ovarian and mammary gland tumors bicin, Doxorubicin, Epirubicin, Idarubicin, Paclitaxel (pacli (Hawkins (1992) Oncology, 6:17-23, Horwitz (1992) Trends taxel is a microtubule affecting agent and is commercially Pharmacol. Sci. 13: 134-146, Rowinsky (1990).J. Natl. Canc. available as Taxol.R.), Paclitaxel derivatives (e.g. taxotere), 45 Inst. 82: 1247-1259). Mithramycin, Deoxyco-formycin, Mitomycin-C. L-Aspara Additional microtubule affecting agents can be assessed ginase, Interferons (especially IFN-a), Etoposide, and Teni using one of many such assays known in the art, e.g., a poside. semiautomated assay which measures the tubulin-polymer Examples of hormones and steroids (including synthetic izing activity of paclitaxel analogs in combination with a analogs) include: 17O.-Ethinylestradiol, Diethylstilbestrol, 50 cellular assay to measure the potential of these compounds to Testosterone, Prednisone, Fluoxymesterone, Dromo block cells in mitosis (see Lopes (1997) Cancer Chemother. stanolone propionate, Testolactone, Megestrolacetate, Pharmacol. 41:37-47). Tamoxifen, Methylprednisolone, Methyl-testosterone, Pred Generally, activity of a test compound is determined by nisolone, Triamcinolone, Chlorotrianisene, Hydroxyproges contacting a cell with that compound and determining terone, Aminoglutethimide, Estramustine, Medroxyprogest 55 whether or not the cell cycle is disrupted, in particular, eroneacetate, Leuprolide, Flutamide, Toremifene, and through the inhibition of a mitotic event. Such inhibition may Zoladex. be mediated by disruption of the mitotic apparatus, e.g., dis Examples of synthetics (including inorganic complexes ruption of normal spindle formation. Cells in which mitosis is Such as platinum coordination complexes): Cisplatin, Carbo interrupted may be characterized by altered morphology platin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, 60 (e.g., microtubule compaction, increased chromosome num Mitoxantrone, Levamisole, and Hexamethylmelamine. ber, etc.). Examples of other chemotherapeutics include: Navelbene, Compounds with possible tubulin polymerization activity CPT-11, Anastrazole, Letrazole, Capecitabinbe, Reloxafine, can be screened in vitro. For example, the compounds are and Droloxafine. screened against cultured WR21 cells (derived from line 69-2 A microtubule affecting agent (e.g., paclitaxel, a paclitaxel 65 wap-ras mice) for inhibition of proliferation and/or for altered derivative or a paclitaxel-like compound), as used herein, is a cellular morphology, in particular for microtubule compac compound that interferes with cellular mitosis, i.e., having an tion. In vivo Screening of positive-testing compounds can US 7,807,672 B2 81 82 then be performed using nude mice bearing the WR21 tumor (5) VEGF inhibitors that are antibodies such as: bevaci cells. Detailed protocols for this screening method are Zumab (Genentech, Inc.), and IMC-C11 (ImClone Systems), described by Porter (1995) Lab. Anim. Sci., 45(2):145-150. DC 101 (a KDRVEGF Receptor 2 from ImClone Systems); Other methods of Screening compounds for desired activ (6) VEGF kinase inhibitors that are small molecules such ity are well known to those of skill in the art. Typically such 5 as SU 5416 (from Sugen, Inc), SU 6688 (from Sugen, Inc.), assays involve assays for inhibition of microtubule assembly Bay 43-9006 (a dual VEGF and bRAF inhibitor from Bayer and/or disassembly. Assays for microtubule assembly are Pharmaceuticals and Onyx Pharmaceuticals); described, for example, by Gaskin et al. (1974) J. Molec. (7) estrogen receptor antagonists or selective estrogen Biol. 89: 737-758. U.S. Pat. No. 5,569,720 also provides in receptor modulators vitro and in vivo assays for compounds with paclitaxel-like 10 (SERMs), such as tamoxifen, idoxifene, raloxifene, trans activity. 2,3-dihydroraloxifene, levormeloxifene, droloxifene, MDL Thus, in the methods of this invention wherein at least one 103.323, and acolbifene (Schering Corp.); chemotherapeutic agent is used, examples of said chemo (8) anti-tumor nucleoside derivatives such as 5-fluorou therapeutic agents include those selected from the group con racil, gemcitabine, capecitabine, cytarabine (Ara-C), fludara sisting of microtubule affecting agents, alkylating agents, 15 bine (F-Ara-A), decitabine, and chlorodeoxyadenosine (Cda, antimetabolites, natural products and their derivatives, hor 2-Cda); mones and steroids (including synthetic analogs), and Syn (9) epothilones such as BMS-247550 (Bristol-Myers thetics. Squibb), and EP0906 (Novartis Pharmaceuticals); In the methods of this invention wherein at least one che (10) topoisomerase inhibitors such as topotecan (Glaxo motherapeutic agent is used, examples of said chemothera SmithKline), and Camptosar (Pharmacia); peutic agents also include: (1) taxanes, (2) platinum coordi (11) Vinca alkaloids. Such as, navelbine (Anvar and Fabre, nator compounds, (3) epidermal growth factor (EGF) France), Vincristine and vinblastine; inhibitors that are antibodies, (4) EGF inhibitors that are (12) antibodies that are inhibitors of CVB3 integrins, such small molecules, (5) vascular endolithial growth factor as, LM-609 (see, Clinical Cancer Research, Vol. 6, page (VEGF) inhibitors that are antibodies, (6) VEGF kinase 25 3056-3061, August 2000, the disclosure of which is incorpo inhibitors that are Small molecules, (7) estrogen receptor rated herein by reference thereto); antagonists or selective estrogen receptor modulators (13) folate antagonists, such as Methotrexate (MTX), and (SERMs), (8) anti-tumor nucleoside derivatives, (9) Premetrexed (Alimta); epothilones, (10) topoisomerase inhibitors, (11) Vinca alka (14) ribonucleotide reductase inhibitors, such as Hydrox loids, (12) antibodies that are inhibitors of CVB3 integrins, 30 yurea (HU); (13) folate antagonists, (14) ribonucleotide reductase inhibi (15) anthracyclines, such as Daunorubicin, Doxorubicin tors, (15) anthracyclines, (16) biologics: (17) inhibitors of (Adriamycin), and Idarubicin; angiogenesis and/or Suppressors of tumor necrosis factor (16) biologics, such as interferon (e.g., Intron-A and Rof alpha (TNF-alpha) such as thalidomide (or related imid), (18) eron), pegylated interferon (e.g., Peg-Intron and Pegasys), Bcr/ablkinase inhibitors, (19). MEK1 and/or MEK2 inhibi 35 and Rituximab (Rituxan, antibody used for the treatment of tors that are small molecules, (20) IGF-1 and IGF-2 inhibitors non-Hodgkin’s lymphoma); that are small molecules, (21) small molecule inhibitors of (17) thalidomide (or related imid); RAF and BRAF kinases, (22) small molecule inhibitors of (18) Bcr/abl kinase inhibitors, such as, for example cell cycle dependent kinases such as CDK1, CDK2, CDK4 Gleevec (STI-571), AMN-17, ONO12380, SU11248 (Suni and CDK6, (23) alkylating agents, and (24) farnesyl protein 40 tinib) and BMS-354825 transferase inhibitors (also know as FPT inhibitors or FTI (19). MEK1 and/or MEK2 inhibitors, such as PD0325901 (i.e., farnesyl transfer inhibitors)). and Arry-142886 (AZD6244); In the methods of this invention wherein at least one che (20) IGF-1 and IGF-2 inhibitors that are small molecules, motherapeutic agent is used, examples of Such chemothera such as, for example, NVP-AEW541: peutic agents include: 45 (21) small molecule inhibitors of RAF and BRAF kinases, such as, for example, BAY 43-9006 (Sorafenib); (1) taxanes such as paclitaxel (TAXOL(R) and/or docetaxel (22) small molecule inhibitors of cell cycle dependent (Taxotere?R); kinases such as CDK1, CDK2, CDK4 and CDK6, such as, for (2) platinum coordinator compounds, such as, for example, example, CYC202, BMS387032, and Flavopiridol; carboplatin, cisplatin and Oxaliplatin (e.g. Eloxatin): 50 (23) alkylating agents, such as, for example, Temodar R (3) EGF inhibitors that are antibodies, such as: HER2 brand oftemozolomide: antibodies (such as, for example trastuzumab (HerceptinR), (24) farnesyl protein transferase inhibitors, such as, for Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone example: Systems), EMD 72000 (Merck KGaA), anti-EFGR mono (a) Sarasar R brand of Ionifarnib (i.e., 4-2-4-(3,10-di clonal antibody ABX (Abgenix). TheraCIM-h-R3 (Center of 55 bromo-8-chloro-6,11-dihydro-5H-benzo 5,6cyclo Molecular Immunology), monoclonal antibody 425 (Merck hepta 1.2-bbyridin-11-yl)-1-piperidinyl)-2-oxoethyl KGaA), monoclonal antibody ICR-62 (ICR, Sutton, 1-piperidinecarboxamide, see for example, U.S. Pat. England); Herzyme (Elan Pharmaceutical Technologies and No. 5,874,442 issued Feb. 23, 1999, and U.S. Pat. No. Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB 569 6,632,455 issued Oct. 14, 2003 the disclosures of each (Wyeth-Ayerst), GW 572016 (GlaxoSmithKline), C11033 60 being incorporated herein by reference thereto), (Pfizer Global Research and Development), trastuzmab-may (b) Zarnestra(R) brand of tipifarnib (i.e., (R)-6-amino (4- tansinoid conjugate (Genentech, Inc.), mitumomab (Imclone chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl-4- Systems and Merck KGaA) and Melvax II (Imclone Systems (3-chlorophenyl)-1-methyl-2(1H)-quinolinone, see for and Merck KgaA); example, WO 97/16443 published May 9, 1997 and U.S. (4) EGF inhibitors that are small molecules, such as, 65 Pat. No. 5,968,952 issued Oct. 19, 1999, the disclosures TarcevaTM (OSI-774, OSI Pharmaceuticals, Inc.), and Iressa of each being incorporated herein by reference thereto), (ZD 1839, AstraZeneca); and US 7,807,672 B2 83 84 (c) Bristol-Myers Squibb 214662: The administration of the chemotherapeutic agents can be made according to treatment protocols already known in the art. N In general when more than one chemotherapeutic agent is | used in the methods of this invention, the chemotherapeutic agents are administered on the same day either concurrently or consecutively in their standard dosage form. For example, the chemotherapeutic agents are usually administered intra venously, preferably by an IV drip using IV solutions well O. O 10 known in the art (e.g., isotonic saline (0.9% NaCl) or dextrose ( \/ Solution (e.g., 5% dextrose)). N N 1 S When two or more chemotherapeutic agents are used, the N / / chemotherapeutic agents are generally administered on the same day; however, those skilled in the art will appreciate that 15 the chemotherapeutic agents can be administered on different days and in different weeks. The skilled clinician can admin ister the chemotherapeutic agents according to their recom mended dosage schedule from the manufacturer of the agent and can adjust the schedule according to the needs of the patient, e.g., based on the patient's response to the treatment. For example, when gemcitabine is used in combination with (see WO97/30992 published Aug. 28, 1997, U.S. Pat. No. a platinum coordinator compound, Such as, for example, cis 6,011,029 issued Jan. 4, 2000, and U.S. Pat. No. 6,455,523, platin, to treat lung cancer, both the gemcitabine and the the disclosures of each being incorporated herein by refer cisplatin are given on the same day on day one of the treat ence thereto). 25 ment cycle, and then gemcitabine is given alone on day 8 and The Bcr/ablkinase inhibitors, EGF receptor inhibitors, and given alone again on day 15 HER-2 antibodies (EGF receptor inhibitors that are antibod The compounds of this invention and chemotherapeutic ies) described above are also known as signal transduction agents can be administered in a treatment protocol that usu inhibitors. Therefore, chemotherapeutic agents, as used ally lasts one to seven weeks, and is repeated typically from 6 herein, include signal transduction inhibitors. 30 to 12 times. Generally the treatment protocol can last one to four weeks. Treatment protocols of one to three weeks can Typical signal transduction inhibitors, that are chemo also be used. A treatment protocol of one to two weeks can therapeutic agents, include but are not limited to: (i) Bcr/abl also be used. During this treatment protocol or cycle the kinase inhibitors such as, for example, STI 571 (Gleevec), (ii) compounds of this invention can be administered daily while Epidermal growth factor (EGF) receptor inhibitor such as, for 35 the chemotherapeutic agents can be administered one or more example, Kinase inhibitors (Iressa, OSI-774) and antibodies times a week. Generally, a compound of this invention can be (Imclone: C225 Goldstein et al. (1995), Clin Cancer Res. administered daily (i.e., once per day), and in one embodi 1:1311-1318), and Abgenix: ABX-EGF) and (iii) HER-2/neu ment twice per day, and the chemotherapeutic agent is admin receptor inhibitors such as, for example, Herceptin R) (tras istered once a week or once every three weeks. For example, tuZumab). 40 the taxanes (e.g., Paclitaxel (e.g., Taxol.R.) or Docetaxel (e.g., Methods for the safe and effective administration of most Taxotere?R)) can be administered once a week or once every of these chemotherapeutic agents are known to those skilled three weeks. in the art. In addition, their administration is described in the However, those skilled in the art will appreciate that treat standard literature. For example, the administration of many ment protocols can be varied according to the needs of the of the chemotherapeutic agents is described in the “Physi 45 patient. Thus, the combination of compounds (drugs) used in cians’ Desk Reference” (PDR), e.g., 1996 edition (Medical the methods of this invention can be administered in varia tions of the protocols described above. For example, the com Economics Company, Montvale, N.J.07645-1742, USA), the pounds of this invention can be administered discontinuously Physician's Desk Reference, 56' Edition, 2002 (published by rather than continuously during the treatment cycle. Thus, for Medical Economics company, Inc. Montvale, N.J. 07645 example, during the treatment cycle the compounds of this 1742), and the Physician's Desk Reference, 57" Edition, invention can be administered daily for a week and then 2003 (published by Thompson PDR, Montvale, N.J. 07645 discontinued for a week, with this administration repeating 1742); the disclosures of which is incorporated herein by during the treatment cycle. Or the compounds of this inven reference thereto. tion can be administered daily for two weeks and discontin For example, the compound of formula 1.0 (e.g., a phar 55 ued for a week, with this administration repeating during the maceutical composition comprising the compound of for treatment cycle. Thus, the compounds of this invention can be mula 1.0); can be administered orally (e.g., as a capsule), and administered daily for one or more weeks during the cycle the chemotherapeutic agents can be administered intrave and discontinued for one or more weeks during the cycle, nously, usually as an IV solution. The use of a pharmaceutical with this pattern of administration repeating during the treat composition comprising more than one drug is within the 60 ment cycle. This discontinuous treatment can also be based Scope of this invention. upon numbers of days rather than a full week. For example, The compound of formula 1.0 and the chemotherapeutic daily dosing for 1 to 6 days, no dosing for 1 to 6 days with this agents are administered in therapeutically effective dosages pattern repeating during the treatment protocol. The number to obtain clinically acceptable results, e.g., reduction or elimi of days (or weeks) wherein the compounds of this invention nation of symptoms or of the tumor. Thus, the compound of 65 are not dosed do not have to equal the number of days (or formula 1.0 and chemotherapeutic agents can be adminis weeks) wherein the compounds of this invention are dosed. tered concurrently or consecutively in a treatment protocol. Usually, if a discontinuous dosing protocol is used, the num US 7,807,672 B2 85 86 ber of days or weeks that the compounds of this invention are folate antagonist Methotrexate (MTX) 20-60 mg/m by oral, dosed is at least equal or greater than the number of days or IV or IM every 3 to 4 weeks, the intermediate dose regimen is weeks that the compounds of this invention are not dosed. 80-250 mg/m IV over 60 minutes every 3 to 4 weeks, and the The chemotherapeutic agent could be given by bolus or high dose regimen is 250-1000 mg/m IV given with leuco continuous infusion. The chemotherapeutic agent could be vorin every 3 to 4 weeks; (r) for the folate antagonist Prem given daily to once every week, or once every two weeks, or etrexed (Alimta)300-600 mg/m (10 minutes IV infusion day once every three weeks, or once every four weeks during the 1) every 3 weeks: (s) for the ribonucleotide reductase inhibi treatment cycle. If administered daily during a treatment tor Hydroxyurea (HU) 20-50 mg/kg/day (as needed to bring cycle, this daily dosing can be discontinuous over the number blood cell counts down), (t) the platinum coordinator com of weeks of the treatment cycle. For example, dosed for a 10 pound Oxaliplatin (Eloxatin) 50-100 mg/m every 3 to 4 week (or a number of days), no dosing for a week (or a weeks (preferably used for Solid tumors such as non-small number of days, with the pattern repeating during the treat cell lung cancer, colorectal cancer and ovarian cancer); (u) for ment cycle. the anthracycline daunorubicin 10-50 mg/m/day IV for 3-5 The compounds of this invention can be administered days every 3 to 4 weeks; (v) for the anthracycline Doxorubi orally, preferably as a Solid dosage form, and in one embodi 15 cin (Adriamycin) 50-100 mg/m IV continuous infusion over ment as a capsule, and while the total therapeutically effective 1-4 days every 3 to 4 weeks, or 10-40 mg/m IV weekly: (w) daily dose can be administered in one to four, or one to two for the anthracycline Idarubicin 10-30 mg/m daily for 1-3 divided doses per day, generally, the therapeutically effective days as a slow IV infusion over 10-20 minutes every 3 to 4 dose is given once or twice a day, and in one embodiment weeks; (x) for the biologic interferon (Intron-A, Roferon) 5 to twice a day. The compounds of this invention can be admin 20 million IU three times per week; (y) for the biologic istered in an amount of about 50 to about 400 mg once per day, pegylated interferon (Peg-intron, Pegasys) 3 to 4 micro and can be administered in an amount of about 50 to about grams/kg/day chronic Sub cutaneous (until relapse or loss of 300 mg once per day. The compounds of this invention are activity); (Z) for the biologic Rituximab (Rituxan) (antibody generally administered in an amount of about 50 to about 350 used for non-Hodgkin's lymphoma) 200-400 mg/m IV mg twice a day, usually 50 mg to about 200 mg twice a day, 25 weekly over 4-8 weeks for 6 months; (aa) for the alkylating and in one embodiment about 75 mg to about 125 mg admin agent temozolomide 75 mg/m to 250 mg/m, for example, istered twice a day, and in another embodiment about 100 mg 150 mg/m, or for example, 200 mg/m, such as 200 mg/m administered twice a day. for 5 days; and (bb) for the MEK1 and/or MEK2 inhibitor If the patient is responding, or is stable, after completion of PD0325901, 15 mg to 30 mg, for example, 15 mg daily for 21 the therapy cycle, the therapy cycle can be repeated according 30 days every 4 weeks. to the judgment of the skilled clinician. Upon completion of Gleevec can be used orally in an amount of about 200 to the therapy cycles, the patient can be continued on the com about 800 mg/day. pounds of this invention at the same dose that was adminis Thalidomide (and related imids) can be used orally in tered in the treatment protocol, or, if the dose was less than amounts of about 200 to about 800 mg/day, and can be con 200 mg twice a day, the dose can be raised to 200 mg twice a 35 tinuously dosed or used until relapse or toxicity. See for day. This maintenance dose can be continued until the patient example Mitsiades et al., “Apoptotic signaling induced by progresses or can no longer tolerate the dose (in which case immunomodulatory thalidomide analogs in human multiple the dose can be reduced and the patient can be continued on myeloma cells; therapeutic implications”. Blood, the reduced dose). 99(12):4525-30, Jun. 15, 2002, the disclosure of which is The chemotherapeutic agents, used with the compounds of 40 incorporated herein by reference thereto. this invention, are administered in their normally prescribed The FPT inhibitor Sarasar R. (brand of Ionifarnib) can be dosages during the treatment cycle (i.e., the chemotherapeu administered orally (e.g., capsule) in amounts of about 50 to tic agents are administered according to the standard of prac about 200 mg given twice a day, or in amounts of about 75 to tice for the administration of these drugs). For example: (a) about 125 mg given twice a day, or in amounts of about 100 to about 30 to about 300 mg/m for the taxanes; (b) about 30 to 45 about 200 mg given twice a day, or in an amount of about 100 about 100 mg/m for Cisplatin; (c) AUC of about 2 to about 8 mg given twice a day. for Carboplatin; (d) about 2 to about 4 mg/m for EGF inhibi Paclitaxel (e.g., Taxol.R.), for example, can be administered tors that are antibodies; (e) about 50 to about 500 mg/m for once per week in an amount of about 50 to about 100 mg/m EGF inhibitors that are small molecules: (f) about 1 to about and in another example about 60 to about 80 mg/m. In 10 mg/m for VEGF kinase inhibitors that are antibodies; (g) 50 another example Paclitaxel (e.g., Taxol.R.) can be adminis about 50 to about 2400 mg/m for VEGF inhibitors that are tered once every three weeks in an amount of about 150 to small molecules: (h) about 1 to about 20 mg for SERMs: (i) about 250 mg/m and in another example about 175 to about about 500 to about 1250 mg/m for the anti-tumor nucleo 225 mg/m. sides 5-Fluorouracil, Gemcitabine and Capecitabine; () for In another example, Docetaxel (e.g., TaxotereR) can be the anti-tumor nucleoside Cytarabine (Ara-C) 100-200 55 administered once per week in an amount of about 10 to about mg/m/day for 7 to 10 days every 3 to 4 weeks, and high doses 45 mg/m. In another example Docetaxel (e.g., TaxotereR) for refractory leukemia and lymphoma, i.e., 1 to 3 gm/m for can be administered once every three weeks in an amount of one hour every 12 hours for 4-8 doses every 3 to four weeks: about 50 to about 100 mg/m. (k) for the anti-tumor nucleoside Fludarabine (F-ara-A) In another example Cisplatin can be administered once per 10-25 mg/m2/day every 3 to 4 weeks; (I) for the anti-tumor 60 week in an amount of about 20 to about 40 mg/m. In another nucleoside Decitabine 30 to 75 mg/m for three days every 6 example Cisplatin can be administered once every three weeks for a maximum of 8 cycles; (m) for the anti-tumor weeks in an amount of about 60 to about 100 mg/m. nucleoside Chlorodeoxyadenosine (CdA, 2-CdA) 0.05-0.1 In another example Carboplatin can be administered once mg/kg/day as continuous infusion for up to 7 days every 3 to per week in an amount to provide an AUC of about 2 to about 4 weeks; (n) about 1 to about 100 mg/m for epothilones; (o) 65 3. In another example Carboplatin can be administered once about 1 to about 350 mg/m for topoisomerase inhibitors; (p) every three weeks in an amount to provide an AUC of about 5 about 1 to about 50 mg/m for vinca alkaloids; (q) for the to about 8. US 7,807,672 B2 87 88 Other embodiments of this invention are described below. Embodiment No. 14 is directed to a compound of formula The embodiments have been numbered for the purpose of 1.0, preferably a compound of formula 1.0C and more pref making it easier to refer to the embodiments. The term “in any erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, one of Embodiment Nos.” or the term “of any of Embodiment 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.10. Nos., as used below, means that the particular embodiment Embodiment No. 15 is directed to a compound of formula using that term is intended to cover any one of the embodi 1.0, preferably a compound of formula 1.0C1 and more pref ments referred to as if any one of the referred to embodiments erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, had been individually described. “Nos. is an abbreviation for 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.11. Numbers. Embodiment No. 16 is directed to a compound of formula Embodiment No. 1 is directed to a compound of formula 10 1.0, preferably a compound of formula 1.0C and more pref 1.0, preferably a compound of formula 1.0C, wherein Q is erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, selected from the group consisting of Substituents 2.1, 2.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.12. 2.3, 2.3A, 2.3B, 2.3C, 2.4A, 2.4B, 2.4C, 2.5A, 2.5B, 2.5C, Embodiment No. 17 is directed to a compound of formula 2.6A, 2.7A, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 2.9 to 2.14, 2.15 1.0, preferably a compound of formula 1.0C1 and more pref and 2.16 (e.g., 2.16A or 2.16B). 15 erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, Embodiment No. 2 is directed to a compound of formula 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.13. 1.1 wherein Q is selected from the group consisting of Sub Embodiment No. 18 is directed to a compound of formula stituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 2.4A, 2.4B, 2.4C, 1.0, preferably a compound of formula 1.0C1 and more pref 2.5A, 2.5B, 2.5C, 2.6A, 2.7A, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 2.9 to 2.14, 2.15, and 2.16 (e.g., 2.16A or 2.16B). 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.14. Embodiment No. 3 is directed to a compound of formula Embodiment No. 19 is directed to a compound of formula 1.2 wherein Q is selected from the group consisting of Sub 1.0, preferably a compound of formula 1.0C1 and more pref stituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 2.4A, 2.4B, 2.4C, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 2.5A, 2.5B, 2.5C, 2.6A, 2.7A, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.15. 2.9 to 2.14, 2.15 and 2.16 (e.g., 2.16A or 2.16B). 25 Embodiment No. 20 is directed to a compound of formula Embodiment No. 4 is directed to a compound of formula 1.3 wherein substituent Q is 2.1. 1.3 wherein Q is selected from the group consisting of Sub Embodiment No. 21 is directed to a compound of formula stituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 2.4A, 2.4B, 2.4C, 1.3 wherein substituent Q is 2.2. 2.5A, 2.5B, 2.5C, 2.6A, 2.7A, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, Embodiment No. 22 is directed to a compound of formula 2.9 to 2.14, 2.15 and 2.16 (e.g., 2.16A or 2.16B). 30 1.3 wherein substituent Q is 2.3. Embodiment No. 5 is directed to a compound of formula Embodiment No. 23 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.3 wherein substituent Q is 2.6. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, Embodiment No. 24 is directed to a compound of formula 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.1. 1.3 wherein substituent Q is 2.6A. Embodiment No. 6 is directed to a compound of formula 35 Embodiment No. 25 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.3 wherein substituent Q is 2.7A. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, Embodiment No. 26 is directed to a compound of formula 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.2. 1.3 wherein substituent Q is 2.7B. Embodiment No. 7 is directed to a compound of formula Embodiment No. 27 is directed to a compound of formula 1.0 (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substitu 40 1.3 wherein substituent Q is 2.7C. ent Q is 2.3 (e.g., 2.3A, 2.3B or 2.3C). Embodiment No. 28 is directed to a compound of formula Embodiment No. 8 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.0, preferably a compound of formula 1.0C, (e.g., 1.1, 1.1A, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.4 (e.g., 1.2A, 1.3 or 1.3A) wherein each R. R. R. and R7 is inde 2.4A, 2.4B or 2.4C). 45 pendently selected from the group consisting of Hand alkyl. Embodiment No. 9 is directed to a compound of formula Embodiment No. 29 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.0, preferably a compound of formula 1.0C1 and more pref erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.5 (e.g., 2.5A, 1.2A, 1.3 or 1.3A) wherein each R. R. R. and R7 is inde 2.5B or 2.5C). 50 pendently selected from the group consisting of H and Embodiment No. 10 is directed to any of compounds of methyl. formulas to a compound of formula 1.0, preferably a com Embodiment No. 30 is directed to a compound of formula pound of formula 1.0C1 and more preferably a compound of 1.0, preferably a compound of formula 1.0C and more pref formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, Substituent Q is 2.6 (e.g., 2.6A). 55 1.2A, 1.3 or 1.3A) wherein each R. R. R. and R7 is H. Embodiment No. 11 is directed to a compound of formula Embodiment No. 31 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.0, preferably a compound of formula 1.0C and more pref erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.7. 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the Embodiment No. 12 is directed to a compound of formula 60 group consisting of moieties 2.1.2.2, 2.3A, 2.3B, and 2.3C. 1.0, preferably a compound of formula 1.0C1 and more pref Embodiment No. 32 is directed to a compound of formula erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.0, preferably a compound of formula 1.0C and more pref 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.8. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, Embodiment No. 13 is directed to a compound of formula 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the 1.0, preferably a compound of formula 1.0C1 and more pref 65 group consisting of moieties 2.1.2.2, 2.3A, 2.3B, and 2.3C. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, and each R. R. R. and R7 is independently selected from 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.9. the group consisting of H and alkyl. US 7,807,672 B2 89 90 Embodiment No. 33 is directed to a compound of formula consisting of moiety 2.1, and: (1) each R. R. R. and R is 1.0, preferably a compound of formula 1.0C1 and more pref independently selected from the group consisting of H and erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, alkyl, or (2) each R,R,R, and R is independently selected 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the from the group consisting of H and methyl, or (3) each R, group consisting of moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C. R, R, and R7 is H. and each R. R. R. and R is independently selected from Embodiment No. 46 is directed to a compound of formula the group consisting of H and methyl. 1.2 or 1.3 wherein substituent Q is selected from the group Embodiment No. 34 is directed to a compound of formula consisting of moiety 2.2, and: (1) each R. R. R. and R is 1.0, preferably a compound of formula 1.0C1 and more pref independently selected from the group consisting of H and erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 10 alkyl, or (2) each R,R,R, and R is independently selected 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the from the group consisting of H and methyl, or (3) each R, group consisting of moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C. R, R, and R7 is H. and each R. R. R. and R7 is H. Embodiment No. 47 is directed to a compound of formula Embodiment No. 35 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group 1.0, preferably a compound of formula 1.0C1 and more pref 15 consisting of moieties 2.3A, 2.3B and 2.3C, and: (1) each R, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, R. R. and R7 is independently selected from the group 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the consisting of H and alkyl, or (2) each R. R. R. and R is group consisting of: moieties 2.1, and: (1) each R. R. R. independently selected from the group consisting of H and and R is independently selected from the group consisting methyl, or (3) each R. R. R. and R7 is H. of H and alkyl, or (2) each R. R. R. and R is indepen Embodiment No. 48 is directed to a compound of formula dently selected from the group consisting of Hand methyl, or 1.3 wherein each R. R. R. and R7 is independently selected (3) each R, R, R, and R7 is H. from the group consisting of H and alkyl. Embodiment No. 36 is directed to a compound of formula Embodiment No. 49 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C and more pref 1.3 wherein each R. R. R. and R is independently selected erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 25 from the group consisting of H and methyl. 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the Embodiment No. 50 is directed to a compound of formula group consisting of: moieties 2.2, and: (1) each R. R. R. 1.3 wherein each R. R. R. and R7 is H. and R is independently selected from the group consisting Embodiment No. 51 is directed to a compound of formula of H and alkyl, or (2) each R. R. R. and R is indepen 1.3 wherein substituent Q is selected from the group consist dently selected from the group consisting of Hand methyl, or 30 ing of moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C. (3) each R, R, R, and R7 is H. Embodiment No. 52 is directed to a compound of formula Embodiment No. 37 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consist 1.0, preferably a compound of formula 1.0C1 and more pref ing of moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R, erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, R. R. and R is independently selected from the group 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the 35 consisting of H and alkyl. group consisting of moieties 2.3A, 2.3B, 2.3C, and: (1) each Embodiment No. 53 is directed to a compound of formula R. R. R. and R is independently selected from the group 1.3 wherein substituent Q is selected from the group consist consisting of H and alkyl, or (2) each R. R. R. and R is ing of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R, independently selected from the group consisting of H and R. R. and R is independently selected from the group methyl, or (3) each R. R. R. and R7 is H. 40 consisting of H and methyl. Embodiment No. 38 is directed to a compound of formula Embodiment No. 54 is directed to a compound of formula 1.2 or 1.3 wherein each R. R. R. and R7 is independently 1.3 wherein substituent Q is selected from the group consist selected from the group consisting of H and alkyl. ing of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R, Embodiment No. 39 is directed to a compound of formula R, R, and R7 is H. 1.2 or 1.3 wherein each R. R. R. and R7 is independently 45 Embodiment No. 55 is directed to a compound of formula selected from the group consisting of H and methyl. 1.3 wherein substituent Q is selected from the group consist Embodiment No. 40 is directed to a compound of formula ing of moiety 2.1, and: (1) each R. R. R. and R7 is inde 1.2 or 1.3 wherein each R. R. R. and R7 is H. pendently selected from the group consisting of Hand alkyl, Embodiment No. 41 is directed to a compound of formula or (2) each R. R. R. and R7 is independently selected from 1.2 or 1.3 wherein substituent Q is selected from the group 50 the group consisting of: Hand methyl, or (3) each R. R. R. consisting of moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C. and R7 is H. Embodiment No. 42 is directed to a compound of formula Embodiment No. 56 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group 1.3 wherein substituent Q is selected from the group consist consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and ing of moiety 2.2, and: (1) each R. R. R. and R7 is inde each R. R. R. and R is independently selected from the 55 pendently selected from the group consisting of Hand alkyl, group consisting of H and alkyl. or (2) each R. R. R. and R7 is independently selected from Embodiment No. 43 is directed to a compound of formula the group consisting of: Hand methyl, or (3) each R. R. R. 1.2 or 1.3 wherein substituent Q is selected from the group and R7 is H. consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and Embodiment No. 57 is directed to a compound of formula each R. R. R. and R is independently selected from the 60 1.3 wherein substituent Q is selected from the group consist group consisting of H and methyl. ing of moieties 2.3A1, 2.3B and 2.3C, and: (1) each R. R. Embodiment No. 44 is directed to a compound of formula R, and R is independently selected from the group consist 1.2 or 1.3 wherein substituent Q is selected from the group ing of Hand alkyl, or (2) each R. R. R. and R7 is indepen consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and dently selected from the group consisting of Hand methyl, or each R,R,R, and R7 is H. 65 (3) each R, R, R, and R7 is H. Embodiment No. 45 is directed to a compound of formula Embodiment No. 58 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group 1.0, preferably a compound of formula 1.0C1 and more pref US 7,807,672 B2 91 92 erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, consisting of moieties 2.6.2.7A, 2.7B and 2.7C, and each R, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the R. R. and R7 is independently selected from the group group consisting of moieties 2.6, 2.7A, 2.7B and 2.7C. consisting of H. Embodiment No. 59 is directed to a compound of formula Embodiment No. 69 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.2 or 1.3 wherein substituent Q is selected from the group erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, consisting of moiety 2.6, and: (1) each R. R. R. and R is 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the independently selected from the group consisting of H and group consisting of moieties 2.6, 2.7A, 2.7B and 2.7C, and alkyl, or (2) each R,R,R, and R is independently selected each R. R. R. and R is independently selected from the from the group consisting of H and methyl, or (3) each R, group consisting of H and alkyl. 10 R, R, and R7 is H. Embodiment No. 60 is directed to a compound of formula Embodiment No. 70 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.2 or 1.3 wherein substituent Q is selected from the group erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, consisting of moiety 2.7A, and: (1) each R. R. R. and R' 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the is independently selected from the group consisting of Hand group consisting of moieties 2.6, 2.7A, 2.7B and 2.7C, and 15 alkyl, or (2) each R,R,R, and R is independently selected each R. R. R. and R is independently selected from the from the group consisting of H and methyl, or (3) each R, group consisting of H and methyl. R, R, and R7 is H. Embodiment No. 71 is directed to a compound of formula Embodiment No. 61 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group 1.0, preferably a compound of formula 1.0C and more pref consisting of moieties 2.7A and 2.7B, and: (1) each R. R. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, R, and R7 is independently selected from the group consist 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the ing of Handalkyl, or (2) each R. R. R. and R is indepen group consisting of moieties 2.6, 2.7A, 2.7B and 2.7C, and dently selected from the group consisting of Hand methyl, or each R,R,R, and R7 is H. (3) each R, R, R, and R7 is H. Embodiment No. 62 is directed to a compound of formula 25 Embodiment No. 72 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more pref 1.3 wherein substituent Q is selected from the group consist erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, ing of moieties 2.6, 2.7A, 2.7B and 2.7C. 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the Embodiment No. 73 is directed to a compound of formula group consisting of: moiety 2.6, and: (1) each R. R. R. and 1.3 wherein substituent Q is selected from the group consist R’ is independently selected from the group consisting of H 30 ing of moieties 2.6, 2.7A, 2.7B and 2.7C, and each R. R. and alkyl, or (2) each R. R. R. and R is independently R, and R is independently selected from the group consist selected from the group consisting of H and methyl, or (3) ing of H and alkyl. each R,R,R, and R7 is H. Embodiment No. 74 is directed to a compound of formula Embodiment No. 63 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consist 1.0, preferably a compound of formula 1.0C1 and more pref 35 ing of moieties 2.6, 2.7A, 2.7B and 2.7C, and each R. R. erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, R, and R is independently selected from the group consist 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the ing of H and methyl. group consisting of moiety 2.7A, and: (1) each R. R. R. Embodiment No. 75 is directed to a compound of formula and R is independently selected from the group consisting 1.3 wherein substituent Q is selected from the group consist of H and alkyl, or (2) each R. R. R. and R7 is indepen 40 ing of moieties 2.6, 2.7A, 2.7B and 2.7C, and each R. R. dently selected from the group consisting of Hand methyl, or R, and R7 is H. (3) each R, R, R, and R7 is H. Embodiment No. 76 is directed to a compound of formula Embodiment No. 64 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consist 1.0, preferably a compound of formula 1.0C1 and more pref ing of: moiety 2.6, and: (1) each R. R. R. and R is inde erably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 45 pendently selected from the group consisting of Hand alkyl, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the or (2) each R, R, and R is independently selected from the group consisting of moieties 2.7Band2.7C, and: (1) each R, group consisting of Hand methyl, or (3) each R. R. R. and R. R. and R7 is independently selected from the group R7 is H. consisting of H and alkyl, or (2) each R. R. R. and R is Embodiment No. 77 is directed to a compound of formula independently selected from the group consisting of H and 50 1.3 wherein substituent Q is selected from the group consist methyl, or (3) each R. R. R. and R7 is H. ing of moiety 2.7A, and: (1) each R. R. R. and R is Embodiment No. 65 is directed to a compound of formula independently selected from the group consisting of H and 1.2 or 1.3 wherein substituent Q is selected from the group alkyl, or (2) each R,R,R, and R is independently selected consisting of moieties 2.6, 2.7A, 2.7B and 2.7C. from the group consisting of H and methyl, or (3) each R, 55 R, R, and R7 is H. Embodiment No. 66 is directed to a compound of formula Embodiment No. 78 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of moieties 2.6.2.7A, 2.7B and 2.7C, and each R, 1.3 wherein substituent Q is selected from the group consist R. R. and R is independently selected from the group ing of: moieties 2.7B and 2.7C, and: (1) each R. R. R. and consisting of H and alkyl. R’ is independently selected from the group consisting of H 60 and alkyl, or (2) each R. R. R. and R is independently Embodiment No. 67 is directed to a compound of formula selected from the group consisting of H and methyl, or (3) 1.2 or 1.3 wherein substituent Q is selected from the group each R,R,R, and R7 is H. consisting of moieties 2.6, 2.7A, 2.7B and 2.7C, and each R, Embodiment No. 79 is directed to a compound of any one R. R. and R is independently selected from the group of Embodiment Nos. 1 to 78, wherein R' is selected from the consisting of H and methyl. 65 group consisting of i-propyl, t-butyl, methyl, cyclopropyl. Embodiment No. 68 is directed to a compound of formula Cl, CF. H. —CH2OH. —C(O)NH2, pyrazolyl, phenyl, 1.2 or 1.3 wherein substituent Q is selected from the group pyridyl, o-F-phenyl, m-F-phenyl and p-F-phenyl US 7,807,672 B2 93 94 Embodiment No. 80 is directed to a compound of any one of Embodiment Nos. 1 to 79 wherein R is selected from the -continued group consisting of

i-Cit. -CHs, -CH, -C(O)NHCH, 15 O

N

s 2O NN Na2 C2H5, Nn 2 C2H5, O / 25 N. : s O N % 30 Cl C(O)CH3, N S. N s sy 35 N Cl4S.

40 N s s F, it. F 45 N 2 2N s H3C

s - CH3,is 50 N C O n

55 N 2 S ? O YCH, O s O 60 N e N2 n it. S f N f Nn 2n-2N S \N / \ 65 US 7,807,672 B2 95 96

-continued -continued

s 21 10

N /o n 15 21 OH,

H

n 25 2 N

30

N OCH, 'Co. 35

40

N CF, & C OCH3, . C s 45 N1 N NS U 50 C(O)OCH Sch, s

55

C C(O)OCH, 60

OH,

65

US 7,807,672 B2 99 100

-continued -continued CN CH

CH3,3 s 5

CH3 CH CH3 CEO 10 Na C(O)CC(CH3), s Cl, s 21 N N1 N HC HC 15 CH3 CH3 CH3 : : N YC(O)CH, N YC(O)CH, 2O Br, I, A N

O s 25

C - C-N O, C s Xc /C C(O)CH3, H | N \/ /N O

30

() (OOO s OCO , s Ns1. - O , N s X ( 35 C

O O N N /r 2 N 40 OlN C(O)CH3, CN , N1SN, N CN, W N N 2 21 NN 45 N CN, N N N

s s n n {N O {N O N N CH H 50 21 NC(O)H, 2 s

N O N r 21 vo A- 55 S-Ns. S F, O s 60 /O

ACH 65 Embodiment No. 81 is\ directed/ to a compound of any one O of Embodiment Nos. 1 to 78 wherein R' is selected from the group consisting of the R' groups in Embodiment No. 79, and US 7,807,672 B2 101 102 wherein R is selected from the group consisting of the R pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of any one groups in Embodiment No. 80 of Embodiment Nos. 1 to 89 and a pharmaceutically accept Embodiment No. 82 is directed to a compound of any one able carrier. of Embodiment Nos. 1 to 81 wherein R is selected from the Embodiment No. 100 is directed to a pharmaceutical com group consisting of H, ethyl, —CHOH, -CHOCH, position comprising an effective amount of a compound of —CHF, CF – CH-NH2, —CH2—C—CH2—NH, and any one of Embodiment Nos. 1 to 89 and a pharmaceutically —CH. acceptable carrier. Embodiment No. 83 is directed to a compound of any one Embodiment No. 101 is directed to a pharmaceutical com of Embodiment Nos. 1 to 81 wherein R is H. position comprising an effective amount of at least one com Embodiment No. 84 is directed to a compound selected 10 pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of from the group consisting of the final compounds of Embodiment No. 90 and a pharmaceutically acceptable car Examples 1-107, 109-110, 112-156,158-163, 166-170, 172 1. 179, 183-192, 194, and 196 to 228. Embodiment No. 102 is directed to a pharmaceutical com Embodiment No. 85 is directed to a compound selected position comprising an effective amount of one compound of from the group consisting of the final compounds of 15 Embodiment No. 90 and a pharmaceutically acceptable car Examples 1-10, 12-14, 18-65, 67-76, 78-98, 100-102, 104 1. 105, 107, 110, 112-114, 117-128, 130-131, 133, 134-136, Embodiment No. 103 is directed to a pharmaceutical com 138, 140, 141, 144, 147,148, 170, 183, 188, 189, 196-223, position of any one of Embodiment Nos. 91 to 102 further and 225-228. comprising an effective amount of at least one (e.g., 1, 2 or 3. Embodiment No. 86 is directed to a compound selected or 1 or 2, or 1, and usually 1) other active pharmaceutically from the group consisting of the final compounds of active ingredient. Examples 1-10, 14, 18-65, 67, 72-75, 78-80, 82-84, 86-95, Embodiment No. 104 is directed to a pharmaceutical com 97, 101, 102,104,107, 110, 117-131, 133-136, 138, 140,141, position of any one of Embodiment Nos. 91 to 102 further 144, 170, 183, 188, 189, 196-223, 225, and 228. comprising an effective amount of another (i.e., one other) Embodiment No. 87 is directed to a compound selected 25 pharmaceutically active ingredient. from the group consisting of the final compounds of Embodiment No. 105 is directed to a pharmaceutical com Examples 1, 19, 20, 23, 25, 119, 196, 197, and 212. position of any one of Embodiment Nos. 91 to 102 further Embodiment No. 88 is directed to a compound selected comprising an effective amount of at least one (e.g., 1, 2 or 3. from the group consisting of the final compounds of or 1 or 2, or 1, and usually 1) chemotherapeutic agent. Examples 1, 19, 20, 23, 25, 119, 196, 197, and 212. 30 Embodiment No. 106 is directed to a pharmaceutical com Embodiment No. 89 is directed to the compound of position of any one of Embodiment Nos. 91 to 102 further Example 25. comprising an effective amount of a chemotherapeutic agent. Embodiment No. 90 is directed to a compound of any one Embodiment No. 107 is directed to a method of treating of Embodiment Nos. 1 to 89 in pure and isolated form. cancer in a patient in need of Such treatment, said method Embodiment No. 91 is directed to a pharmaceutical com 35 comprising administering to said patient an effective amount position comprising an effective amount of at least one com of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula compound of formula 1.0 (preferably formula 1.0C). 1.0, preferably a compound of formula 1.0C, and a pharma Embodiment No. 108 is directed to a method of treating ceutically acceptable carrier. cancer in a patient in need of Such treatment, said method Embodiment No. 92 is directed to a pharmaceutical com 40 comprising administering to said patient an effective amount position comprising an effective amount of a compound of of one compound of formula 1.0 (preferably formula 1.0C). formula 1.0, preferably a compound of formula 1.0C, and a Embodiment No. 109 is directed to a method of treating pharmaceutically acceptable carrier. cancer in a patient in need of Such treatment, said method Embodiment No. 93 is directed to a pharmaceutical com comprising administering to said patient an effective amount position comprising an effective amount of at least one com 45 of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula compound of formula 1.1. 1.1, and a pharmaceutically acceptable carrier. Embodiment No. 110 is directed to a method of treating Embodiment No. 94 is directed to a pharmaceutical com cancer in a patient in need of Such treatment, said method position comprising an effective amount of a compound of comprising administering to said patient an effective amount formula 1.1 and a pharmaceutically acceptable carrier. 50 of one compound of formula 1.1. Embodiment No. 95 is directed to a pharmaceutical com Embodiment No. 111 is directed to a method of treating position comprising an effective amount of at least one com cancer in a patient in need of Such treatment, said method pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula comprising administering to said patient an effective amount 1.2, and a pharmaceutically acceptable carrier. 55 of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) Embodiment No. 96 is directed to a pharmaceutical com compound of formula 1.2. position comprising an effective amount of a compound of Embodiment No. 112 is directed to a method of treating formula 1.2 and a pharmaceutically acceptable carrier. cancer in a patient in need of Such treatment, said method Embodiment No. 97 is directed to a pharmaceutical com comprising administering to said patient an effective amount position comprising an effective amount of at least one com 60 of one compound of formula 1.2. pound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula Embodiment No. 113 is directed to a method of treating 1.3, and a pharmaceutically acceptable carrier. cancer in a patient in need of Such treatment, said method Embodiment No. 98 is directed to a pharmaceutical com comprising administering to said patient an effective amount position comprising an effective amount of a compound of of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) formula 1.3 and a pharmaceutically acceptable carrier. 65 compound of formula 1.3. Embodiment No. 99 is directed to a pharmaceutical com Embodiment No. 114 is directed to a method of treating position comprising an effective amount of at least one com cancer in a patient in need of Such treatment, said method US 7,807,672 B2 103 104 comprising administering to said patient an effective amount administering to said patient a therapeutically effective of one compound of formula 1.3. amount at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually Embodiment No. 115 is directed to a method of treating 1) compound of formula 1.0 (for example, as described in any cancer in a patient in need of Such treatment, said method one of Embodiment Nos. 1 to 90), and therapeutically effec comprising administering to said patient an effective amount 5 tive amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) 1) chemotherapeutic agent selected from the group consisting compound of any one of Embodiment Nos. 1 to 85. of: (1) taxanes, (2) platinum coordinator compounds, (3) Embodiment No. 116 is directed to a method of treating epidermal growth factor (EGF) inhibitors that are antibodies, cancer in a patient in need of Such treatment, said method (4) EGF inhibitors that are small molecules, (5) vascular comprising administering to said patient an effective amount 10 endolithial growth factor (VEGF) inhibitors that are antibod of a compound of any one of Embodiment Nos. 1 to 90. ies, (6) VEGF kinase inhibitors that are small molecules, (7) Embodiment No. 117 is directed to a method of treating estrogen receptor antagonists or selective estrogen receptor cancer in any one of Embodiment Nos. 107 to 116 further modulators (SERMs), (8) anti-tumor nucleoside derivatives, comprising the administration of an effective amount of at (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) chemothera 15 alkaloids, (12) antibodies that are inhibitors of CVB3 inte peutic agent. grins, (13) folate antagonists, (14) ribonucleotide reductase Embodiment No. 118 is directed to a method of treating inhibitors, (15) anthracyclines, (16) biologics: (17) inhibitors cancer in any one of Embodiment Nos. 107 to 116 further of angiogenesis and/or Suppressors of tumor necrosis factor comprising the administration of an effective amount of a alpha (TNF-alpha) such as thalidomide (or related imid), (18) chemotherapeutic agent. Bcr/ablkinase inhibitors, (19). MEK1 and/or MEK2 inhibi Embodiment No. 119 is directed to a method of treating tors that are small molecules, (20) IGF-1 and IGF-2 inhibitors cancer in a patient in need of Such treatment comprising that are small molecules, (21) small molecule inhibitors of administering to said patient an effective amount of a phar RAF and BRAF kinases, (22) small molecule inhibitors of maceutical composition of any one of Embodiment Nos. 91 to cell cycle dependent kinases such as CDK1, CDK2, CDK4 106. 25 and CDK6, (23) alkylating agents, and (24) farnesyl protein Embodiment No. 120 is directed to a method of treating transferase inhibitors (also know as FPT inhibitors or FTI cancer in a patient in need of Such treatment comprising (i.e., farnesyl transfer inhibitors)). administering to said patient an effective amount of a phar This invention also provides a method of treating cancer in maceutical composition of any one of Embodiment Nos. 91 to a patient in need of such treatment, said treatment comprising 102. 30 administering to said patient a therapeutically effective Embodiment No. 121 is directed to a method of treating amount at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually cancer in a patient in need of such treatment comprising 1) compound of formula 1.0 (for example, as described in any administering to said patient an effective amount of a phar one of Embodiment Nos. 1 to 90), and therapeutically effec maceutical composition of any one of Embodiment Nos. 91 to tive amounts of at least two (e.g., 2 or 3, or 2, and usually 2) 102, in combination with an effective amount of at least one 35 different antineoplastic agents selected from the group con (1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic sisting of: (1) taxanes, (2) platinum coordinator compounds, agent (3) epidermal growth factor (EGF) inhibitors that are antibod Embodiment No. 122 is directed to a method of treating ies, (4) EGF inhibitors that are small molecules, (5) vascular cancer in a patient in need of Such treatment comprising endolithial growth factor (VEGF) inhibitors that are antibod administering to said patient an effective amount of a phar 40 ies, (6) VEGF kinase inhibitors that are small molecules, (7) maceutical composition of any one of Embodiment Nos. 91 to estrogen receptor antagonists or selective estrogen receptor 102, in combination with an effective amount of one chemo modulators (SERMs), (8) anti-tumor nucleoside derivatives, therapeutic agent. (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca Embodiment No. 123 is directed to a method of treating alkaloids, (12) antibodies that are inhibitors of CVB3 inte cancer of any one of Embodiment Nos. 117, 118, 121 and 122 45 grins, (13) folate antagonists, (14) ribonucleotide reductase wherein the chemotherapeutic agent is selected from the inhibitors, (15) anthracyclines, (16) biologics: (17) inhibitors group consisting of paclitaxel, docetaxel, carboplatin, cispl of angiogenesis and/or Suppressors of tumor necrosis factor atin, gemcitabine, tamoxifen, Herceptin, Cetuximab, alpha (TNF-alpha) such as thalidomide (or related imid), (18) Tarceva, Iressa, bevacizumab, navelbine, IMC-1C11, Bcr/ablkinase inhibitors, (19). MEK1 and/or MEK2 inhibi SU5416 and SU6688. 50 tors that are small molecules, (20) IGF-1 and IGF-2 inhibitors Embodiment No. 124 is directed to a method of treating that are small molecules, (21) small molecule inhibitors of cancer of any one of Embodiment Nos. 117, 118, 121 and 122 RAF and BRAF kinases, (22) small molecule inhibitors of wherein the chemotherapeutic agent is selected from the cell cycle dependent kinases such as CDK1, CDK2, CDK4 group consisting of paclitaxel, docetaxel, carboplatin, cispl and CDK6, (23) alkylating agents, and (24) farnesyl protein atin, navelbine, gemcitabine, and Herceptin. 55 transferase inhibitors (also know as FPT inhibitors or FTI Embodiment No. 125 is directed to a method of treating (i.e., farnesyl transfer inhibitors)). cancer of any one of Embodiment Nos. 117, 118, 121 and 122 This invention also provides a method of treating cancer in wherein the chemotherapeutic agent is selected from the a patient in need of Such treatment, said method comprising group consisting of Cyclophasphamide, 5-Fluorouracil, administering to said patient therapeutically effective Temozolomide, Vincristine, Cisplatin, Carboplatin, and 60 amounts at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually Gemcitabine. 1) compound of formula 1.0 (for example, as described in any Embodiment No. 126 is directed to a method of treating one of Embodiment Nos. 1 to 90), and an antineoplastic agent cancer of any one of Embodiment Nos. 117, 118,121 and 122 selected from the group consisting of: (1) EGF inhibitors that wherein the chemotherapeutic agent is selected from the are antibodies, (2) EGF inhibitors that are small molecules, group consisting of Gemcitabine, Cisplatin and Carboplatin. 65 (3) VEGF inhibitors that are antibodies, and (4) VEGF inhibi This invention also provides a method of treating cancer in tors that are small molecules. Radiation therapy can also be a patient in need of such treatment, said treatment comprising used in conjunction with this above combination therapy, i.e., US 7,807,672 B2 105 106 the above method using a combination of compounds of the cally effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 invention and antineoplastic agent can also comprise the or 2, or 1, and usually 1) compound of formula 1.0 (for administration ofatherapeutically effect amount of radiation. example, as described in any one of Embodiment Nos. 1 to This invention also provides a method of treating leuke 90), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) mias (e.g., acute myeloid leukemia (AML), and chronic antineoplastic agent selected from the group consisting of: (1) myeloid leukemia (CML)) in a patient in need of such treat taxanes, (2) platinum coordinator compounds, (3) anti-tumor ment, said method comprising administering to said patient nucleoside derivatives, (4) topoisomerase inhibitors, and (5) therapeutically effective amounts at least one (e.g., 1, 2 or 3. Vinca alkaloids. or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for This invention also provides a method of treating non Small example, as described in any one of Embodiment Nos. 1 to 10 cell lung cancer in a patient in need of Such treatment, said 90), and: (1)Gleevec and interferonto treat CML; (2) Gleevec method comprising administering therapeutically effective and pegylated interferon to treat CML; (3) Gleevec to treat amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and CML; (4) an anti-tumor nucleoside derivative (e.g., Ara-C) to usually 1) compound of formula 1.0 (for example, as treat AML, or (5) an anti-tumor nucleoside derivative (e.g., described in any one of Embodiment Nos. 1 to 90), (b) car Ara-C) in combination with an anthracycline to treat AML. 15 boplatin, and (c) paclitaxel. This invention also provides a method of treating non This invention also provides a method of treating non Small Hodgkin’s lymphoma in a patient in need of Such treatment, cell lung cancer in a patient in need of Such treatment, said said method comprising administering therapeutically effec method comprising administering to said patient therapeuti tive amounts at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and cally effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 usually 1) compound of formula 1.0 (for example, as or 2, or 1, and usually 1) compound of formula 1.0 (for described in any one of Embodiment Nos. 1 to 90) and: (1) a example, as described in any one of Embodiment Nos. 1 to biologic (e.g., Rituxan); (2) a biologic (e.g., Rituxan) and an 90), (b) cisplatin, and (c) gemcitabine. anti-tumor nucleoside derivative (e.g., Fludarabine); or (3) This invention also provides a method of treating non Small Genasense (antisense to BCL-2). cell lung cancer in a patient in need of Such treatment, said This invention also provides a method of treating multiple 25 method comprising administering therapeutically effective myeloma in a patient in need of such treatment, said method amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and comprising administering to said patient therapeutically usually 1) compound of formula 1.0 (for example, as effective amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or described in any one of Embodiment Nos. 1 to 90), (b) car 1, and usually 1) compound of formula 1.0 (for example, as boplatin, and (c) gemcitabine. described in any one of Embodiment Nos. 1 to 90) and: (1) a 30 This invention also provides a method of treating non Small proteosome inhibitor (e.g., PS-341 from Millenium); or (2) cell lung cancer in a patient in need of Such treatment, said Thalidomide (or related imid). method comprising administering therapeutically effective This invention also provides a method of treating cancer in amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and a patient in need of Such treatment, said method comprising usually 1) compound of formula 1.0 (for example, as administering to said patient therapeutically effective 35 described in any one of Embodiment Nos. 1 to 90), (b) Car amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and boplatin, and (c) Docetaxel. usually 1) compound of formula 1.0 (for example, as This invention also provides a method of treating cancer in described in any one of Embodiment Nos. 1 to 90), and (b) at a patient in need of Such treatment, said method comprising least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic administering therapeutically effective amounts of: (a) at agent selected from the group consisting of: (1) taxanes, (2) 40 least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) platinum coordinator compounds, (3) EGF inhibitors that are compound of formula 1.0 (for example, as described in any antibodies, (4) EGF inhibitors that are small molecules, (5) one of Embodiment Nos. 1 to 90), and (b) an antineoplastic VEGF inhibitors that are antibodies, (6) VEGF kinase inhibi agent selected from the group consisting of: (1) EGF inhibi tors that are Small molecules, (7) estrogen receptor antago tors that are antibodies, (2) EGF inhibitors that are small nists or selective estrogen receptor modulators, (8) anti-tumor 45 molecules, (3) VEGF inhibitors that are antibodies, (4) VEGF nucleoside derivatives, (9) epothilones, (10) topoisomerase kinase inhibitors that are small molecules. This invention also inhibitors, (11) Vinca alkaloids, and (12) antibodies that are provides a method of treating squamous cell cancer of the inhibitors of CVB3 integrins. head and neck, in a patient in need of Such treatment, said This invention also provides a method of treating non Small method comprising administering to said patient therapeuti cell lung cancer in a patient in need of Such treatment, said 50 cally effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 method comprising administering to said patient therapeuti or 2, or 1, and usually 1) compound of formula 1.0 (for cally effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 example, as described in any one of Embodiment Nos. 1 to or 2, or 1, and usually 1) compound of formula 1.0 (for 90), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) example, as described in any one of Embodiment Nos. 1 to antineoplastic agent selected from the group consisting of: (1) 90), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) 55 taxanes, and (2) platinum coordinator compounds. antineoplastic agent selected from the group consisting of: (1) This invention also provides a method of treating squa taxanes, (2) platinum coordinator compounds, (3) EGF mous cell cancer of the head and neck, in a patient in need of inhibitors that are antibodies, (4) EGF inhibitors that are Such treatment, said method comprising administering to said small molecules, (5) VEGF inhibitors that are antibodies, (6) patient therapeutically effective amounts of: (a) at least one VEGF kinase inhibitors that are small molecules, (7) estrogen 60 (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of receptor antagonists or selective estrogen receptor modula formula 1.0 (for example, as described in any one of Embodi tors, (8) anti-tumor nucleoside derivatives, (9) epothilones, ment Nos. 1 to 90), and (b) at least one (e.g., 1, 2 or 3, or 1 or (10) topoisomerase inhibitors, (11) Vinca alkaloids, and (12) 2, or 2, or 1) antineoplastic agent selected from the group antibodies that are inhibitors of CVB3 integrins. consisting of: (1) taxanes, (2) platinum coordinator com This invention also provides a method of treating non Small 65 pounds, and (3) anti-tumor nucleoside derivatives (e.g., cell lung cancer in a patient in need of Such treatment, said 5-Fluorouracil). This invention also provides a method of method comprising administering to said patient therapeuti treating CML in a patient in need of Such treatment, said US 7,807,672 B2 107 108 method comprising administering therapeutically effective one of Embodiment Nos. 1 to 105), and (b) a proteosome amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and inhibitor (e.g., PS-341 (Millenium)). usually 1) compound of formula 1.0 (for example, as This invention also provides a method of treating multiple described in any one of Embodiment Nos. 1 to 90), (b) myeloma in a patient in need of Such treatment, said method Gleevec, and (c) interferon (e.g., Intron-A). 5 comprising administering to said patient therapeutically This invention also provides a method of treating CML in effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, a patient in need of Such treatment comprising administering or 1, and usually 1) compound of formula 1.0 (for example, as therapeutically effective amounts of: (a) at least one (e.g., 1, described in any one of Embodiment Nos. 1 to 90), and (b) 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 Thalidomide or related imid. (for example, as described in any one of Embodiment Nos. 1 10 This invention also provides a method of treating multiple to 90), (b) Gleevec; and (c) pegylated interferon (e.g., Peg myeloma in a patient in need of Such treatment, said method Intron, and Pegasys). comprising administering therapeutically effective amounts This invention also provides a method of treating CML in of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually a patient in need of Such treatment comprising administering 1) compound of formula 1.0 (for example, as described in any therapeutically effective amounts of: (a) at least one (e.g., 1, 15 one of Embodiment Nos. 1 to 90), and (b) Thalidomide. 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 This invention is also directed to the methods of treating (for example, as described in any one of Embodiment Nos. 1 cancer described herein, particularly those described above, to 90) and (b) Gleevec. wherein in addition to the administration of the compound of This invention also provides a method of treating CMML formula 1.0 (for example, as described in any one of Embodi in a patient in need of such treatment, said method comprising ment Nos. 1 to 90) and antineoplastic agents, radiation administering to said patient therapeutically effective therapy is also administered prior to, during, or after the amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and treatment cycle. usually 1) compound of formula 1.0 (for example, as This invention also provides a method for treating cancer described in any one of Embodiment Nos. 1 to 90). (e.g., lung cancer, prostate cancer and myeloid leukemias) in This invention also provides a method of treating AML in 25 a patient in need of Such treatment, said method comprising a patient in need of Such treatment, said method comprising administering to said patient (1) an effective amount of at administering to said patient therapeutically effective least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and compound of formula 1.0 (for example, as described in any usually 1) compound of formula 1.0 (for example, as one of Embodiment Nos. 1 to 90), in combination with (2) at described in any one of Embodiment Nos. 1 to 90), and (b) an 30 least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara agent, microtubule affecting agent and/or radiation therapy. C)). This invention also provides a method of treating cancer in This invention also provides a method of treating AML in a patient in need of Such treatment, said method comprising a patient in need of Such treatment, said method comprising administering to said patient an effective amount of at least administering to said patient therapeutically effective 35 one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and formula 1.0 (for example, as described in any one of Embodi usually 1) compound of formula 1.0 (for example, as ment Nos. 1 to 90) in combination with an effective amount of described in any one of Embodiment Nos. 1 to 90), (b) an at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) signal anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara transduction inhibitor. C)), and (c) an anthracycline. 40 Thus, in one example (e.g., treating non Small cell lung This invention also provides a method of treating non cancer): (1) the compound of formula 1.0 (for example, as Hodgkin’s lymphoma in a patient in need of Such treatment, described in any one of Embodiment Nos. 1 to 90) is admin said method comprising administering to said patient thera istered in an amount of about 50 mg to about 200 mg twice a peutically effective amounts of: (a) at least one (e.g., 1, 2 or 3. day, and in another example about 75 mg to about 125 mg or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for 45 administered twice a day, and in yet another example about example, as described in any one of Embodiment Nos. 1 to 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol.R. 90), and (b) Rituximab (Rituxan). is administered once per week in an amount of about 50 to This invention also provides a method of treating non about 100 mg/m, and in another example about 60 to about Hodgkin’s lymphoma in a patient in need of Such treatment, 80 mg/m, and (3) Carboplatin is administered once per week said method comprising administering to said patient thera 50 in an amount to provide an AUC of about 2 to about 3. peutically effective amounts of: (a) at least one (e.g., 1, 2 or 3. In another example (e.g., treating non Small cell lung can or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for cer): (1) the compound of formula 1.0 (for example, as example, as described in any one of Embodiment Nos. 1 to described in any one of Embodiment Nos. 1 to 90) is admin 90), (b) Rituximab (Rituxan), and (c) an anti-tumor nucleo istered in an amount of about 50 mg to about 200 mg twice a side derivative (e.g., Fludarabine (i.e., F-ara-A). 55 day, and in another example about 75 mg to about 125 mg This invention also provides a method of treating non administered twice a day, and yet in another example about Hodgkin’s lymphoma in a patient in need of Such treatment, 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol.R. said method comprising administering to said patient thera is administered once per week in an amount of about 50 to peutically effective amounts of: (a) at least one (e.g., 1, 2 or 3. about 100 mg/m, and in another example about 60 to about or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for 60 80 mg/m, and (3) Cisplatin is administered once per week in example, as described in any one of Embodiment Nos. 1 to an amount of about 20 to about 40 mg/m. 90), and (b) Genasense (antisense to BCL-2). In another example (e.g., treating non Small cell lung can This invention also provides a method of treating multiple cer): (1) the compound of formula 1.0 (for example, as myeloma in a patient in need of such treatment, said method described in any one of Embodiment Nos. 1 to 90) is admin comprising administering therapeutically effective amounts 65 istered in an amount of about 50 mg to about 200 mg twice a of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually day, and in another example about 75 mg to about 125 mg 1) compound of formula 1.0 (for example, as described in any administered twice a day, and in yet another example about US 7,807,672 B2 109 110 100 mg administered twice a day, (2) Docetaxel (e.g., Taxo 50 to about 100 mg/m, and (3) Cisplatin is administered once tereR) is administered once per week in an amount of about every three weeks in an amount of about 60 to about 100 10 to about 45 mg/m, and (3) Carboplatin is administered mg/m. once per week in an amount to provide an AUC of about 2 to In another example for treating non Small cell lung cancer about 3. using the compounds of formula 1.0, Docetaxel and Carbo In another example (e.g., treating non Small cell lung can platin: (1) the compound of formula 1.0 (for example, as cer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) is admin described in any one of Embodiment Nos. 1 to 90) is admin istered in an amount of about 50 mg to about 200 mg twice a istered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg day, and in another example about 75 mg to about 125 mg 10 administered twice a day, and in yet another example about administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., Taxo 100 mg administered twice a day, (2) Docetaxel (e.g., Taxo tere?R. is administered once every three weeks in an amount of tereR) is administered once per week in an amount of about about 75 mg/m, and (3) Carboplatin is administered once 10 to about 45 mg/m, and (3) Cisplatin is administered once every three weeks in an amount to provide an AUC of about 6. per week in an amount of about 20 to about 40 mg/m. 15 In another example of the treatments of non-Small cell lung In another example (e.g., treating non Small cell lung can cancer described above the Docetaxel (e.g., Taxotere?R) and cer): (1) the compound of formula 1.0 (for example, as Cisplatin, the Docetaxel (e.g., Taxotere?R) and Carboplatin, described in any one of Embodiment Nos. 1 to 90) is admin the Paclitaxel (e.g., Taxol.R) and Carboplatin, or the Pacli istered in an amount of about 50 mg to about 200 mg twice a taxel (e.g., Taxol.R and Cisplatin are administered on the day, and in another example about 75 mg to about 125 mg same day. administered twice a day, and in yet another example about In another example (e.g., CML): (1) the compound of 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol.R. formula 1.0 (for example, as described in any one of Embodi is administered once every three weeks in an amount of about ment Nos. 1 to 90) is administered in an amount of about 100 150 to about 250 mg/m, and in another example about 175 to mg to about 200 mg administered twice a day, (2) Gleevec is about 225 mg/m, and in yet anotherexample 175 mg/m, and 25 administered in an amount of about 400 to about 800 mg/day (3) Carboplatin is administered once every three weeks in an orally, and (3) interferon (Intron-A) is administered in an amount to provide an AUC of about 5 to about 8, and in amount of about 5 to about 20 million IU three times per another example 6. week. In another example of treating non Small cell lung cancer: In another example (e.g., CML): (1) the compound of (1) the compound of formula 1.0 (for example, as described in 30 formula 1.0 (for example, as described in any one of Embodi any one of Embodiment Nos. 1 to 90) is administered in an ment Nos. 1 to 90) is administered in an amount of about 100 amount of 100 mg administered twice a day, (2) Paclitaxel mg to about 200 mg administered twice a day, (2) Gleevec is (e.g., Taxol.R is administered once every three weeks in an administered in an amount of about 400 to about 800 mg/day amount of 175 mg/m, and (3) Carboplatin is administered orally, and (3) pegylated interferon (Peg-Intron or Pegasys) is once every three weeks in an amount to provide an AUC of 6. 35 administered in an amount of about 3 to about 6 micrograms/ In another example (e.g., treating non Small cell lung can kg/day. cer): (1) the compound of formula 1.0 (for example, as In another example (e.g., non-Hodgkin’s lymphoma): (1) described in any one of Embodiment Nos. 1 to 90) is admin the compound of formula 1.0 (for example, as described in istered in an amount of about 50 mg to about 200 mg twice a 40 any one of Embodiment Nos. 1 to 90) is administered in an day, and in another example about 75 mg to about 125 mg amount of about 50 mg to about 200 mg twice a day, and in administered twice a day, and in yet another example about another example about 75 mg to about 125 mg administered 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol.R. twice a day, and in yet another example about 100 mg admin is administered once every three weeks in an amount of about istered twice a day, and (2) Genasense (antisense to BCL-2) is 150 to about 250 mg/m, and in another example about 175 to administered as a continuous IV infusion at a dose of about 2 about 225 mg/m, and (3) Cisplatin is administered once 45 to about 5 mg/kg/day (e.g., 3 mg/kg/day) for 5 to 7 days every every three weeks in an amount of about 60 to about 100 3 to 4 weeks. mg/m. In another example (e.g., multiple myeloma): (1) the com In another example (e.g., treating non Small cell lung can pound of formula 1.0 (for example, as described in any one of cer): (1) the compound of formula 1.0 (for example, as 50 Embodiment Nos. 1 to 90) is administered in an amount of described in any one of Embodiment Nos. 1 to 90) is admin about 50 mg to about 200 mg twice a day, and in another istered in an amount of about 50 mg to about 200 mg twice a example about 75 mg to about 125 mg administered twice a day, and in another example about 75 mg to about 125 mg day, and in yet another example about 100 mg administered administered twice a day, and in yet another example about twice a day, and (2) the proteosome inhibitor (e.g., PS-341— 100 mg administered twice a day, (2) Docetaxel (e.g., Taxo 55 Millenium) is administered in an amount of about 1.5 mg/m tereR) is administered once every three weeks in an amount of twice weekly for two consecutive weeks with a one week rest about 50 to about 100 mg/m, and (3) Carboplatin is admin period. istered once every three weeks in an amount to provide an In another example (e.g., multiple myeloma): (1) the com AUC of about 5 to about 8. pound of formula 1.0 (for example, as described in any one of In another example (e.g., treating non Small cell lung can 60 Embodiment Nos. 1 to 90) is administered in an amount of cer): (1) the compound of formula 1.0 (for example, as about 50 mg to about 200 mg twice a day, and in another described in any one of Embodiment Nos. 1 to 90) is admin example about 75 mg to about 125 mg administered twice a istered in an amount of about 50 mg to about 200 mg twice a day, and in yet another example about 100 mg administered day, in another example about 75 mg to about 125 mg admin twice a day, and (2) the Thalidomide (or related imid) is istered twice a day, and in yet another example about 100 mg 65 administered orally in an amount of about 200 to about 800 administered twice a day, (2) Docetaxel (e.g., TaxotereR is mg/day, with dosing being continuous until relapse or toxic administered once every three weeks in an amount of about US 7,807,672 B2 111 112 In one embodiment of the methods of treating cancer of this week per cycle, wherein the treatment is given for one to four invention, the chemotherapeutic agents are selected from the weeks per cycle. In another embodiment said compound of group consisting of paclitaxel, docetaxel, carboplatin, cispl formula 1.0 is administered twice per day. In another embodi atin, gemcitabine, tamoxifen, Herceptin, Cetuximab, ment said carboplatin and said paclitaxel are administered on Tarceva, Iressa, bevacizumab, navelbine, IMC-1C11, the same day, and in another embodiment said carboplatin SU5416 and SU6688. and said paclitaxel are administered consecutively, and in In another embodiment of the methods of treating cancer of another embodiment said carboplatin is administered after this invention, the chemotherapeutic agents are selected from said paclitaxel. the group consisting of paclitaxel, docetaxel, carboplatin, Another embodiment of this invention is directed to a cisplatin, navelbine, gemcitabine, and Herceptin. 10 method for treating non Small cell lung cancer in a patient in Thus, one embodiment of this invention is directed to a need of Such treatment comprising administering daily a method of treating cancer comprising administering to a therapeutically effective amount of a compound of formula patient in need of such treatment therapeutically effective 1.0 (for example, as described in any one of Embodiment amounts of the compound of formula 1.0 (for example, as Nos. 1 to 90), administering a therapeutically effective described in any one of Embodiment Nos. 1 to 90), a taxane, 15 amount of carboplatin once every three weeks per cycle, and and a platinum coordination compound. administering atherapeutically effective amount of paclitaxel Another embodiment of this invention is directed to a once every three weeks per cycle, wherein the treatment is method of treating cancer comprising administering to a given for one to three weeks. In another embodiment com patient in need of such treatment therapeutically effective pound of formula 1.0 is administered twice per day. In another amounts of the compound of formula 1.0 (for example, as embodiment said carboplatin and said paclitaxel are admin described in any one of Embodiment Nos. 1 to 90), a taxane, istered on the same day, and in another embodiment said and a platinum coordination compound, wherein said com carboplatin and said paclitaxel are administered consecu pound of formula 1.0 is administered every day, said taxane is tively, and in another embodiment said carboplatin is admin administered once per week per cycle, and said platinum istered after said paclitaxel. coordinator compound is administered once per week per 25 Another embodiment of this invention is directed to a cycle. In another embodiment the treatment is for one to four method for treating non Small cell lung cancer in a patient in weeks per cycle. need of such treatment comprising administering about 50 to Another embodiment of this invention is directed to a about 200 mg of a compound of formula 1.0 (for example, as method of treating cancer comprising administering to a described in any one of Embodiment Nos.1 to 90) twice a day, patient in need of such treatment therapeutically effective 30 administering carboplatin once per week per cycle in an amounts of the compound of formula 1.0 (for example, as amount to provide an AUC of about 2 to about 8 (and in described in any one of Embodiment Nos. 1 to 90), a taxane, another embodiment about 2 to about 3), and administering and a platinum coordination compound, wherein said com once per week per cycle about 60 to about 300 mg/m (and in pound of formula 1.0 is administered every day, said taxane is another embodiment about 50 to 100 mg/m, and in yet administered once every three weeks per cycle, and said 35 another embodiment about 60 to about 80 mg/m) of pacli platinum coordinator compound is administered once every taxel, wherein the treatment is given for one to four weeks per three weeks per cycle. In another embodiment the treatment is cycle. In another embodiment said compound of formula 1.0 for one to three weeks per cycle. is administered in amount of about 75 to about 125 mg twice Another embodiment of this invention is directed to a a day, and in another embodiment about 100 mg twice a day. method of treating cancer comprising administering to a 40 In another embodiment said carboplatin and said paclitaxel patient in need of such treatment therapeutically effective are administered on the same day, and in another embodiment amounts of the compound of formula 1.0 (for example, as said carboplatin and said paclitaxel are administered con described in any one of Embodiment Nos. 1 to 90), paclitaxel, secutively, and in another embodiment said carboplatin is and carboplatin. In another embodiment, said compound of administered after said paclitaxel. formula 1.0 is administered every day, said paclitaxel is 45 In another embodiment, this invention is directed to a administered once per week per cycle, and said carboplatin is method for treating non Small cell lung cancer in a patient in administered once per week per cycle. In another embodi need of such treatment comprising administering about 50 to ment the treatment is for one to four weeks per cycle. about 200 mg of a compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos.1 to 90) twice a day, method of treating cancer comprising administering to a 50 administering carboplatin once every three weeks per cycle in patient in need of such treatment therapeutically effective an amount to provide an AUC of about 2 to about 8 (in another amounts of the compound of formula 1.0 (for example, as embodiment about 5 to about 8, and in another embodiment described in any one of Embodiment Nos. 1 to 90), paclitaxel, 6), and administering once every three weeks per cycle about and carboplatin. In another embodiment, said compound of 150 to about 250 mg/m (and in another embodiment about formula 1.0 is administered every day, said paclitaxel is 55 175 to about 225 mg/m, and in another embodiment 175 administered once every three weeks per cycle, and said mg/m) of paclitaxel, wherein the treatment is given for one to carboplatin is administered once every three weeks per cycle. three weeks. In another embodiment said compound of for In another embodiment the treatment is for one to three weeks mula 1.0 is administered in an amount of about 75 to about per cycle. 125 mg twice a day, and in another embodiment about 100 mg Another embodiment of this invention is directed to a 60 twice a day. In another embodiment said carboplatin and said method for treating non Small cell lung cancer in a patient in paclitaxel are administered on the same day, and in another need of Such treatment comprising administering daily a embodiment said carboplatin and said paclitaxel are admin therapeutically effective amount of the compound of formula istered consecutively, and in another embodiment said carbo 1.0 (for example, as described in any one of Embodiment platin is administered after said paclitaxel. Nos. 1 to 90), administering a therapeutically effective 65 Other embodiments of this invention are directed to meth amount of carboplatin once a week per cycle, and adminis ods of treating cancer as described in the above embodiments tering a therapeutically effective amount of paclitaxel once a (i.e., the embodiments directed to treating cancer and to treat US 7,807,672 B2 113 114 ing non Small cell lung cancer with a taxane and platinum Another embodiment of this invention is directed to a coordinator compound) except that in place of paclitaxel and method of treating cancer comprising administering to a carboplatin the taxanes and platinum coordinator compounds patient in need of such treatment therapeutically effective used together in the methods are: (1) docetaxel (TaxotereR) amounts of a compound of formula 1.0 (for example, as and cisplatin; (2) paclitaxel and cisplatin; and (3) docetaxel 5 described in any one of Embodiment Nos. 1 to 90), an anti and carboplatin. In another embodiment of the methods of tumor nucleoside derivative, and a platinum coordination this invention cisplatin is used in amounts of about 30 to about compound, wherein said compound of formula 1.0 is admin 100 mg/m. In the another embodiment of the methods of this istered every day, said anti-tumor nucleoside derivative is invention docetaxel is used in amounts of about 30 to about administered once per week per cycle, and said platinum 100 mg/m. 10 coordinator compound is administered once per week per In another embodiment this invention is directed to a cycle. Although the treatment can be for one to four weeks per method of treating cancer comprising administering to a cycle, in one embodiment the treatment is for one to seven patient in need of such treatment therapeutically effective weeks per cycle. amounts of a compound of formula 1.0 (for example, as 15 Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), a taxane, method of treating cancer comprising administering to a and an EGF inhibitor that is an antibody. In another embodi patient in need of such treatment therapeutically effective ment the taxane used is paclitaxel, and the EGF inhibitor is a HER2 antibody (in one embodiment Herceptin) or Cetux amounts of a compound of formula 1.0 (for example, as imab, and in another embodiment Herceptin is used. The described in any one of Embodiment Nos. 1 to 90), an anti length of treatment, and the amounts and administration of tumor nucleoside derivative, and a platinum coordination said compound of formula 1.0 and the taxane areas described compound, wherein said compound of formula 1.0 is admin in the embodiments above. The EGF inhibitor that is an istered every day, said an anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum antibody is administered once a week per cycle, and in coordinator compound is administered once every three another embodiment is administered on the same day as the 25 taxane, and in another embodiment is administered consecu weeks per cycle. Although the treatment can be for one to four tively with the taxane. For example, Herceptin is adminis weeks per cycle, in one embodiment the treatment is for one tered in aloading dose of about 3 to about 5 mg/m (in another to seven weeks per cycle. embodiment about 4 mg/m), and then is administered in a Another embodiment of this invention is directed to a maintenance dose of about 2 mg/m once per week per cycle method of treating cancer comprising administering to a for the remainder of the treatment cycle (usually the cycle is 30 patient in need of such treatment therapeutically effective 1 to 4 weeks). In one embodiment the cancer treated is breast amounts of a compound of formula 1.0 (for example, as CaCC. described in any one of Embodiment Nos. 1 to 90), gemcit In another embodiment this invention is directed to a abine, and cisplatin. In another embodiment, said compound of formula 1.0 is administered every day, said gemcitabine is method of treating cancer comprising administering to a 35 patient in need of such treatment therapeutically effective administered once per week per cycle, and said cisplatin is amounts of: (1) a compound of formula 1.0 (for example, as administered once per week per cycle. In one embodiment the described in any one of Embodiment Nos. 1 to 90), (2) a treatment is for one to seven weeks per cycle. taxane, and (3) an antineoplastic agent selected from the Another embodiment of this invention is directed to a group consisting of: (a) an EGF inhibitor that is a small 40 method of treating cancer comprising administering to a molecule, (b) a VEGF inhibitor that is an antibody, and (c) a patient in need of such treatment therapeutically effective VEGF kinase inhibitor that is a small molecule. In another amounts of a compound of formula 1.0 (for example, as embodiment, the taxane paclitaxel or docetaxel is used. In described in any one of Embodiment Nos. 1 to 90), gemcit another embodiment the antineoplastic agent is selected from abine, and cisplatin. In another embodiment, said compound the group consisting of tarceva, Iressa, bevacizumab, 45 of formula 1.0 is administered every day, said gemcitabine is SU5416, SU6688 and BAY 43-9006. The length of treatment, administered once per week per cycle, and said cisplatin is and the amounts and administration of said compound of administered once every three weeks per cycle. In another formula 1.0 and the taxane are as described in the embodi embodiment the treatment is for one to seven weeks. ments above. The VEGF kinase inhibitor that is an antibody is Another embodiment of this invention is directed to a usually given once per week per cycle. The EGF and VEGF 50 method of treating cancer comprising administering to a inhibitors that are small molecules are usually given daily per patient in need of such treatment therapeutically effective cycle. In another embodiment, the VEGF inhibitor that is an amounts of a compound of formula 1.0 (for example, as antibody is given on the same day as the taxane, and in another described in any one of Embodiment Nos. 1 to 90), gemcit embodiment is administered concurrently with the taxane. In abine, and carboplatin. In another embodiment said com another embodiment, when the EGF inhibitor that is a small 55 pound of formula 1.0 is administered every day, said gemcit molecule or the VEGF inhibitor that is a small molecule is abine is administered once per week per cycle, and said administered on the same day as the taxane, the administra carboplatin is administered once per week per cycle. In tion is concurrently with the taxane. The EGF or VEGF another embodiment the treatment is for one to seven weeks kinase inhibitor is generally administered in an amount of per cycle. about 10 to about 500 mg/m. 60 Another embodiment of this invention is directed to a In another embodiment this invention is directed to a method of treating cancer comprising administering to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), gemcit described in any one of Embodiment Nos. 1 to 90), an anti 65 abine, and carboplatin. In another embodiment said com tumor nucleoside derivative, and a platinum coordination pound of formula 1.0 is administered every day, said gemcit compound. abine is administered once per week per cycle, and said US 7,807,672 B2 115 116 carboplatin is administered once every three weeks per cycle. tration. Preferably the pharmaceutically acceptable carrier is In another embodiment the treatment is for one to seven an isotonic saline solution (0.9% NaCl) or a dextrose solution weeks per cycle. (e.g., 5% dextrose). In the above embodiments using gemcitabine, the com Other embodiments of this invention are directed to the use of a combination of at least one (e.g., one) compound of pound of formula 1.0 (for example, as described in any one of 5 formula 1.0 (for example, as described in any one of Embodi Embodiment Nos. 1 to 90) and the platinum coordinator ment Nos. 1 to 90) and drugs for the treatment of breast compound are administered as described above for the cancer, i.e., this invention is directed to a combination therapy embodiments using taxanes. Gemcitabine is administered in for the treatment of breast cancer. Those skilled in the art will an amount of about 500 to about 1250 mg/m. In one embodi 10 appreciate that the compounds of formula 1.0 and drugs are ment the gemcitabine is administered on the same day as the generally administered as individual pharmaceutical compo platinum coordinator compound, and in another embodiment sitions. The use of a pharmaceutical composition comprising consecutively with the platinum coordinator compound, and more than one drug is within the scope of this invention. in another embodiment the gemcitabine is administered after Thus, another embodiment of this invention is directed to a the platinum coordinator compound. 15 method of treating (or preventing) breast cancer (i.e., post Another embodiment of this invention is directed to a menopausal and premenopausal breast cancer, e.g., hormone method of treating cancer in a patient in need of Such treat dependent breast cancer) inapatient in need of such treatment ment comprising administering to said patient a compound of comprising administering to said patient a therapeutically formula 1.0 (for example, as described in any one of Embodi effective amount of at least one (e.g., one) compound of ment Nos. 1 to 90) and an antineoplastic agent selected from: formula 1.0 (for example, as described in any one of Embodi (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that ment Nos. 1 to 90) and a therapeutically effective amount of are small molecules, (3) VEGF inhibitors that are antibodies, at least one antihormonal agent selected from the group con and (4) VEGF kinase inhibitors that are small molecules all as sisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) described above. The treatment is for one to seven weeks per LHRH analogues; and said treatment optionally including the cycle, and generally for one to four weeks per cycle. The 25 administration of at least one chemotherapeutic agent. compound of formula 1.0 is administered in the same manner The compound of formula 1.0 is preferably administered as described above for the other embodiments of this inven orally, and in one embodiment is administered in capsule tion. The Small molecule antineoplastic agents are usually form. administered daily, and the antibody antineoplastic agents are Examples of aromatase inhibitors include but are not lim usually administered once per week per cycle. In one embodi 30 ited to: Anastrozole (e.g., Arimidex), Letrozole (e.g., ment the antineoplastic agents are selected from the group Femara), Exemestane (Aromasin), Fadrozole and Formes consisting of Herceptin, Cetuximab, Tarceva, Iressa, bevaci tane (e.g., Lentaron). Zumab, IMC-1C11, SU5416, SU6688 and BAY 43-9006. Examples of antiestrogens include but are not limited to: In the embodiments of this invention wherein a platinum Tamoxifen (e.g., Nolvadex), Fulvestrant (e.g., Faslodex), coordinator compound is used as well as at least one other 35 Raloxifene (e.g., Evista), and Acolbifene. antineoplastic agent, and these drugs are administered con Examples of LHRH analogues include but are not limited secutively, the platinum coordinator compound is generally to: Goserelin (e.g., Zoladex) and Leuprolide (e.g., Leuprolide administered after the other antineoplastic agents have been Acetate. Such as Lupron or Lupron Depot). administered. Examples of chemotherapeutic agents include but are not Other embodiments of this invention include the adminis 40 limited to: Trastuzumab (e.g., Herceptin), Gefitinib (e.g., tration ofatherapeutically effective amount of radiation to the Iressa), Erlotinib (e.g., Erlotinib HCl, such as Tarceva), Beva patient in addition to the administration of a compound of cizumab (e.g., Avastin), Cetuximab (e.g., ErbituX), and Bort formula 1.0 (for example, as described in any one of Embodi eZomib (e.g., Velcade). ment Nos. 1 to 90) and antineoplastic agents in the embodi Preferably, when more than one antihormonal agent is ments described above. Radiation is administered according 45 used, eachagentis selected from a different category of agent. to techniques and protocols well know to those skilled in the For example, one agent is an aromatase inhibitor (e.g., Anas trozole, Letrozole, or Exemestane) and one agent is an anti art. estrogen (e.g., Tamoxifen or Fulvestrant). Another embodiment of this invention is directed to a phar Another embodiment of this invention is directed to a maceutical composition comprising at least two different 50 method of treating or preventing breast cancer in a patient in chemotherapeutic agents and a pharmaceutically acceptable need of Such treatment wherein said treatment comprises carrier for intravenous administration. Preferably the phar administering a therapeutically effective amount of at least maceutically acceptable carrier is an isotonic saline Solution one (e.g., one) compound of formula 1.0 (for example, as (0.9% NaCl) or a dextrose solution (e.g., 5% dextrose). described in any one of Embodiment Nos. 1 to 90) and at least Another embodiment of this invention is directed to a phar 55 one antihormonal agent selected from the group consisting maceutical composition comprising a compound of formula of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH 1.0 (for example, as described in any one of Embodiment analogues; and administering an effective amount of at least Nos. 1 to 90)) and at least two different antineoplastic agents one chemotherapeutic agent. and a pharmaceutically acceptable carrier for intravenous Another embodiment of this invention is directed to a administration. Preferably the pharmaceutically acceptable 60 method of treating or preventing breast cancer in a patient in carrier is an isotonic saline solution (0.9% NaCl) or a dextrose need of Such treatment wherein said treatment comprises Solution (e.g., 5% dextrose). administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a phar one (e.g., one) compound of formula 1.0 (for example, as maceutical composition comprising a compound of formula described in any one of Embodiment Nos. 1 to 90) and at least 1.0 (for example, as described in any one of Embodiment 65 one antihormonal agent selected from the group consisting Nos. 1 to 90) and at least one antineoplastic agent and a of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH pharmaceutically acceptable carrier for intravenous adminis analogues. US 7,807,672 B2 117 118 Another embodiment of this invention is directed to a as described in any one of Embodiment Nos. 1 to 90); and (2) method of treating or preventing breast cancer in a patient in at least one antihormonal agent selected from the group con need of Such treatment wherein said treatment comprises sisting of: (a) aromatase inhibitors that are selected from the administering a therapeutically effective amount of at least group consisting of AnastroZole, Letrozole, Exemestane, one (e.g., one) compound of formula 1.0 (for example, as Fadrozole and Formestane, and (b) antiestrogens that are described in any one of Embodiment Nos. 1 to 90) and at least selected from the group consisting of Tamoxifen, Fulves one antihormonal agent selected from the group consisting trant, Raloxifene, and Acolbifene. of: (a) aromatase inhibitors, and (b) antiestrogens. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in 10 need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at administering a therapeutically effective amount of at least least one (e.g., one) compound of formula 1.0 (for example, one (e.g., one) compound of formula 1.0 (for example, as as described in any one of Embodiment Nos. 1 to 90); and (2) described in any one of Embodiment Nos.1 to 90), at least one at least one antihormonal agent selected from the group con antihormonal agent selected from the group consisting of: (a) 15 sisting of: (a) aromatase inhibitors that are selected from the aromatase inhibitors and (b) antiestrogens; and at least one group consisting of AnastroZole, Letrozole, Exemestane, chemotherapeutic agent. Fadrozole and Formestane, (b) antiestrogens that are selected Another embodiment of this invention is directed to a from the group consisting of Tamoxifen, Fulvestrant, Ralox method of treating or preventing breast cancer in a patient in ifene, and Acolbifene; and administering an effective amount need of Such treatment wherein said treatment comprises of at least one chemotherapeutic agents are selected from the administering a therapeutically effective amount of at least group consisting of Trastuzumab, Gefitinib, Erlotinib, Beva one (e.g., one) compound of formula 1.0 (for example, as cizumab, Cetuximab, and Bortezomib. described in any one of Embodiment Nos. 1 to 90) and at least Another embodiment of this invention is directed to a one aromatase inhibitor. method of treating or preventing breast cancer in a patient in Another embodiment of this invention is directed to a 25 need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of: (1) at need of Such treatment wherein said treatment comprises least one (e.g., one) compound of formula 1.0 (for example, administering a therapeutically effective amount of at least as described in any one of Embodiment Nos. 1 to 90); and (2) one (e.g., one) compound of formula 1.0 (for example, as at least one aromatase inhibitor selected from the group con described in any one of Embodiment Nos.1 to 90), at least one 30 sisting of AnastroZole, Letrozole, Exemestane, Fadrozole and aromatase inhibitor, and at least one chemotherapeutic agent. Formestane. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at 35 administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90); and (2) as described in any one of Embodiment Nos. 1 to 90); (2) at at least one antihormonal agent selected from the group con least one aromatase inhibitor that is selected from the group sisting of: (a) aromatase inhibitors that are selected from the consisting of AnastroZole, Letrozole, Exemestane, Fadrozole group consisting of Anastrozole, Letrozole, Exemestane, 40 and Formestane; and (3) administering an effective amount of Fadrozole and Formestane, (b) antiestrogens that are selected at least one chemotherapeutic agent selected from the group from the group consisting of Tamoxifen, Fulvestrant, Ralox consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci ifene, and Acolbifene, and (c) LHRH analogues that are Zumab, Cetuximab, and Bortezomib. selected from the group consisting of Goserelin and Leupro Another embodiment of this invention is directed to a lide; and administering an effective amount of at least one 45 chemotherapeutic agent selected from the group consisting method of treating or preventing breast cancer in a patient in of Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetux need of Such treatment wherein said treatment comprises imab, and Bortezomib. administering a therapeutically effective amount of: (1) at Another embodiment of this invention is directed to a least one (e.g., one) compound of formula 1.0 (for example, method of treating or preventing breast cancer in a patient in 50 as described in any one of Embodiment Nos. 1 to 90); (2) at need of Such treatment wherein said treatment comprises least one aromatase inhibitor; and (3) at least one LHRH administering a therapeutically effective amount of: (1) at analogue. least one (e.g., one) compound of formula 1.0 (for example, Another embodiment of this invention is directed to a as described in any one of Embodiment Nos. 1 to 90); and (2) method of treating or preventing breast cancer in a patient in at least one antihormonal agent selected from the group con 55 need of Such treatment wherein said treatment comprises sisting of: (a) aromatase inhibitors that are selected from the administering a therapeutically effective amount of: (1) at group consisting of Anastrozole, Letrozole, Exemestane, least one (e.g., one) compound of formula 1.0 (for example, Fadrozole and Formestane, (b) antiestrogens that are selected as described in any one of Embodiment Nos. 1 to 90); (2) at from the group consisting of Tamoxifen, Fulvestrant, Ralox least one antiestrogen; and (3) at least one LHRH analogue. ifene, and Acolbifene, and (c) LHRH analogues that are 60 Another embodiment of this invention is directed to a selected from the group consisting of Goserelin and Leupro method of treating or preventing breast cancer in a patient in lide. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of: (1) at method of treating or preventing breast cancer in a patient in least one (e.g., one) compound of formula 1.0 (for example, need of Such treatment wherein said treatment comprises 65 as described in any one of Embodiment Nos. 1 to 90); (2) at administering a therapeutically effective amount of: (1) at least one aromatase inhibitor that is selected from the group least one (e.g., one) compound of formula 1.0 (for example, consisting of AnastroZole, Letrozole, Exemestane, Fadrozole US 7,807,672 B2 119 120 and Formestane; and (3) at least one LHRH analogue that is one (e.g., one) compound of formula 1.0 (for example, as selected from the group consisting of Goserelin and Leupro described in any one of Embodiment Nos. 1 to 90) and Ral lide. oxifene. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in 5 method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at administering a therapeutically effective amount of at least least one (e.g., one) compound of formula 1.0 (for example, one (e.g., one) compound of formula 1.0 (for example, as as described in any one of Embodiment Nos. 1 to 90); (2) at described in any one of Embodiment Nos. 1 to 90) and Acol least one antiestrogen that is selected from the group consist 10 bifene. ing of Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene: Another embodiment of this invention is directed to a and (3) at least one LHRH analogue that is selected from the method of treating or preventing breast cancer in a patient in group consisting of Goserelin and Leuprolide. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in 15 one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90) and Gos administering a therapeutically effective amount of at least erelin. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90) and Anas method of treating or preventing breast cancer in a patient in trozole. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90) and Leu administering a therapeutically effective amount of at least prolide. one (e.g., one) compound of formula 1.0 (for example, as 25 Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90) and Letra method of treating or preventing breast cancer in a patient in Zole. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises 30 described in any one of Embodiment Nos. 1 to 90), Anastro administering a therapeutically effective amount of at least Zole, and an antiestrogen selected from the group consisting one (e.g., one) compound of formula 1.0 (for example, as of Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. described in any one of Embodiment Nos. 1 to 90) and Another embodiment of this invention is directed to a Exemestane. method of treating or preventing breast cancer in a patient in Another embodiment of this invention is directed to a 35 need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises one (e.g., one) compound of formula 1.0 (for example, as administering a therapeutically effective amount of at least described in any one of Embodiment Nos. 1 to 90), Letrozole, one (e.g., one) compound of formula 1.0 (for example, as and an antiestrogen selected from the group consisting of 40 Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. described in any one of Embodiment Nos. 1 to 90) and Fadro Another embodiment of this invention is directed to a Zole. method of treating or preventing breast cancer in a patient in Another embodiment of this invention is directed to a need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises 45 one (e.g., one) compound of formula 1.0 (for example, as administering a therapeutically effective amount of at least described in any one of Embodiment Nos. 1 to 90), Exemes one (e.g., one) compound of formula 1.0 (for example, as tane, and an antiestrogen selected from the group consisting described in any one of Embodiment Nos. 1 to 90) and Form of Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. eStane. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a 50 method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), Fadrozole, described in any one of Embodiment Nos. 1 to 90) and 55 and an antiestrogen selected from the group consisting of Tamoxifen. Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least 60 administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) Fulves described in any one of Embodiment Nos. 1 to 90), Formes trant. tane, and an antiestrogen selected from the group consisting Another embodiment of this invention is directed to a of Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. method of treating or preventing breast cancer in a patient in 65 Another embodiment of this invention is directed to a need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises US 7,807,672 B2 121 122 administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Anastro need of Such treatment wherein said treatment comprises Zole, and Tamoxifen. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Anastro need of Such treatment wherein said treatment comprises Zole, and a chemotherapeutic agent selected from the group administering a therapeutically effective amount of at least consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci one (e.g., one) compound of formula 1.0 (for example, as Zumab, Cetuximab, and Bortezomib. described in any one of Embodiment Nos. 1 to 90), Letrozole, 10 Another embodiment of this invention is directed to a and Tamoxifen. method of treating or preventing breast cancer in a patient in Another embodiment of this invention is directed to a need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises one (e.g., one) compound of formula 1.0 (for example, as administering a therapeutically effective amount of at least 15 described in any one of Embodiment Nos. 1 to 90), Letrozole, one (e.g., one) compound of formula 1.0 (for example, as and a chemotherapeutic agent selected from the group con described in any one of Embodiment Nos. 1 to 90), Exemes sisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, tane, and Tamoxifen. Cetuximab, and Bortezomib. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), Fadrozole, described in any one of Embodiment Nos. 1 to 90), Exemes and Tamoxifen. 25 tane, and a chemotherapeutic agent selected from the group Another embodiment of this invention is directed to a consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci method of treating or preventing breast cancer in a patient in Zumab, Cetuximab, and Bortezomib. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as 30 need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Formes administering a therapeutically effective amount of at least tane, and Tamoxifen. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Fadrozole, method of treating or preventing breast cancer in a patient in and a chemotherapeutic agent selected from the group con need of Such treatment wherein said treatment comprises 35 sisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, administering a therapeutically effective amount of at least Cetuximab, and Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Anastro method of treating or preventing breast cancer in a patient in Zole, and Fulvestrant. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a 40 administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Formes administering a therapeutically effective amount of at least tane, and a chemotherapeutic agent selected from the group one (e.g., one) compound of formula 1.0 (for example, as consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci described in any one of Embodiment Nos. 1 to 90), Letrozole, 45 Zumab, Cetuximab, and Bortezomib. and Fulvestrant. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least administering a therapeutically effective amount of at least 50 one (e.g., one) compound of formula 1.0 (for example, as one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), Tamox described in any one of Embodiment Nos. 1 to 90), Exemes ifen, and a chemotherapeutic agent selected from the group tane, and Fulvestrant. consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci Another embodiment of this invention is directed to a Zumab, Cetuximab, and Bortezomib. method of treating or preventing breast cancer in a patient in 55 Another embodiment of this invention is directed to a need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises one (e.g., one) compound of formula 1.0 (for example, as administering a therapeutically effective amount of at least described in any one of Embodiment Nos. 1 to 90), Fadrozole, one (e.g., one) compound of formula 1.0 (for example, as and Fulvestrant. 60 described in any one of Embodiment Nos. 1 to 90), Fulves Another embodiment of this invention is directed to a trant, and a chemotherapeutic agent selected from the group method of treating or preventing breast cancer in a patient in consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci need of Such treatment wherein said treatment comprises Zumab, Cetuximab, and Bortezomib. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as 65 method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Formes need of Such treatment wherein said treatment comprises tane, and Fulvestrant. administering a therapeutically effective amount of at least US 7,807,672 B2 123 124 one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Ralox administering a therapeutically effective amount of at least ifene, and a chemotherapeutic agent selected from the group one (e.g., one) compound of formula 1.0 (for example, as consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci described in any one of Embodiment Nos. 1 to 90), Fadrozole, Zumab, Cetuximab, and Bortezomib. an antiestrogen selected from the group consisting of Tamox Another embodiment of this invention is directed to a ifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemo method of treating or preventing breast cancer in a patient in therapeutic agent selected from the group consisting of Tras need of Such treatment wherein said treatment comprises tuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and administering a therapeutically effective amount of at least Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as 10 Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Acolb method of treating or preventing breast cancer in a patient in ifene, and a chemotherapeutic agent selected from the group need of Such treatment wherein said treatment comprises consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci administering a therapeutically effective amount of at least Zumab, Cetuximab, and Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a 15 described in any one of Embodiment Nos. 1 to 90), Formes method of treating or preventing breast cancer in a patient in tane, an antiestrogen selected from the group consisting of need of Such treatment wherein said treatment comprises Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a administering a therapeutically effective amount of at least chemotherapeutic agent selected from the group consisting one (e.g., one) compound of formula 1.0 (for example, as of Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetux described in any one of Embodiment Nos. 1 to 90), Goserelin, imab, and Bortezomib. and a chemotherapeutic agent selected from the group con Another embodiment of this invention is directed to a sisting of Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, method of treating or preventing breast cancer in a patient in Cetuximab, and Bortezomib. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in 25 one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Anastro administering a therapeutically effective amount of at least Zole, Tamoxifen, and a chemotherapeutic agent selected from one (e.g., one) compound of formula 1.0 (for example, as the group consisting of Trastuzumab, Gefitinib, Erlotinib, described in any one of Embodiment Nos. 1 to 90), Leupro Bevacizumab, Cetuximab, and Bortezomib. lein, and a chemotherapeutic agent selected from the group 30 Another embodiment of this invention is directed to a consisting of Trastuzumab, Gefitinib, Erlotinib, Bevaci method of treating or preventing breast cancer in a patient in Zumab, Cetuximab, and Bortezomib. need of such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises 35 described in any one of Embodiment Nos. 1 to 90), Letrozole, administering a therapeutically effective amount of at least Tamoxifen, and a chemotherapeutic agent selected from the one (e.g., one) compound of formula 1.0 (for example, as group consisting of Trastuzumab, Gefitinib, Erlotinib, Beva described in any one of Embodiment Nos. 1 to 90), Anastro cizumab, Cetuximab, and Bortezomib. Zole, an antiestrogen selected from the group consisting of Another embodiment of this invention is directed to a Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a 40 method of treating or preventing breast cancer in a patient in chemotherapeutic agent selected from the group consisting need of Such treatment wherein said treatment comprises of Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetux administering a therapeutically effective amount of at least imab, and Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Exemes method of treating or preventing breast cancer in a patient in 45 tane, Tamoxifen, and a chemotherapeutic agent selected from need of Such treatment wherein said treatment comprises the group consisting of Trastuzumab, Gefitinib, Erlotinib, administering a therapeutically effective amount of at least Bevacizumab, Cetuximab, and Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Letrozole, method of treating or preventing breast cancer in a patient in an antiestrogen selected from the group consisting of Tamox 50 need of Such treatment wherein said treatment comprises ifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemo administering a therapeutically effective amount of at least therapeutic agent selected from the group consisting of Tras one (e.g., one) compound of formula 1.0 (for example, as tuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and described in any one of Embodiment Nos. 1 to 90), Fadrozole, Bortezomib. Tamoxifen, and a chemotherapeutic agent selected from the Another embodiment of this invention is directed to a 55 group consisting of Trastuzumab, Gefitinib, Erlotinib, Beva method of treating or preventing breast cancer in a patient in cizumab, Cetuximab, and Bortezomib. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Exemes 60 administering a therapeutically effective amount of at least tane, an antiestrogen selected from the group consisting of one (e.g., one) compound of formula 1.0 (for example, as Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a described in any one of Embodiment Nos. 1 to 90), Formes chemotherapeutic agent selected from the group consisting tane, Tamoxifen, and a chemotherapeutic agent selected from of Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetux the group consisting of Trastuzumab, Gefitinib, Erlotinib, imab, and Bortezomib. 65 Bevacizumab, Cetuximab, and Bortezomib. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in US 7,807,672 B2 125 126 need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), Goserelin described in any one of Embodiment Nos. 1 to 90), Anastro and Acolbifene. Zole, Fulvestrant, and a chemotherapeutic agent selected 5 Another embodiment of this invention is directed to a from the group consisting of Trastuzumab, Gefitinib, Erlo method of treating or preventing breast cancer in a patient in tinib, Bevacizumab, Cetuximab, and Bortezomib. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises 10 described in any one of Embodiment Nos. 1 to 90), Leupro administering a therapeutically effective amount of at least lide, and Tamoxifen. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Letrozole, method of treating or preventing breast cancer in a patient in Fulvestrant, and a chemotherapeutic agent selected from the need of Such treatment wherein said treatment comprises group consisting of Trastuzumab, Gefitinib, Erlotinib, Beva 15 administering a therapeutically effective amount of at least cizumab, Cetuximab, and Bortezomib. one (e.g., one) compound of formula 1.0 (for example, as Another embodiment of this invention is directed to a described in any one of Embodiment Nos. 1 to 90), Leupro method of treating or preventing breast cancer in a patient in lide, and Fulvestrant. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to a administering a therapeutically effective amount of at least method of treating or preventing breast cancer in a patient in one (e.g., one) compound of formula 1.0 (for example, as need of Such treatment wherein said treatment comprises described in any one of Embodiment Nos. 1 to 90), Exemes administering a therapeutically effective amount of at least tane, Fulvestrant, and a chemotherapeutic agent selected one (e.g., one) compound of formula 1.0 (for example, as from the group consisting of Trastuzumab, Gefitinib, Erlo described in any one of Embodiment Nos. 1 to 90), Leupro tinib, Bevacizumab, Cetuximab, and Bortezomib. 25 lide, and Raloxifene. Another embodiment of this invention is directed to a Another embodiment of this invention is directed to a method of treating or preventing breast cancer in a patient in method of treating or preventing breast cancer in a patient in need of Such treatment wherein said treatment comprises need of Such treatment wherein said treatment comprises administering a therapeutically effective amount of at least administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as 30 one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), Fadrozole, described in any one of Embodiment Nos. 1 to 90), Leupro Fulvestrant, and a chemotherapeutic agent selected from the lide and Acolbifene. group consisting of Trastuzumab, Gefitinib, Erlotinib, Beva Another embodiment of this invention is directed to a cizumab, Cetuximab, and Bortezomib. method of treating or preventing breast cancer in a patient in Another embodiment of this invention is directed to a 35 need of Such treatment wherein said treatment comprises method of treating or preventing breast cancer in a patient in administering a therapeutically effective amount of at least need of Such treatment wherein said treatment comprises one (e.g., one) compound of formula 1.0 (for example, as administering a therapeutically effective amount of at least described in any one of Embodiment Nos. 1 to 90), Goserelin one (e.g., one) compound of formula 1.0 (for example, as and AnastroZole. described in any one of Embodiment Nos. 1 to 90), Formes 40 Another embodiment of this invention is directed to a tane, Fulvestrant, and a chemotherapeutic agent selected method of treating or preventing breast cancer in a patient in from the group consisting of Trastuzumab, Gefitinib, Erlo need of Such treatment wherein said treatment comprises tinib, Bevacizumab, Cetuximab, and Bortezomib. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in 45 described in any one of Embodiment Nos. 1 to 90), Goserelin need of Such treatment wherein said treatment comprises and Letrozole. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin need of Such treatment wherein said treatment comprises and Tamoxifen. 50 administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin need of Such treatment wherein said treatment comprises and Exemestane. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as 55 method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin, need of Such treatment wherein said treatment comprises and Fulvestrant. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin need of Such treatment wherein said treatment comprises 60 and Fadrozole. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin, need of Such treatment wherein said treatment comprises and Raloxifene. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to a 65 one (e.g., one) compound of formula 1.0 (for example, as method of treating or preventing breast cancer in a patient in described in any one of Embodiment Nos. 1 to 90), Goserelin need of Such treatment wherein said treatment comprises and Formestane. US 7,807,672 B2 127 128 Another embodiment of this invention is directed to a Such treatment, said treatment comprising the administration method of treating or preventing breast cancer in a patient in ofatherapeutically effective amount of at least one (e.g., one) need of Such treatment wherein said treatment comprises compound of formula 1.0 (for example, as described in any administering a therapeutically effective amount of at least one of Embodiment Nos. 1 to 90), Anastrozole, and Fulves one (e.g., one) compound of formula 1.0 (for example, as trant. described in any one of Embodiment Nos. 1 to 90), Leupro Another embodiment of this invention is directed to the lide and AnastroZole. treatment or prevention of breast cancer in a patient in need of Another embodiment of this invention is directed to a Such treatment, said treatment comprising the administration method of treating or preventing breast cancer in a patient in of a therapeutically effective amount of at least one com need of Such treatment wherein said treatment comprises 10 pound of formula I (e.g., one), Letrozole, and Fulvestrant. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to the one (e.g., one) compound of formula 1.0 (for example, as treatment or prevention of breast cancer in a patient in need of described in any one of Embodiment Nos. 1 to 90), Leupro Such treatment, said treatment comprising the administration lide and Letrozole. ofatherapeutically effective amount of at least one (e.g., one) Another embodiment of this invention is directed to a 15 compound of formula 1.0 (for example, as described in any method of treating or preventing breast cancer in a patient in one of Embodiment Nos. 1 to 90), Exemestane, and Fulves need of Such treatment wherein said treatment comprises trant. administering a therapeutically effective amount of at least Another embodiment of this invention is directed to the one (e.g., one) compound of formula 1.0 (for example, as treatment or prevention of breast cancer in a patient in need of described in any one of Embodiment Nos. 1 to 90), Leupro Such treatment, said treatment comprising the administration lide and Exemestane. ofatherapeutically effective amount of at least one (e.g., one) Another embodiment of this invention is directed to a compound of formula 1.0 (for example, as described in any method of treating or preventing breast cancer in a patient in one of Embodiment Nos. 1 to 90), Anastrozole, and Tamox need of Such treatment wherein said treatment comprises ifen. administering a therapeutically effective amount of at least 25 Another embodiment of this invention is directed to the one (e.g., one) compound of formula 1.0 (for example, as treatment or prevention of breast cancer in a patient in need of described in any one of Embodiment Nos. 1 to 90), Leupro Such treatment, said treatment comprising the administration lide and Fadrozole. ofatherapeutically effective amount of at least one (e.g., one) Another embodiment of this invention is directed to a compound of formula 1.0 (for example, as described in any method of treating or preventing breast cancer in a patient in 30 one of Embodiment Nos. 1 to 90), Letrozole, and Tamoxifen. need of Such treatment wherein said treatment comprises Another embodiment of this invention is directed to the administering a therapeutically effective amount of at least treatment or prevention of breast cancer in a patient in need of one (e.g., one) compound of formula 1.0 (for example, as Such treatment, said treatment comprising the administration described in any one of Embodiment Nos. 1 to 90), Leupro ofatherapeutically effective amount of at least one (e.g., one) lide and Formestane. 35 compound of formula 1.0 (for example, as described in any Another embodiment of this invention is directed to the one of Embodiment Nos. 1 to 90), Exemestane, and Tamox treatment or prevention of breast cancer in a patient in need of ifen. Such treatment, said treatment comprising the administration Other embodiments of this invention are directed to any of ofatherapeutically effective amount of at least one (e.g., one) the above described embodiments for the treatment of Breast compound of formula 1.0 (for example, as described in any 40 Cancer wherein the chemotherapeutic agent is Trastuzumab. one of Embodiment Nos. 1 to 90) and Anastrozole. Other embodiments of this invention are directed to any of Another embodiment of this invention is directed to the the above described embodiments for the treatment or pre treatment or prevention of breast cancer in a patient in need of vention of Breast Cancer wherein the method is directed to Such treatment, said treatment comprising the administration the treatment of breast cancer. ofatherapeutically effective amount of at least one (e.g., one) 45 The compound of formula 1.0 (for example, as described in compound of formula 1.0 (for example, as described in any any one of Embodiment Nos. 1 to 90), antihormonal agents one of Embodiment Nos. 1 to 90) and Letrozole. and chemotherapeutic agents can be administered concur Another embodiment of this invention is directed to the rently or sequentially. treatment or prevention of breast cancer in a patient in need of The antihormonal agents and optional chemotherapeutic Such treatment, said treatment comprising the administration 50 agents are administered according to their protocols, dosage ofatherapeutically effective amount of at least one (e.g., one) amounts, and dosage forms that are well know to those skilled compound of formula 1.0 (for example, as described in any in the art (e.g., the Physician’s Desk Reference or published one of Embodiment Nos. 1 to 90) and Exemestane. literature). For example, for Tamoxifen, Fulvestrant, Ralox Another embodiment of this invention is directed to the ifene, AnastroZole, Letrozole, Exemestane, Leuprolide and treatment or prevention of breast cancer in a patient in need of 55 Goserelin, see the Physician's Desk Reference, 57" Edition, Such treatment, said treatment comprising the administration 2003, published by Thomas PDR at Montvale, N.J. 07645 ofatherapeutically effective amount of at least one (e.g., one) 1742, the disclosure of which is incorporated herein by ref compound of formula 1.0 (for example, as described in any erence thereto. one of Embodiment Nos. 1 to 90) and Tamoxifen. In general, in the embodiments directed to the methods of Another embodiment of this invention is directed to the 60 treating Breast Cancer: (1) the compound of formula 1.0 (for treatment or prevention of breast cancer in a patient in need of example, as described in any one of Embodiment Nos. 1 to Such treatment, said treatment comprising the administration 90) can be administered daily (e.g., once per day, and in one ofatherapeutically effective amount of at least one (e.g., one) embodiment twice a day), (2) the aromatase inhibitors can be compound of formula 1.0 (for example, as described in any administered in accordance with the known protocol for the one of Embodiment Nos. 1 to 90) and Fulvestrant. 65 aromatase inhibitor used (e.g., once per day), (3) the anties Another embodiment of this invention is directed to the trogens can be administered in accordance with the known treatment or prevention of breast cancer in a patient in need of protocol for the antiestrogen used (e.g., from once a day to US 7,807,672 B2 129 130 once a month), (4) the LHRH analogue can be administered in the compound of formula 1.0 (for example, as described in accordance with the known protocol for the LHRH analogue any one of Embodiment Nos. 1 to 90) being dosed twice a day used (e.g., once a month to once every three months), and (5) at 200 mg per dose. the chemotherapeutic agent can be administered in accor AnastroZole is administered p.o. and is dosed once a day in dance with the known protocol for the chemotherapeutic amounts of about 0.5 to about 10 mg per dose, and in one agent used (e.g., from once a day to once a week). embodiment in an amount of about 1.0 mg per dose. Letrozole is administered p.o. and is dosed once a day in Radiation therapy, if administered in the above treatments amounts of about 1.0 to about 10 mg per dose, and in one for breast cancer, is generally administered according to embodiment in an amount of about 2.5 mg per dose. known protocols before administration of the compound of 10 Exemestane is administered p.o. and is dosed once a day in formula 1.0 (for example, as described in any one of Embodi amounts of about 10 to about 50 mg per dose, and in one ment Nos. 1 to 90), antihormonal agents and optional chemo embodiment in an amount of about 25 mg per dose. therapeutic agents. Fadrozole is administered p.o. and is dosed twice a day in Treatment according to the methods of treating breast can amounts of about 0.5 to about 10 mg per dose, and in one cer is continuous (i.e., a continuous dosing schedule is fol 15 embodiment in an amount of about 2.0 mg per dose. lowed). The treatment is continued until there is a complete Formestane is administered i.m. and is dosed once every response, or until the skilled clinician determines that the two weeks in amounts of about 100 to about 500 mg per dose, patient is not benefiting from the treatment (for example, and in one embodiment in an amount of about 250 mg per when there is disease progression). dose. Tamoxifen is administered p.o. and is dosed once a day in The continuous treatment protocol for breast cancer can be amounts of about 10 to about 100 mg per dose, and in one changed to a discontinuous treatment schedule if, in the judg embodiment in an amount of about 20 mg per dose. ment of the skilled clinician, the patient would benefit from a Fulvestrant is administered i.m. and is dosed once a month discontinuous treatment schedule with one or more of the in amounts of about 100 to about 1000 mg perdose, and in one administered drugs. For example, the compound of formula 25 embodiment in an amount of about 250 mg per dose. 1.0 (for example, as described in any one of Embodiment Raloxifene is administered p.o. and is dosed once a day in Nos. 1 to 90) can be given using a discontinuous treatment amounts of about 10 to about 120 mg per dose, and in one schedule while the remaining drugs used in the treatment are embodiment in an amount of about 60 mg per dose. given as described herein. An example of a discontinuous Acolbifene is administered p.o. and is dosed once a day in treatment protocol for the compound of formula 1.0 (for 30 amounts of about 5 to about 20 mg per dose, and in one example, as described in any one of Embodiment Nos. 1 to embodiment in an amount of about 20 mg per dose. 90) is a repeating cycle of three weeks with the compound of Goserelin is administered s.c. and is dosed once a month, or formula 1.0 followed by one week without the compound of once every three months, in amounts of about 2 to about 20 formula 1.0. mg per dose, and in one embodiment in an amount of about After a complete response is achieved with the breast can 35 3.6 mg per dose when administered once a month, and in cer treatment, maintenance therapy with the compound of another embodiment in an amount of about 10.8 mg per dose formula 1.0 (for example, as described in any one of Embodi when administered once every three months. ment Nos. 1 to 90) can be continued using the dosing Leuprolide is administered s.c. and is dosed once a month, described in the methods of this invention. Maintenance or once every three months, in amounts of about 2 to about 20 therapy can also include administration of the antihormonal 40 mg per dose, and in one embodiment in an amount of about agents using the dosing described in the methods of this 3.75 mg per dose when administered once a month, and in invention. Maintenance therapy can just be with the antihor another embodiment in an amount of about 11.25 mg perdose monal agents. For example, after a complete response is when administered once every three months. achieved, an aromatase inhibitor (e.g., AnastroZole, Letrozole Trastuzumab is administered by i.v. and is dosed once a or Exemestane) can be continued for up to five years. Or, for 45 week in amounts of about 2 to about 20 mpk per dose, and in example, an antiestrogen, e.g., Tamoxifen, may be used for up one embodiment in an amount of about 2 mpk per dose. to five years after a complete response is achieved. Or, for Trastuzumab is generally initially administered in a loading example, an antiestrogen (e.g., Tamoxifen) can be used for up dose that is generally twice the dose of the weekly dose. Thus, to five years after a complete response is achieved followed for example, a 4 mpk loading dose is administered and then by the use of an aromatase inhibitor (e.g., Anastrozole, Letro 50 dosing is 2 mpk per dose per week. Zole or Exemestane) for up to five years. Gefitinib is administered p.o. and is dosed once a day in In the embodiments directed to the treatment of breast amounts of about 100 to about 1000 mg per dose, and in one cancer described above, the compound of formula 1.0 (for embodiment in an amount of about 250 mg per dose. example, as described in any one of Embodiment Nos. 1 to Erlotinib is administered p.o. and is dosed once a day in 90) is administered continuously in a total daily dose of about 55 amounts of about 100 to about 500 mg per dose, and in one 100 mg to about 600 mg. Usually this amount is administered embodiment in an amount of about 150 mg per dose. in divided doses, and in one embodiment this amount is Bevacizumab is administered i.v. and is dosed once every administered twice a day. In one embodiment the compound two weeks in amounts of about 2.5 to about 15 mg per kilo of formula 1.0 (for example, as described in any one of gram of body weight per dose, and in one embodiment in an Embodiment Nos. 1 to 90) is dosed twice a day in an amount 60 amount of about 10 mg per kilogram per dose. of about 50 mg to about 300 mg per dose. In another embodi Cetuximab is administered i.v. and is dosed once a week in ment the compound of formula 1.0 (for example, as described amounts of about 200 to about 500 mg per meter squared in any one of Embodiment Nos. 1 to 90) is dosed twice a day dose, and in one embodiment in an amount of about 250 mg in an amount of about 100 mg to about 200 mg per dose. per meter squared per dose. Examples include the compound of formula 1.0 (for example, 65 Bortezomib is administered i.v. and is dosed twice a week as described in any one of Embodiment Nos. 1 to 90) being for 2 weeks followed by a 10 day rest period (21 day treatment dosed twice a day at 100 mg per dose. Examples also include cycle) for a maximum of 8 treatment cycles in amounts of US 7,807,672 B2 131 132 about 1.0 to about 2.5 mg per meter squared per dose, and in In another embodiment of this invention breast cancer is one embodiment in an amount of about 1.3 mg per meter treated (or prevented) in a patient in need of Such treatment squared per dose. wherein said treatment comprises administering to said Thus in one embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) orally in an wherein said treatment comprises administering to said amount of about 100 to 200 mg per dose, wherein each dose patient: (1) the compound of formula 1.0 (for example, as is administered twice a day, and (2) Fulvestrant i.m. in an described in any one of Embodiment Nos. 1 to 90) orally in an amount of about 250 mg per dose wherein each dose is given amount of about 50 mg to about 300 mg per dose wherein once a month. each dose is administered twice a day, and (2) AnastroZole 10 In another embodiment of this invention breast cancer is p.o. in an amount of about 0.5 to about 10 mg per dose treated (or prevented) in a patient in need of Such treatment wherein each dose is given once a day. wherein said treatment comprises administering to said In another embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) p.o. in an wherein said treatment comprises administering to said 15 amount of about 50 mg to about 300 mg per dose wherein patient: (1) the compound of formula 1.0 (for example, as each dose is administered twice a day, and (2) Tamoxifen p.o. described in any one of Embodiment Nos. 1 to 90) orally in an in an amount of about 10 to about 100 mg per dose wherein amount of about 100 to 200 mg per dose, wherein each dose each dose is given once a day. is administered twice a day, and (2) AnastroZole in an amount In another embodiment of this invention breast cancer is of about 1.0 mg per dose wherein each dose is given once a treated (or prevented) in a patient in need of Such treatment day. wherein said treatment comprises administering to said In another embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) p.o. in an wherein said treatment comprises administering to said amount of about 100 to 200 mg per dose, wherein each dose patient: (1) the compound of formula 1.0 (for example, as 25 is administered twice a day, and (2) Tamoxifen p.o. in an described in any one of Embodiment Nos. 1 to 90) orally in an amount of about 20 mg per dose wherein each dose is given amount of about 50 mg to about 300 mg per dose wherein once a day. each dose is administered twice a day, and (2) Letrozole p.o. In other embodiments of the invention breast cancer is in an amount of about 1.0 to about 10 mg per dose wherein treated in a patient in need of Such treatment wherein said each dose is given once a day. 30 treatment comprises the administration of the compound of In another embodiment of this invention breast cancer is formula 1.0 (for example, as described in any one of Embodi treated (or prevented) in a patient in need of Such treatment ment Nos. 1 to 90), one of the aromatase inhibitors (e.g., wherein said treatment comprises administering to said Anastrozole, Letrozole, or Exemestane, and in one embodi patient: (1) the compound of formula 1.0 (for example, as ment Anastrozole), and one of the antiestrogens (e.g., Fulves described in any one of Embodiment Nos. 1 to 90) orally in an 35 trant or Tamoxifen), wherein the compound of formula 1.0, amount of about 100 to 200 mg per dose, wherein each dose aromatase inhibitor and antiestrogen are administered in the is administered twice a day, and (2) Letrozole p.o. in an dosages described above. amount of about 2.5 mg per dose wherein each dose is given Thus, for example in another embodiment of this invention once a day. 40 breast cancer is treated (or prevented) in a patient in need of In another embodiment of this invention breast cancer is Such treatment wherein said treatment comprises administer treated (or prevented) in a patient in need of Such treatment ing to said patient: (1) the compound of formula 1.0 (for wherein said treatment comprises administering to said example, as described in any one of Embodiment Nos. 1 to patient: (1) the compound of formula 1.0 (for example, as 90) p.o. in an amount of about 50 mg to about 300 mg perdose described in any one of Embodiment Nos. 1 to 90) orally in an 45 wherein each dose is administered twice a day, (2) Anastro amount of about 50 mg to about 300 mg per dose wherein Zole p.o. in an amount of about 0.5 to about 10 mg per dose each dose is administered twice a day, and (2) Exemestane wherein each dose is given once a day, and (3) Fulvestranti.m. p.o. in an amount of about 10 to about 50 mg per dose wherein in an amount of about 100 to about 1000 mg per dose wherein each dose is given once a day. each dose is given once a month. In another embodiment of this invention breast cancer is 50 In another embodiment of this invention breast cancer is treated (or prevented) in a patient in need of Such treatment treated (or prevented) in a patient in need of Such treatment wherein said treatment comprises administering to said wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) orally in an described in any one of Embodiment Nos. 1 to 90) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose 55 amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Exemestane in an amount is administered twice a day, (2) AnastroZole p.o. in an amount of about 25 mg per dose wherein each dose is given once a of about 1.0 mg per dose wherein each dose is given once a day. day, and (3) Fulvestranti.m. in an amount of about 250 mg per In another embodiment of this invention breast cancer is dose wherein each dose is given once a month. treated (or prevented) in a patient in need of Such treatment 60 In another embodiment of this invention breast cancer is wherein said treatment comprises administering to said treated (or prevented) in a patient in need of Such treatment patient: (1) the compound of formula 1.0 (for example, as wherein said treatment comprises administering to said described in any one of Embodiment Nos. 1 to 90) orally in an patient: (1) the compound of formula 1.0 (for example, as amount of about 50 mg to about 300 mg per dose wherein described in any one of Embodiment Nos. 1 to 90) p.o. in an each dose is administered twice a day, and (2) Fulvestranti.m. 65 amount of about 50 mg to about 300 mg per dose wherein in an amount of about 100 to about 1000 mg per dose wherein each dose is administered twice a day, (2) Letrozole p.o. in an each dose is given once a month. amount of about 1.0 to about 10 mg per dose wherein each US 7,807,672 B2 133 134 dose is given once a day, and (3) Fulvestrant in an amount of each dose is administered twice a day, (2) Letrozole p.o. in an about 100 to about 1000 mg per dose wherein each dose is amount of about 1.0 to about 10 mg per dose wherein each given once a month. dose is given once a day, and (3) Tamoxifen p.o. in an amount In another embodiment of this invention breast cancer is of about 10 to about 100 mg per dose wherein each dose is treated (or prevented) in a patient in need of Such treatment given once a day. wherein said treatment comprises administering to said In another embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) p.o. in an wherein said treatment comprises administering to said amount of about 100 to 200 mg per dose, wherein each dose 10 patient: (1) the compound of formula 1.0 (for example, as is administered twice a day, (2) Letrozole p.o. in an amount of described in any one of Embodiment Nos. 1 to 90) p.o. in an about 2.5 mg per dose wherein each dose is given once a day, amount of about 100 to 200 mg per dose, wherein each dose and (3) Fulvestrant im. in an amount of about 250 mg per is administered twice a day, (2) Letrozole p.o. in an amount of dose wherein each dose is given once a month. about 2.5 mg per dose wherein each dose is given once a day, In another embodiment of this invention breast cancer is 15 and (3) Tamoxifen p.o. in an amount of about 20 mg per dose treated (or prevented) in a patient in need of Such treatment wherein each dose is given once a day. wherein said treatment comprises administering to said In another embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) p.o. in an wherein said treatment comprises administering to said amount of about 50 mg to about 300 mg per dose wherein patient: (1) the compound of formula 1.0 (for example, as each dose is administered twice a day, (2) Exemestane p.o. in described in any one of Embodiment Nos. 1 to 90) p.o. in an an amount of about 10 to about 50 mg per dose wherein each amount of about 50 mg to about 300 mg per dose wherein dose is given once a day, and (3) Fulvestranti.m. in an amount each dose is administered twice a day, (2) Exemestane p.o. in of about 100 to about 1000 mg per dose wherein each dose is 25 an amount of about 10 to about 50 mg per dose wherein each given once a month. dose is given once a day, and (3) Tamoxifen p.o. in an amount In another embodiment of this invention breast cancer is of about 10 to about 100 mg per dose wherein each dose is treated (or prevented) in a patient in need of Such treatment given once a day. wherein said treatment comprises administering to said 30 In another embodiment of this invention breast cancer is patient: (1) the compound of formula 1.0 (for example, as treated (or prevented) in a patient in need of Such treatment described in any one of Embodiment Nos. 1 to 90) p.o. in an wherein said treatment comprises administering to said amount of about 100 to 200 mg per dose, wherein each dose patient: (1) the compound of formula 1.0 (for example, as is administered twice a day, (2) Exemestane p.o. in an amount described in any one of Embodiment Nos. 1 to 90) p.o. in an of about 25 mg per dose wherein each dose is given once a 35 amount of about 100 to 200 mg per dose, wherein each dose day, and (3) Fulvestranti.m. in an amount of about 250 mg per is administered twice a day, (2) Exemestane p.o. in an amount dose wherein each dose is given once a month. of about 25 mg per dose wherein each dose is given once a In another embodiment of this invention breast cancer is day, and (3) Tamoxifen p.o. in an amount of about 20 mg per treated (or prevented) in a patient in need of Such treatment dose wherein each dose is given once a day. wherein said treatment comprises administering to said 40 Those skilled in the art will appreciate that when other patient: (1) the compound of formula 1.0 (for example, as combinations of antihormonal agents are used, the individual described in any one of Embodiment Nos. 1 to 90) p.o. in an antihormonal agent is used in the amounts specified above for amount of about 50 mg to about 300 mg per dose wherein that individual antihormonal agent. each dose is administered twice a day, (2) Anastrozole p.o. in 45 Other embodiments of the treatment of Breast Cancer are an amount of about 0.5 to about 10 mg per dose wherein each directed to the methods of treating Breast Cancer described dose is given once a day, and (3) Tamoxifen p.o. in an amount above wherein the compound of formula 1.0 (for example, as of about 10 to about 100 mg per dose wherein each dose is described in any one of Embodiment Nos. 1 to 90) is dosed given once a day. twice a day in an amount of about 100 mg per dose. In another embodiment of this invention breast cancer is 50 Other embodiments of the treatment of Breast Cancer are treated (or prevented) in a patient in need of Such treatment directed to the methods of treating Breast Cancer described wherein said treatment comprises administering to said above wherein the compound of formula 1.0 (for example, as patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) is dosed described in any one of Embodiment Nos. 1 to 90) p.o. in an 55 twice a day in an amount of about 200 mg per dose. amount of about 100 to 200 mg per dose, wherein each dose Other embodiments of the treatment of Breast Cancer are is administered twice a day, (2) AnastroZole p.o. in an amount directed to the methods of treating Breast Cancer described of about 1.0 mg per dose wherein each dose is given once a above wherein a chemotherapeutic agent is administered in day, and (3) Tamoxifen p.o. in an amount of about 20 mg per addition to the compound of formula 1.0 (for example, as dose wherein each dose is given once a day. 60 described in any one of Embodiment Nos. 1 to 90) and anti In another embodiment of this invention breast cancer is hormonal agent (or antihormonal agents). In these embodi treated (or prevented) in a patient in need of Such treatment ments the dosage ranges of the compound of formula 1.0 and wherein said treatment comprises administering to said antihormonal agents are as those described above in the com patient: (1) the compound of formula 1.0 (for example, as 65 bination therapies, or those described above for the individual described in any one of Embodiment Nos. 1 to 90) p.o. in an compound of formula I and antihormonal agents, and the amount of about 50 mg to about 300 mg per dose wherein dosages of the chemotherapeutic agents are those described US 7,807,672 B2 135 136 above for the individual chemotherapeutic agent. The dos knowledge of the skilled clinician, the therapeutic protocols ages for the chemotherapeutic agents are well known in the (e.g., dosage amounts and times of administration) can be art. varied in view of the observed effects of the administered Other embodiments of this invention are directed to phar therapeutic agents on the patient, and in view of the observed maceutical compositions comprising the compound of for responses of the cancer to the administered therapeutic mula 1.0 (for example, as described in any one of Embodi agents. ment Nos. 1 to 90) and at least one antihormonal agent and a The initial administration can be made according to estab pharmaceutically acceptable carrier. lished protocols known in the art, and then, based upon the Other embodiments of this invention are directed to phar 10 observed effects, the dosage, modes of administration and maceutical compositions comprising the compound of for times of administration can be modified by the skilled clini mula 1.0 (for example, as described in any one of Embodi C1a. ment Nos. 1 to 90), at least one antihormonal agent, at least The particular choice of chemotherapeutic agent will one chemotherapeutic agent, and a pharmaceutically accept depend upon the diagnosis of the attending physicians and 15 their judgment of the condition of the patient and the appro able carrier. priate treatment protocol. Other embodiments of this invention are directed to phar The determination of the order of administration, and the maceutical compositions comprising the compound of for number of repetitions of administration of the chemothera mula 1.0 (for example, as described in any one of Embodi peutic agent during a treatment protocol, is well within the ment Nos. 1 to 107), at least one chemotherapeutic agent, and knowledge of the skilled physician after evaluation of the a pharmaceutically acceptable carrier. cancer being treated and the condition of the patient. Those skilled in the art will appreciate that the compounds Thus, in accordance with experience and knowledge, the (drugs) used in the methods of this invention are available to practicing physician can modify each protocol for the admin the skilled clinician in pharmaceutical compositions (dosage istration of an chemotherapeutic agent according to the indi forms) from the manufacturer and are used in those compo 25 vidual patient’s needs, as the treatment proceeds. All Such sitions. So, the recitation of the compound or class of com modifications are within the scope of the present invention. pounds in the above described methods can be replaced with The particular choice of antihormonal agents, optional a recitation of a pharmaceutical composition comprising the chemotherapeutic agents and optional radiation will depend upon the diagnosis of the attending physicians and their judg particular compound or class of compounds. For example, the 30 embodiment directed to a method of treating cancer compris ment of the condition of the patient and the appropriate treat ing administering to a patient in need of such treatment thera ment protocol. The determination of the order of administration, and the peutically effective amounts of the compound of formula 1.0, number of repetitions of administration of the antihormonal a taxane, and a platinum coordination compound, includes agents, optional chemotherapeutic agents and optional radia within its scope a method of treating cancer comprising 35 tion during a treatment protocol, is well within the knowledge administering to a patient in need of such treatment therapeu of the skilled physician after evaluation of the breast cancer tically effective amounts of a pharmaceutical composition being treated and the condition of the patient. comprising the compound of formula 1.0, a pharmaceutical Thus, in accordance with experience and knowledge, the composition comprising a taxane, and a pharmaceutical com practicing physician can modify each protocol for the admin position comprising a platinum coordination compound. 40 istration of antihormonal agents, optional chemotherapeutic Those skilled in the art will recognize that the actual dos agents and optional radiation according to the individual ages and protocols for administration employed in the meth patient’s needs, as the treatment proceeds. All Such modifi ods of this invention may be varied according to the judgment cations are within the scope of the present invention. of the skilled clinician. The actual dosage employed may be 45 The attending clinician, in judging whether treatment is varied depending upon the requirements of the patient and the effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as severity of the condition being treated. Determination of the relief of cancer-related symptoms (e.g., pain, cough (for lung proper dosage for a particular situation is within the skill of cancer), and shortness of breath (for lung cancer)), inhibition the art. A determination to vary the dosages and protocols for 50 of tumor growth, actual shrinkage of the tumor, or inhibition administration may be made after the skilled clinician takes of metastasis. Size of the tumor can be measured by standard into account Such factors as the patients age, condition and methods such as radiological studies, e.g., CAT or MRI scan, size, as well as the severity of the cancer being treated and the and Successive measurements can be used to judge whether or response of the patient to the treatment. not growth of the tumor has been retarded or even reversed. The amount and frequency of administration of the com 55 Relief of disease-related symptoms Such as pain, and pound of formula 1.0 and the chemotherapeutic agents will be improvement in overall condition can also be used to help regulated according to the judgment of the attending clinician judge effectiveness of treatment. (physician) considering Such factors as age, condition and Compounds of this invention are exemplified in the follow size of the patient as well as severity of the cancer being ing examples, which should not be construed as limiting the 60 Scope of the disclosure. Alternative mechanistic pathways treated. and analogous structures within the scope of the invention The chemotherapeutic agent can be administered accord may be apparent to those skilled in the art. ing to therapeutic protocols well known in the art. It will be The LCMS conditions are: (1) column: C-18 reverse phase, apparent to those skilled in the art that the administration of 5 um, 4.6x50 mm, (2) MS:PE Sciex API-150EX, and (3) the chemotherapeutic agent can be varied depending on the 65 HPLC: Shimadzu LC-10 ADVp, 1 ml/min, linear gradient cancer being treated and the known effects of the chemothera 10% acetonitirle in water to 95% acetonitrile in water, both peutic agent on that disease. Also, in accordance with the contain 0.05% TFA

US 7,807,672 B2 141 142

-continued Rs

O O R7 O ul R6

\ N He1) LiOH 2 X 2) HATU or R N appropriate 3 Rs coupling agent R4 CHCl2 Y=Y HO y 4y-Ni, R R8 O O R Y=Y N R6 HO \ / NH R N Y X n R R3 Rs R4

30 Scheme 4 (Me)Si N1 NoMe COEt R ls -- -N- 74 BOC. R6 35 Ph N BrRs 29B ph 30B He- -/ N PD(OAC) EtOC N EtOC NH R DBBP CSCO Her R4 40 74 74 6B H 31B 32B -C-Z = R2 R (Bioorganic & Medicinal Chemistry Letters, 8, 15 (1998) pages 1953 to 1958) BOCN R6 45 N acidic The appropriately substituted pyrrolidine 32B can be NS obtained by reacting 29B with the appropriately substituted R3 Rs compound 30B in the presence of trifluoroacetic acid to obtain 31B. Compound 31B can then be deprotected under R4 50 hydrogenation conditions (Pd/C, H) to obtain 32B. 7B R7 Alternative Process For Scheme 5 R6 HN SS EtOC NBoc 1) LDA- EtOC NBoc TFA Na 2) E R Rs 33B R4 74 7C 60 34EtO2C NH The R substituted piperazine is prepared by Buchwald type coupling of the piperazine 6B with an aryl bromide in the 32B presence of palladium to obtain the piperazine 7B. The BOC 65 (E = electrophile) group is removed using acidic conditions (e.g., TFA) to give piperazine 7C. US 7,807,672 B2 143 144 Alternatively, 32B can be obtained by reaction 33B with colboronate 34B to obtain 35B. The ring double bond can LDA followed by the addition of a suitable electrophile such then be hydrogenated to obtain 36B followed by as allylbromide, as in example 127, to obtain 34B. Treatment removal of the Boc protecting group under trifluoroacetic of 34B with trifluoroacetic acid yields 32B. acid condi

BocN PdCl2(dppf), R6 R6 potassium phosphate BocN BocN R3 B-O dioxane H2, Pd/C A Airl-XE R4 O Ar' = aryl, heteroaryl R3 Arl R Arl XF = Br or Cl R4

34B 35B 36B FA

R7 R7 R6 R6 HN HN

R3 Arl R Arl R4 R4 37B 38B

Aryl or heteroaryl substituted piperidines can be prepared by tions. Alternatively the double bond can be retained and the Suzuki coupling of an aryl or heteroarylhalide with the pini- Boc group removed to give 38B.

Scheme 7 R7 R7 R R6 Pd(PPh3)2Cl2 R6 R6 BocN Cul, CH3CN BocN H2, Pd/C BocN TFA + Arl-XE -Ar' -= aryl, heteroaryl--> -- He R X = Br or C1 3 Šs R Šs R R4 R4 Arl R4 Arl

R7 R7 R6 R6 HN HN

R3 R Šs R4 Arl R4 Arl 43B US 7,807,672 B2 145 146 Similarly aryl or heteroaryl substituted piperizines with a 2 carbon spacer can be prepared as shown in Scheme 12 by -continued coupling an aryl or heteroarylhalide with an acetylene deriva OH tive 39B that can be prepared according to procedures known Br in the art to obtain 40B. 40B can then be reduced to 41 B followed by removal of the Boc protecting group under trif luoroacetic acid conditions. Alternatively the Boc protecting group from 40B can be removed under trifluoroacetic acid conditions to give 43B. 10 NH2 PREPARATIVE EXAMPLE 1 1-Benzyloxy-2-bromo-4-nitrobenzene was prepared from Preparation of 4-Amino-2-trifluoromethyl-phenol 2-bromo-1-fluoro-4-nitrobenzene using the same procedure 15 described in Scheme 1. To a solution of 1-benzyloxy-2-bromo-4-nitrobenzene (50 mg, 0.16 mmol) in ethanol (5 mL) and H2O (0.5 mL) was F OB added iron (134 mg, 2.43 mmol) and one drop of concentrated CF CF HC1. The mixture was refluxed for 6 hrs and filtrated. The BnOH, NaH H --- He filtrate was diluted with ethyl acetate, washed with saturated THF Pd(C sodium bicarbonated solution, dried over sodium sulfate and concentrated to afford crude 4-amino-1-benzyloxy-2-bro NO NO mobenzene. OH 25 To a solution of 4-amino-1-benzyloxy-2-bromobenzene in 2 mL of dichloromethane at -78 C was added boron trichlo CF ride (0.4 mL, 1 M in DCM) dropwise. The reaction was quenched with water at 0 C, concentrated and dried under vacuum to afford 4-amino-2-bromo-1-hydroxybenzene (17 mg, 56% two steps) NH2 PREPARATIVE EXAMPLE 3 To a solution of 2-fluoro-5-nitrobenzotrifluoride (500 mg. 2.48 mmol) and benzyl alcohol (267mg, 2.48 mmol) in THF 35 Preparation of 5-Amino-biphenyl-2-ol was added sodium hydride (95.1 mg, 2.48 mmol) at 0°C. The reaction was followed by TLC and quenched with saturated ammonium chloride solution after 0.5 h. The mixture was OB extracted with dichloromethane three times. The combined 40 Br Pd(dppf)Cl. organic layer was dried over Sodium sulfate and concentrated. Her The residue was triturated with 2.5 mL of hexanes and ethyl K3PO4, dioxane acetate (7:1) and a yellow precipitate was collected by filtra tion to give 1-benzyloxy-4-nitro-2-trifluoromethylbenzene pi B n (580 mg, 79%). 45 NO OH To the suspension of 1-benzyloxy-4-nitro-2-trifluorometh ylbenzene (575 mg, 1.96 mmol) in methanol was added cata lytic amount of 5% palladium on carbon under a hydrogen atmosphere. The mixture was stirred for 4 hrs and filter through celite. The filtrate was concentrated to afford 50 4-amino-2-trifluoromethylphenol (311 mg, 90%). OB O OH PREPARATIVE EXAMPLE 2 O HerH2, Pd/C Preparation of 4-Amino-2-Bromo-phenol 55 NO NH2

F OB To a mixture of 1-benzyloxy-2-bromo-4-nitrobenzene 60 (100 mg, 0.33 mmol), Pd(dppf)C12.DCM (12 mg, 0.016 Br Br mmol), phenylboronic acid (48 mg, 0.39 mmol) and potas NaH, BnOH 1. Fe, HCI --- Her sium phosphate (207 mg, 0.98 mmol) was added dioxane 2. BCl3 under an argon atmosphere. The mixture was stirred over 65 night at 80 Cand filtered. The filtrate was concentrated and NO NO purified by flash chromatography (5:1 hexanes/ethyl acetate) to give 2-benzyloxy-5-nitro-biphenyl (81 mg). US 7,807,672 B2 147 148 PREPARATIVE EXAMPLE 4 PREPARATIVE EXAMPLE 5 Preparation of 5-Amino-aryl(heteroaryl)-phenols Preparation of 4-Amino-2-isopropyl-phenol To a solution of 2-benzyloxy-5-nitro-biphenyl (81 mg, 0.27 mmol)) in 5 mL of methanol was added catalytic amount OH of 5% palladium on carbon under H2. The mixture was stirred under H2 for 3 hrs and filtered through celite. The filtrate was HCl, NaNO concentrated to give 2-hydroxy-5-nitro-biphenyl (38 mg). 10 He

15 OH OH

F

F 2O Hass

NH2 NH2

HO 25 F OH OH

30 To a solution of 2-isopropylphenol (2.7g, 0.02 mol) in 15 mL of 95% ethanol and 15 mL of concentrated hydrochloric acid at -5 C was added sodium nitrite (2.1 g, 0.03 mmol) NH2 NH2 portionwise. The resulting mixture was stirred at 0C for 5 hr, poured in 125 mL of cold water and filtered. The brown solid 35 washed with water, taken up in concentrated sodium carbon ate solution and filtered. The filtrate was acidified with con OH 21 centrated hydrochloric acid to pH ca. 2. The oil separated N soon solidified and the solid was collected by filtration and washed with water to 2-isopropyl-1,4-benzoquinone 40 4-oxime (1.2g, 41%) To a solution of 2-isopropyl-1,4-benzoquinone 4-oxime (1.1 g, 6.7 mmol) in methanol was added catalytic amount of Ra/Ni complex. The reaction was stirred under 50 psi H2 45 atmosphere for 5 hrs and filtered through celite. The filtrate was concentrated to give 4-amino-2-isopropyl-phenol (762 mg, 76%) The building blocks were prepared via same methods described in the above scheme to prepare 5-Amino-biphenyl- 50 PREPARATIVE EXAMPLE 6 2-ol Preparation of 4-amino-2-t-butylphenol 4-amino-2-t-butylphenol was prepared by the procedure described in the preparation of 4-Amino-2-isopropyl-phenol -N -N 55 substituting 2-tert. butylphenol for 2-isopropylphenol.

OH 60

NO NH2

4-Amino-2-(2H-pyrazol-3-yl)phenol was prepared by the 6s procedure described in the preparation of 5-Amino-aryl(het eroaryl)-phenols US 7,807,672 B2 149 150 PREPARATIVE EXAMPLE 7 over 10 min. and the reaction mixture let warm to ambient temperature gradually. The reaction mixture was stirred for Preparation of 18 hrs. A saturated solution of Ammonium chloride (75 ml) 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid was added and the reaction mixture stirred for 5 min. 85% tert-butyl ester o-Phosphoric acid (7.27 gm) was added and the reaction mixture stirred for 1 hr. The reaction mixture was extracted with ethylacetate three times, dried over magnesium sulfate, filtered and evaporated. The crude product was chromato graphed on a silica column to obtain 5.74 gm of title product. 10 N PREPARATIVE EXAMPLE 9 --- Preparation of 4-(4-Pyrimidin-2-yl-phenyl)-pipera Zine-1-carboxylic acid tert-butyl ester 15

N

Br He B1 O NH 1-(4-Bromo-phenyl)-piperazine hydrochloride (9 gm, 38 25 O NH mmol) was dissolved in 250 ml of dichloromethane and 9 ml 8 of triethylamine added. Di-tert.butyldicarbonate (8.34gm, 39 Boc mmol) was added and the reaction mixture stirred for 1 hr. The reaction mixture washed with a solution of saturated Sr. Sodium bicarbonate (100 ml), the organic layer separated, 30 N dried over magnesium sulfate and evaporated to obtain 10.19 gm of crystalline product. N

PREPARATIVE EXAMPLE 8 s 35 N 21 Preparation of 4-(4-boronic 9 acid-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 4-(4-boronic acid-phenyl)-piperazine-1-carboxylic acid 40 tert-butyl ester (5.93 gm, 19.3 mmol) was dissolved in 50 ml of a 50% mixture of N,N-dimethylformamide/water. K2CO3 (16 gm) was added and the mixture de-gassed and purged Boc with nitrogen. Pd(dppf),C12 (1.57gm) and 2-chloropyrimi -> dine (2.72 gm) was added and the reaction mixture stirred at N- Ho 45 80 C. After 8 hours the product was extracted into ethylac etate, dried over magnesium Sulfate, filtered and evaporated. The crude product was chromatographed on silica gel to Br obtain 5.03 gm (76.6%) of title product. 7 Boc 50 PREPARATIVE EXAMPLE 10 Sr. Preparation of N 2-(4-piperazin-1-yl-phenyl)-pyrimidine r O NH 55 O NH

60 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-bu tyl ester (10.19 gm, 30 mmol) was dissolved in 26 ml of tetrahydrofuran. The mixture was cooled to -78 Cunder a dry nitrogen atmosphere. A 2.5 N solution nButyl lithium in 65 hexanes (26 ml, 65 mmol) was added dropwise and stirred for 30 min. Triisopropylborate (14.68 ml, 63.6 mmol) was added US 7,807,672 B2 151 152

-continued -continued

ON

10

15 4-(4-Pyrimidin-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 5.03 gm was dissolved in 25 ml dichlo romethane and 10 ml of 4N HCl dioxane added. After stirring for 2 hrs, the mixture was then evaporated to obtain the title product. In a similar manner the following piperazine derivatives were prepared: 25

30

35

40

45 lp:11 O 50

55 OH

N 60

65 US 7,807,672 B2 153 154 PREPARATIVE EXAMPLE 11 removed under vacuum and the residue was purified using prep-HPLC to give desired product (45 mg, 62% yield for two Preparation of steps) as TFA salt. 4-(3-Bromo-phenyl)-piperazine-1-carboxylic acid Through this method, the following analogues were pre tert-butyl ester pared:

10 -O-3-\ / Br 15

Boc-N N

To a solution of 4-(3-bromo-phenyl)-piperidine (2.8 g. 12 mmol), triethylamine (2.4g, 24 mmol) and DMAP (150 mg. 1.2 mmol) in acetonitrile (15 ml) was added di-tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 mL) was added and the formed 25 slurry was stirred for 30 min. The formed product was col lected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95% yield).

PREPARATIVE EXAMPLE 12 30 Preparation of 1-(3-Thiophen-2-yl-phenyl)-piperazine 35 IO-() Br

Boc-N N -e- \ / 40 s/N 45 IO-() Boc-N N s/N

HN N \ / 55 IO-() A mixture containing 2-Thiopheneboronic acid (56 mg, 0.44 mmol), 4-(3-Bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), Pd(dppf)Cl. (12 mg, 0.015 mmol) and KPO (184 mg) in dioxane was 60 ( ) /" degassed with Ar and the reaction mixture stirred at 80 C. After 8 hours the product was filter through celite and the Solvent was evaporated. To the crude product obtained in the previous step, was 65 added 90% TFA (1 mL) and the reaction mixture was stirred od at ambient temperature for 1 hour. The excess TFA was US 7,807,672 B2 155 156 Through this method, the following analogues were pre -continued pared: ( )

10 IO-K)\ /

15 PREPARATIVE EXAMPLE 13 HN N Preparation of 3-piperazin-1-yl-benzoic acid methyl \ / ester ( y FN

HN N 25 \ /

Br 30 HN N Boc-N NH \ /

35 PREPARATIVE EXAMPLE 1.4 Preparation of 1-(4-Furan-2-yl-phenyl)-piperazine

Boc-N\ /-3 \ Her 40

Boc-N N Br -- \ / 45 / v O Boc-N\ /N N He \ / y O -O-3 50 HN N N

A mixture containing 2-furanboronic acid (49 mg, 0.44 To a mixture containing piperazine-1-carboxylic acid tert 55 mmol), 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid tert-butyl ester (100 mg, 0.29 mmol), Pd(dppf)C1 (12 mg, methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 0.015 mmol) and KPO (184 mg) in dioxane was degassed mmol), 2-(di-t-butylphosphino)biphenyl (80 mg, 0.28 mmol) with Arand the reaction mixture stirred at 80 C. After 8 hours and sodium t-butoxide (400 mg, 4 mmol) in toluene (20 mL) the product was filter through celite and the solvent was was degassed with Ar. The reaction mixture was heated at 50 60 evaporated. C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal To the crude product obtained in the previous step, was of solvent, TFA was added to the residue. The reaction mix added 90% TFA (1 mL) and the reaction mixture was stirred ture was stirred at ambient temperature for 1 hour. The excess at ambient temperature for 1 hour. The excess TFA was TFA was removed under vacuum and the residue was purified 65 removed under vacuum and the residue was purified using using prep-HPLC to give desired product (250 mg, 37% yield prep-HPLC to give desired product (40 mg, 60% yield for two for two steps) as TFA salt. steps) as TFA salt. US 7,807,672 B2 157 158 Through this method, the following analogues were pre residue was purified using prep-HPLC to give desired product pared: (60 mg, 41% yield for two steps) as TFA salt.

PREPARATIVE EXAMPLE 16 Preparation of 2-(6-Bromo-pyridin-3-yl)-pyrimidine IO-(\ / ) (ON 10 s IO-()-O\ / le HON-OH Na2N

15 HN N O N N Pd(PPh3)4,34 toluene N -- Her \ / N N. 2N MeOHVH2O/CSCO 2N

Br Br Br IO-K)-()\ / als 76 A mixture of 2-bromopyridine (0.43g, 2.70 mmol), 2-bro mopyridine-5-boronic acid (0.55g, 2.72 mmol), tetrakis A w S 25 (triphenylphosphine)palladium(0) (300 mg, 0.259 mmol), cesium carbonate (1.15g, 3.03 mmol) was stirred in MeOH/ "V / K ) () toluene/water (15 ml, 1/1/1) at reflux temperature overnight. The reaction was cooled to room temperature and diluted with 30 EtOAc (200 ml) and water (50 ml). The organic layer was PREPARATIVE EXAMPLE 1.5 separated, dried over MgSO filtered and solvent evaporated yielding a residue which was purified on silica gel eluting Preparation of 2-(3-Fluoro-phenyl)-2,5-diaza-bicyclo with 25% V/vEtOAc/hexanes yielding product 76 as white 2.2.1]heptane solid. (0.55g, 5%) ESMS (MH, 236). 35 PREPARATIVE EXAMPLE 17 Preparation of 5-(4-Bromo-phenyl)-pyrimidin-2-ylamine 40 Br

Boc-N NH Hoss Br F 45

Br Br F 50 N Pd(PPh3)4 N -- He N. CSCO, MeOHVH2O N.

55 B (OH)2 NH2 NH2 To a mixture containing 2,5-Diaza-bicyclo[2.2.1]heptane 2-carboxylic acid tert-butyl ester (100 mg. 0.5 mmol), 3-fluoro-phenylbromide (103.8 mg, 0.6 mmol), Pd(AcO) (8 A mixture of 5-bromo-pyrimidin-2-ylamine (0.8 g. 4.59 mg, 0.03 mmol), 2-(di-t-butylphosphino)biphenyl (20 mg. mmol), 4-bromophenylboronic acid (1 g, 4.97 mmol), tet 0.07 mmol) and sodium t-butoxide (100 mg, 1 mmol) in 60 rakis(triphenylphosphine)palladium(0) (300 mg, 0.259 toluene (3 mL) was degassed with Ar. The reaction mixture mmol), cesium carbonate (1.15g, 3.03 mmol) was stirred in was heated at 50 C for overnight. At the end of reaction, ethyl MeOH/HO (20 ml, 1/1) at reflux temperature overnight. The acetate was added and the mixture was filter through celite. reaction was cooled to room temperature and diluted with After removal of solvent, TFA was added to the residue. The 65 EtOAc (200 ml) and water (50 ml). The organic layer was reaction mixture was stirred at ambient temperature for 1 separated, dried over MgSO filtered and solvent evaporated hour. The excess TFA was removed under vacuum and the yielding a residue which was purified on silica gel eluting US 7,807,672 B2 159 160 with 85% V/vEtOAc/hexanes yielding product 81 as white A mixture of (S,S)-5-(4-Bromo-phenyl)-2,5-diaza-bicyclo solid. (0.7 g. 63%). ESMS (MH, 250). 2.2.1]heptane-2-carboxylic acid tert-butyl ester (4.0 g, 11.3 PREPARATIVE EXAMPLE 1.8 mmol), Bis(pinacolato)diboron (4.0 g, 15.7 mmol), KOAc (3.2 g) and ClPd(dppf)CHCl (800 mg) in 40 mL dioxane Preparation of was evacuated and recharged with N. Several times. The reac 5-(4-piperazin-1-yl-phenyl)-pyrimidin-2-ylamine tion mixture was then heated to 85°C. overnight. After cool ing down to rt, 150 mL ethyl acetate and 30 mL water was added. The mixture was filtered through a pad of Celite and washed with additional ethyl acetate. The separated organic layer was dried (MgSO) and concentrated. The crude was Br O purified on silica gel column eluting with 30% to 50% ethyl H N acetate/hexanes to yield the title compound as a white solid Pd(OAc) (3.3 g). MS (401, MH) -e- -- DBBP 15 N CS2CO3, dioxane/H2O Step 2 H Preparation of (S,S)-5-4-(5-Fluoro-pyrimidin-2-yl)- rs N phenyl-2,5-diaza-bicyclo[2.2.1-heptane-2-carboxy N N. lic acid tert-butyl ester NH2 NH2 81 82 25 A mixture of 5-(4-bromo-phenyl)-pyrimidin-2-ylamine (100 mg, 0.401 mmol), palladium acetate (20 mg, 0.089 mmol), cesium carbonate (200 mg, 0.62 mmol), piperazine Boc Boc (100 mg, 1.16 mmol) and 2-di-t-butylphosphino)-biphenyl 30 (50 mg, 0.167 mmol) was stirred in dioxane:water (10 ml, V/v 5:1) at reflux temperature for 4 hours. The reaction was cooled, diluted with MeC1 (100 ml) and HO (50 ml). The N N organic layer was separated, dried (MgSO), filtered and sol vent evaporated. The residue was purified by chromatography 35 eluting with 100% EtOAc then with 10% v/v MeOH/EtOAc/ NHOH yielding product 82 as a white solid. (70 mg. 68%) ESMS (MH, 256). PREPARATIVE EXAMPLE 19 B 40 o1 No N21 Step 1 )-k N Preparation of (S,S)-5-4-(4.4.5.5-Tetramethyl-1,3, 105 F 2dioxaborolan-2-yl)-phenyl)-2,5-diaza-bicyclo 2.2.1]heptane-2-carboxylic acid tert-butyl ester 45 106

Boc Boc 50

A mixed DMF/HO (5 mL/5 mL) solution of (S,S)-5-4- N N (4,4,5,5-Tetramethyl-1,3,2dioxaborolan-2-yl)-phenyl-2, 55 5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (800 mg, 2 mmol), 2-chloro-5-fluoro-pyrimidine (340 mg, 2.6 mmol), KCO (552 mg, 4 mmol) and Cl2Pd(dppf) CHCl (160 mg) was evacuated and recharged with N sev eral times. The reaction was heated at 70° C. over 18hrs. After B B r /N 60 cooling down to rt, 40 mL ethyl acetate and 10 mL water was added. The mixture was filtered through a pad of Celite and 104 Sk washed with additional ethyl acetate. The separated organic layer was dried (MgSO) and concentrated. The crude was 105 65 purified on silica gel column eluting with 50% ethyl acetate/ hexanes to yield the title compound (420mg) as a light yellow solid. US 7,807,672 B2 161 162 In a similar manner, 106a: PREPARATIVE EXAMPLE 21 Preparation of (S,S)-5-(5-Vinyl-pyrimidin-2-yl)-2,5- diaza-bicyclo2.2.1]heptane-2-carboxylic acid tert butyl ester 106a

Boc Boc 10

N N

15 N S.

Br N 109 110

(S,S)-5-(5-Bromo-pyrimidin-2-yl)-2,5-diaza-bicyclo 2.2.1]heptane-2-carboxylic acid tert-butyl ester (177 mg, 0.5 25 mmol), tributyl vinyl tin (634 mg, 2 mmol) and ClPd(dppf) was prepared by Substituting 2-chloropyrimidine for CHCl (60 mg) was mixed in DMF (3 mL). The mixture was 2-chloro-5-fluoro-pyrimidine heated at 90° C. over 3 days. The cooled down reaction was participate between ethyl acetate (50 mL) and H2O (10 mL). PREPARATIVE EXAMPLE 20 The organic layer washed with H2O (10 mL), brine (10 mL), 30 dried (MgSO) and filtered. The conc. filtrate was purified on Preparation of 4-4-(5-Fluoro-pyrimidin-2-yl)-phe silica gel column eluting with 33% to 50% ethyl acetate/ nyl-piperazine-1-carboxylic acid tert-butyl ester hexanes to yield the title compound as a white Solid (54 mg). MS (303, MH). 35 PREPARATIVE EXAMPLE 21 A

Step 1 Boc Boc 40 Preparation of 4-(5-Pyrimidin-2-yl-thiazol-2-yl)- piperazine-1-carboxylic acid tert-butyl ester

CN CN

45 Boc-N( )N { He 117 B(OH) 2 N21 NN 50 N 107 Boc-N S-( \ / Y. e N F ! N 108 55 N f 118

A round bottom flask containing 4-(5-bromo-thiazol-2- 4-4-(5-Fluoro-pyrimidin-2-yl)-phenyl-piperazine-1-car 60 yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg. 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 boxylic acid tert-butyl ester was prepared similarly as the mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium above substituting (S,S)-5-4-(4.4.5.5-tetra-methyl 1.3.2di di-tert-butylphosphine was degassed three times with Ar. oxaborolan-2-yl)-phenyl-2,5-diaza-bicyclo2.2.1]heptane Dioxane was added and the formed reaction mixture was 2-carboxylic acid tert-butyl ester with 4-4-(tert-Butoxycar 65 stirred at 90° C. overnight under Ar. Then the reaction mixture bony)piperazin-1-yl)phenylboronic acid (C. Chen et. al. J. was filter through celite and the solvent was removed under Org. Chem. 2003, 68,2633). vacuum and crude product was used directly in the next step. US 7,807,672 B2 163 164 Step 2 Step 2 Preparation of Preparation of 4-(4-Pyrimidin-2-yl-phenyl)-piperi 2-(2-piperazin-1-yl-thiazol-5-yl)-pyrimidine dine-1-carboxylic acid tert-buyl ester

/ \ N ne-O-K)-- - - Boc- '( )-( 123 ON 118 15 124

A mixture containing 4-(4-bromo-phenyl)-piperidine-1- carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tribu / \ N tylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluo ride (85 mg, 0.56 mmol) and palladium di-tert in( )-( e N butylphosphine was degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at 90° N C. overnight under Ar. Then the reaction mixture was filter NJ through celite and the solvent was removed under vacuum 119 25 and crude product was used directly in the next step. Step 3 To the crude product obtained in the previous step, was Preparation of added 90% TFA (1 mL) and the reaction mixture was stirred 2-(4-Piperidin-4-yl-phenyl)-pyrimidine at ambient temperature for 1 hour. The excess TFA was 30 removed under vacuum and the residue was purified using prep-HPLC to give desired product (45 mg. 44% yield for two steps) as TFA salt. ne-O-() () - 35 PREPARATIVE EXAMPLE 22

Step 1 IO-() () Preparation of 40 4-(4-Bromo-phenyl)-piperidine-1-carboxylic acid To the crude product obtained in the previous step, was tert-butyl ester added 90% TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was 45 removed under vacuum and the residue was purified using prep-HPLC to give desired product (38 mg, 37% yield for two steps) as TFA salt. IO) ()-n --- PREPARATIVE EXAMPLE 23 50 Step 1 re-O-K)- Br Preparation of 4-methyl-benzenesulfonyl azide 123 55

C N To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g. 12 mmol), triethylamine (2.4g, 24 mmol) and DMAP (150 mg. OESEO OFSFO 1.2 mmol) in acetonitrile (15 ml) was added di-tert-butyl 60 dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 mL) was added and the formed slurry was stirred for 30 min. The formed product was collected by 65 filtration and washed with water. After dry in air, 3.8g product 132 133 was obtained (95% yield). US 7,807,672 B2 165 166 To a solution of tosyl chloride (4.g., 21 mmols) in acetone temperature overnight, filtered and concentrated. The residue (60 ml) was added at 0-5C a solution of sodium azide (1.37 was chromatographed on silica gel using a solution of ethyl g, 21 mmols) and the resulting Solution was stirred at that acetate in hexanes (1:5) to provide the title compound (308 temperature for 2 hours. Acetone was removed and the aque mg, 88%) as colorless crystals. LCMS m/e (154, M-t-Bu-- ous mixture was extracted with ether three times. The com bined extracts were dried over MgSO4. Evaporation of sol 2H). (J. Am. Chem. Soc. 2003, 125, 3714.) vents provided tosyl azide (4 g, 97%). (Eur: J. Org. Chem. Step 4 2003, 821-832.) Step 2 Preparation of 10 4-phenylethynyl-piperidine-1-carboxylic acid Preparation of (1-diazo-2-oxo-propyl)-phosphonic tert-butyl ester acid dimethyl ester

15 N OFSFO Q O -- \-OMe -e- PN OMe BOC 135

133 25 Q O \-OMe PS OMe to O-K) 136 N 30 134 Iodobenzene (135ul, 1.2 mmols), 4-ethynyl-piperidine-1- To a suspension of NaH (60% in mineral oil, 0.83 g, 20.8 carboxylic acid tert-butyl ester (209 mg, 1 mmols) and tri mmols) in THF (50 ml) was added dropwise at 0C (2-oxo 35 propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) ethylamine (167 ul, 1.2 mmols) were dissolved inacetonitrile in THF (50 ml), and the solution was stirred at 0C for one (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 hour. Tosyl azide (4.g. 20 mmols) was added in one portion, mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) were added, stirred at 0C for 10 minutes, filtered through Celite and and reaction mixture was stirred at room temperature over concentrated. The residue was purified by column chroma 40 night and continued to stir at 50 C. for two more hours before tography on silica gel using ethyl acetate to yield the title partitioning between ethyl acetate and water. Organic layer compound (2.9 g, 81%) as oil. (Eur: J. Org. Chem. 2003, was isolated, washed with 1 NHCl, brine and dried (MgSO). 821-832.) Solvents were removed and residue was purified by column Step 3 chromatography on silica gel using Solutions of ethyl acetate 45 in hexanes (1:4; 1:2) to yield the title compound (74 mg). Preparation of 4-ethynyl-piperidine-1-carboxylic LCMS m/e (230, M-t-Bu--2H) acid tert-butyl ester Step 5 50 Preparation of 4-phenylethynyl-piperidine

CHO O O V -OMe PYoMe -- -- N to O-K) Ho N N 136 BOC BOC 131 134 135 60 NH

At 0 C., to a stirred mixture of 4-formyl-piperidine-1- 137 carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg., 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-pro 65 4-Phenylethynyl-piperidine-1-carboxylic acid tert-butyl pyl)-phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in ester was treated with TFA for 10 minutes and concentrated, methanol (2 ml). The resulting mixture was stirred at room lyophilized to provide the title product. US 7,807,672 B2 167 168 PREPARATIVE EXAMPLE 24 4-Pyrimidin-2-ylethynyl-piperidine-1-carboxylic acid tert-butyl ester was treated with TFA for 10 minutes and Step 1 concentrated, lyophilized to provide the title product. Preparation of PREPARATIVE EXAMPLE 25 4-pyrimidin-2-ylethynyl-piperidine-1-carboxylic acid tert-butyl ester Preparation of 4-(4-iodophenyl)-piperazine-1-carboxylic acid 10 tert-butyl ester

Br CuI NaI 's- 15 BocN N N Null BOC 135

25

138 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-bu tylester (3.2g, 9.4 mmol), Cul (0.18 g. 0.95 mmol), Nal (2.81 30 g, 19 mmol) and N,N-Dimethyl-ethane-1,2-diamine (0.2 mL, 1.88 mmol) were mixed in 10 mL Toluene in a pressure To a suspension of 2-bromopyrimidine (175 mg, 1.1 vessel. The vessel was heated at 110° C. for 72 hrs. After mmols), dichlorobis(triphenylphosphine)palladium(II) (35 cooling, the insoluble was filtered off and washed with tolu mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) was added a ene several times. The filtrate was concentrated to give a solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl 35 white solid (3.5 g) as the title compound. M+H 388. ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was parti PREPARATIVE EXAMPLE 26 tioned between ethyl acetate and water, organic layer was Preparation of 4-(4-Imidazol-1-yl-phenyl)-pipera isolated, dried (MgSO), and concentrated. The residue was 40 chromatographed on silica gel eluting with ethyl acetate in Zine-1-carboxylic acid tert-butyl ester hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M+H). 45 Step 2 BocN\ /N NO Preparation of 2-piperidin-4-ylethynyl-pyrimidine

50 NN BocN N M BOCN( ) E & / Ho 55 138

4-(4-Iodo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.194g, 0.5 mmol), Cul (0.01 g), CsCO (0.326 g, 1.0 60 NH E mmol), 1,10Phenanthroline (0.027 g., 0.15 mmol) and imi ()-() dazole (0.034g, 0.5 mmol) were mixed in 3 mL dry DMF in 139 a pressure vessel. The vessel was heated at 110°C. overnight. After cooling tort, the insoluble was filtered and washed with 65 CHC1. The filtrate was concentrated and the crude was purified with prep TLC (7.5% MeOH-2M NH3/CHCl) to yield the title compound (0.077 g). M+H 328. US 7,807,672 B2 169 170 PREPARATIVE EXAMPLE 27 Partial "H NMR (400 MHz, CDC1)O 8.60 (d. 2H) 8.20(d, 2H) 7.0(m, 1H) 6.60 (d. 2H) Preparation of 4-(4-Fluoro-biphenyl-4-yl)-pipera Zine-1-carboxylic acid tert-butyl ester PREPARATIVE EXAMPLE 29 Preparation of piperidin-4-yl-(4-pyrimidin-2-yl-phenyl)-amine hydrochloride by \, 10 C O 15 4M HCl dioxane 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-bu N tyl ester (0.171 g, 0.5 mmol), NaCO (0.16 g, 1.5 mmol), H 4-fluoro phenylboronic acid (0.21 g, 1.5 mmol) and (PPh.) PdCl (0.035 g, 0.05 mmol) were mixed in a mixture of M y THF/HO (4:1, 7.5 mL) and heated at 70° C. overnight. After N HCI cooling tort, the reaction mixture was partitioned between 50 mL ethyl acetate and 25 mL sat. NaCl solution. The separated organic layer washed with brine (10 mL), dried (MgSO)and concentrated. The crude was purified with prep TLC (15% 25 ethyl acetate in hexanes) to give a solid (0.071 g). M+H 356. Stirred 4-(4-Pyrimidin-2-yl-phenylamino)-piperidine-1- carboxylic acid tert-butyl ester (110 mg, 0.310 mmol) in 4M PREPARATIVE EXAMPLE 28 HCl (20 ml) at room temperature for 1 hour. Solvent was evaporated yielding desired product piperidin-4-yl-(4-pyri Preparation of 4-(4-Pyrimidin-2-yl-phenylamino)- 30 midin-2-yl-phenyl)-amine, hydrochloride (114 mg). piperidine-1-carboxylic acid tert-butyl ester Partial "H NMR (400 MHz, CDC1)o 9.0 (d. 2H)8.20(d. 2H) 7.60(m, 1H) 6.90 (d. 2H).

35 PREPARATIVE EXAMPLE 30 Preparation of 4-(5-Nitro-pyridin-2-yl)-piperazine-1- carboxylic acid tert-butyl ester

7. Br 40

45 DME T-C- -- K2CO3, dioxane os-()- -- 50

Co. ox 55 -O-O- A solution of 4-(4-Bromo-phenylamino)-piperidine-1-car Potassium carbonate (1.7g, 12.31 mmol) was added to a boxylic acid tert-butyl ester (355 mg: 1.002 mmol); 2-tribu solution of 2-Chloro-5-nitropyridine (1.33 g, 8.38 mmol) and tylstannanyl-pyrimidine (1.1 g; 2.98 mmol); triphenylphos piperazine-1-carboxylic acid tert-butyl ester (1.57 g, 8.42 phine palladium dichloride (35 mg, 0.049 mmol) was stirred 60 mmol) in dioxane (10 ml) then stirred at reflux for 4 hours. The reaction was cooled, and solvent evaporated. The residue in DME (4 ml) at 100° C. overnight. Reaction mixture was was extracted with MeC1 (100 ml) washed with H2O (50 ml), cooled to room temperature, diluted with EtOAc (100 ml) and separated organic layer washed with brine (50 ml) dried over water (50 ml). Separated organic layer, washed with brine, MgSO filtered and solvent evaporated yielding a residue dried over NaSO, then chromatographed on silica gel elut 65 which chromatographed on silica gel eluting with 10% V/v ing with 70% v/v EtOAc/Hexanes yielding product at solid EtOAc/hexanes yielding desired product as a pale yellow (110 mg; 31%) solid (2.3 g 88%) US 7,807,672 B2 171 172 Partial "H NMR (400 MHz, CDC1)o 9.0 (s, 1H) 8.20(d, Added 4MHCl/dioxane (15 ml) to a solution of 4-(5-Nitro 1H)6.50 (d. 1H). pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.3 g, 7.46 mmol) in Mecla (20 ml) at room temperature. PREPARATIVE EXAMPLE 31 Reaction was stirred for 3 hours and solvent was evaporated 5 yielding the product as hydrochloride salt 1-(5-Nitro-pyridin Preparation of 1-(5-nitro-pyridin-2-yl)-piperazine 2-yl)-piperazine hydrochloride 8 (2.2 g) MS (ESMS, MH, 209) PREPARATIVE EXAMPLE 32 10 Preparation of 4-Piperidin-4-yl-benzamide ON / \ / )-( 4M HCl dioxane = N \ / Y) / N= 15 HN N \ / NO IO) ()-cost Commercially Available

SCHEME 8

TMSCHN O ( V HCI O ( V HCI O He- ''' N He- ''' NH --- X- N- Boc y n Boc y O O HO \ \ y-C-X. FA- y-C-. FA V V -O-O.\

HOBt, EDC ---

HO US 7,807,672 B2 173 174 PREPARATIVE EXAMPLE 33 PREPARATIVE EXAMPLE 35 Preparation of Pyrrolidine-3-carboxylic acid methyl Preparation of ester 1-Carboxymethyl-pyrrolidine-3-carboxylic acid 5 methyl ester

O \m. TMSCHN 10 N HO YBoe 1 -Out: O O 15 HCI X-ON Her X-K NH V n Boc V HCI 2 3 2O Clu. 5 R-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.15gm, 10 mmol) was dissolved in 12 ml of toluene and 3.5 R-1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic ml of methanol. Trimethylsilyldiazomethane 2N solution in 25 acid methyl ester (2.15gm, 8.8 mmol) was dissolved in 20 ml hexanes (6.56 ml, 13.12 mmol) was added dropwise and the of 50% trifluoroacetic acid/dichloromethane and stirred for 2 reaction mixture stirred for 2 hours. The mixture was evapo hrs. The reaction mixture was evaporated to oil and rated to obtain 2.1 gm of an oil. The oil was dissolved in exchanged with hydrochloric acid by dissolving in 20 ml of dichloromethane and adding 10 ml of 1 NHCl in ether to dichloromethane (15 ml) and 5 ml of 4N hydrochloric acid in 30 dioxane added. The reaction mixture was stirred for 1 hr and obtain 3.35gm of a gummy Solid. evaporated to give an oil that crystallizes to give 1.68 gm of title product. PREPARATIVE EXAMPLE 36 Preparation of 1-2-Oxo-2-[4-(4-pyrimidin-2-yl PREPARATIVE EXAMPLE 34 35 phenyl)-piperazin-1-yl-ethyl-pyrrolidine-3-car Preparation of 1-tert-Butoxycarbonylmethyl-pyrroli boxylic acid methyl ester dine-3-carboxylic acid methyl ester

5 + 10 -O.C su-k 45 Clic N s Cluk Nn 2 11

R-pyrrolidine-3-carboxylic acid methyl ester (1.5gm, 9.1 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10 mmol) was dissolved in N,N-dimethylformamide (45 ml). from Step 7, 14.7 mmol) and 1-Carboxymethyl-pyrrolidine Diisopropylethylamine (5.7 ml, 31 ml) was added followed 3-carboxylic acid methyl ester (compound 5 from Step 3, by cesium carbonate (4.35 gm, 13.3 mmol). Tert. butylbro 17.6 mmol) were dissolved in 72 ml of DMF. Triethylamine moacetate (1.5 ml, 10 mmol) was added dropwise and the 60 (8 ml, 57 mmol), 1-hydroxybenztriazole (2.29 gm) and 1-(3- reaction mixture stirred for 1 hr. Brine was added to the dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride reaction mixture which was then extracted with ethylacetate (EDC1) (3.43 gm, 18 mmol) were added and the reaction three times. The ethylacetate extracts were dried over mag mixture stirred for 24 hrs. After washing with brine, extract nesium sulfate, filtered and evaporated to obtain crude title 6s ing with dichloromethane, and drying over magnesium Sul product. The crude product was chromatographed to obtain fate, the mixture was evaporated and chromatographed on 2.15 gm, 97% of title product. silica gel to obtain 5.0gm of title product. US 7,807,672 B2 175 176 PREPARATIVE EXAMPLE 37 -continued phenyl)-piperazin-1-yl-ethyl-pyrrolidine-3-car-Preparation of 1-2-Oxo-2-[4-(4-pyrimidin-2-yl- "y .C N Oy boxylic acid 5 NH N/ Os HO C)

O O 10

OV Nulls N LiOH To a solution of 1-2-oxo-2-4-(4-pyrimidin-2-yl-phenyl)-py y1-pneny N- piperazin-1-yl-ethyl-pyrrolidine-3-carboxylic acid (40 mg. is 0.10 mmol) and 4-amino-2-cyclopropyl-phenol (22 mg, 0.15 N mmol) in 1.5 mL of DMF was added DIEA (26 uL, 0.15 mL) s followed by HATU (57 mg, 0.15 mmol). The reaction was N 21 stirred at room temperature for 2 hand purified by chroma tography to afford 17 (23 mg), MS found 527.2 (M--H) 2O ) Cul st

O CluxO -

N 22' 30 HO susO X 12 O O

1-2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1- 35 HO NH2 CluxO i. yl-ethyl-pyrrolidine-3-carboxylic acid methyl ester (com pound 11 from Step 8, 3.3 gm, 8.06 mmol) was dissolved in C methanol and 10 ml of 1 N lithium hydroxide added. The O reaction mixture was stirred for 18 hrs. 10 ml of 1 NHCl was ym. added to the reaction mixture and evaporated to a white solid HO NH KO (3.94 gm)

PREPARATIVE EXAMPLE 38 C 45 O y phenyl)-piperazin-1-yl-ethyl-pyrrolidine-3-car-Preparation of 1-2-Oxo-2-[4-(4-pyrimidin-2-yl- ye N N N O's boxylic acid (3-cyclopropyl-4-hydroxy-phenyl)- HO \ Z amide 50 C

O PREPARATIVE EXAMPLE 39 O s \U/ N Preparation of 1-tert-Butoxycarbonylmethyl-pyrroli HO s dine-3-carboxylic acid, Lithium Salt \ 2 HO 60 HOBt, EDC

65 Clus. 4 US 7,807,672 B2 177 178 PREPARATIVE EXAMPLE 41 -continued Preparation of 3-(3-Chloro-4-hydroxy-phenylcar bamoyl)-pyrrolidin-1-yl)-acetic acid Clu-k 5 63 10 HO Clux

1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic C acid methyl ester 4 (see Example 1 Step 2) (0.753 g, 3.098 mmol) was dissolved in MeOH/THF (10 ml; 1/1) and 2N 15 Lithium hydroxide (1.5 ml, 3 mmol) was added. The resultant HO Solution was stirred for 2 hours, and solvent was evaporated yielding title compound 63 as a white solid (0.71 g, 100%). Mass Spec ES (230, M+H). C PREPARATIVE EXAMPLE 40 3-(3-Chloro-4-hydroxy-phenylcarbamoyl)-pyrrolidin-1- yl)-acetic acid tert-butyl ester was dissolved in TFA/DCM Preparation of 3-(3-Chloro-4-hydroxy-phenylcar (90:10) solution. After stirring at RT for 30 min, the reaction bamoyl)-pyrrolidin-1-yl)-acetic acid tert-butyl ester 25 mixture was concentrated and acetonitrile/water (10 ml, 3:1) was added. After removal of solvent, the residue was purified using Prep-HPLC to give 450 mg of product. Mass Spec ES (299.1, M+H) 30 PREPARATIVE EXAMPLE 42 Preparation of 1-2-Oxo-2-5-(4-pyrimidin-2-yl phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl-ethyl Clu X. 35 pyrrolidine-3-carboxylic acid (3-chloro-4-hydroxy phenyl)-amide

HOBt, EDC HO NH2 Her 40 O

\ III I O

HO NH) Clu OH --

45 C 10, HOB, EDC

HO . Clux YK N 50 NH -- C HO N

C N s 55 O To a mixture of 1-tert-Butoxycarbonylmethyl-pyrrolidine 3-carboxylic acid, Lithium salt (0.5g, 2.12 mmol) and HOBt To a mixture of 3-(3-Chloro-4-hydroxy-phenylcarbam (0.45 g, 3.3 mmol) in DMF (10 ml) at 0°C. was added EDC1 oyl)-pyrrolidin-1-yl)-acetic acid (10 mg, 0.034 mmol) and (630 mg, 3.3 mmol). The formed reaction mixture was stirred 60 HOBt (6.8 mg, 0.050 mmol) in DMF (0.5 ml) at 0°C. was at 0°C. for 0.5 hour and then 4-amino-2-chloro-phenol was added EDC1 (9.6 mg 0.050 mmol). The formed reaction added. After stirred at RT for overnight, the reaction mixture mixture was stirred at 0° C. for 0.5 hour and then 2-(4- was added to ice-water (50g) and the formed precipitated was Pyrimidin-2-yl-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane collected by filtration, washed with sodium bicarbonate and hydrochloride salt (12.6 mg, 0.05 mmol) was added. After HCl (0.1 N). After drying in air, the crude product (720 mg) 65 stirred at RT for overnight, the reaction mixture was purified was used directly in the next step. Mass Spec ES (355.2, using a Prep-HPLC to give titled compound (3.4 mg, 19% M+H) yield). Mass Spec ES (533.1, M+H) US 7,807,672 B2 179 180 PREPARATIVE EXAMPLE 43 Step 3 Preparation of 3-(tert-butyl-dimethyl-silanyloxym Step 1 ethyl)-pyrrolidine-3-carboxylic acid ethyl ester Preparation of 2-(tert-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester EtOOC

10 HCOONH Pd(C EtOOC OH EtOOC O-S

He- ) / 15 87 84 85 EtOOC

To a stirred solution of 2-hydroxymethyl-acrylic acid ethyl O ester (260 mg, 2 mmol) and imidazole (163 mg, 2.4 mmol) in dry DMF (5 ml) was added tert-butyldimethylsilyl chloride N/ (362 mg, 2.4 mmol). The reaction mixture was stirred over night and diluted with ether, washed with water three times X and dried over MgSO4. Solvent was removed under reduced 88 pressure to provide a crude product that was purified by 25 column chromatography using a solution of ethyl acetate in A mixture of 1-benzyl-3-(tert-butyl-dimethyl-silany hexanes (1:6) to obtain the title product (463 mg, 95%). loxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (690 mg, 1.83 mmol), ammonium formate (461 mg, 7.31 mmol), Step 2 10% Pd/C (100mg) in methanol (10 ml) and water (1 ml) was 30 refluxed overnight. The mixture was filtered through celite, Preparation of 1-benzyl-3-(tert-butyl-dimethyl-sila washed with ethylacetate. The combined filtrate was concen nyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl trated and the residue was taken into ethyl acetate, washed ester with brine and dried over MgSO4. Evaporation of solvent 35 provided the title compound as oil (444 mg. 84%). Step 4 S1N1,No. Synthesis of 1-tert-butoxycarbonylmethyl-3-(tert 1 ls -- butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3- 40 Ph carboxylic acid ethyl ester 86

EtOOC O-S TFA EtOOC --- 45 NH

85 EtOOC

N N1 Ph O n/ XR EtOOC Nulls,O 87 k To a cold solution of 2-(tert-butyl-dimethyl-silanyloxym ethyl)-acrylic acid ethyl ester (463 mg, 1.89 mmol) and 60 X N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (540 ul, 2.11 mmol) in dichloromethane (3 ml) was added at 0° C. trifluoroacetic acid (26 ul, 0.34 mmol). The resulting Solution was warmed to room temperature in two hours. The To a stirred mixture of 3-(tert-butyl-dimethyl-silany crude product was purified by column chromatography on 65 loxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (444 silica get eluting with a solution of ethyl acetate in hexanes mg, 1.54 mmol), triethylamine (214 ul, 1.54 mmol) and (1:10, 1:5) to give the title compound (490 mg, 69%). cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) US 7,807,672 B2 181 182 was added tert-butyl bromoacetate (351 ul, 2.38 mmol) Step 2 slowly. The mixture was stirred for 1 hour, filtered and con centrated. The residue was diluted with ethyl acetate, washed Preparation of with water and dried over MgSO. Solvent was removed 1-benzyl-3-methoxymethyl-pyrrolidine-3-carboxylic under reduced pressure to give a crude product that was 5 acid methyl ester purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound. \ MeOOC Step 5 S1N1,No. TFA 1. ls -- He Preparation of 1-tert-butoxycarbonylmethyl-3-hy Ph MeO droxymethyl-pyrrolidine-3-carboxylic acid ethyl 93 92 ester 15

MeOOC EtOOC O N N1 Ph OMe Nulls, 94 \/ k He XX 25 89 To a stirred solution of methyl 2-(methoxymethyl)acrylate (176 mg, 1.35 mmol) and N-(methoxymethyl)-N-(trimethyl EtOOC O silylmethyl)benzylamine (416 ul, 1.63 mmol) in dichlo romethane (2 ml) was added at 0°C. trifluoroacetic acid (21 NullsO 30 ul, 0.27 mmol). The resulting solution was warmed to room temperature and stirred overnight. The crude product was OH k purified by column chromatography on silica, eluted with a 90 solution of ethyl acetate in hexanes (1:3), then 5% methanol in ethyl acetate to give the title compound (293 mg, 82%). 35 Tetrabutylammonium fluoride (1.8 ml, 1 M in THF) was Step 3 added to 1-tert-butoxycarbonylmethyl-3-(tert-butyl-dim ethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl Preparation of ester (726 mg, 1.8 mmol). The reaction solution was stirred 3-methoxymethyl-pyrrolidine-3-carboxylic acid for half hour and purified by column chromatography using 40 methyl ester solution of ethyl acetate in hexanes (1:1), then ethyl acetate to provide the title product (350 mg, 68%).

PREPARATIVE EXAMPLE 44 45 Step 1 MeOOC MeOOC N N1 Ph HCOON H4 NH Preparation of methyl 2-(methoxymethyl)acrylate Pd(C 50 OMe OMe 94 95

MeOOC MeOOC + MeONa --> Br MeO 55 91 92 A mixture of 1-benzyl-3-methoxymethyl-pyrrolidine-3- carboxylic acid methyl ester (373 mg, 1.42 mmol), ammo nium formate (358 mg, 5.68 mmol), 10% Pd/C (100 mg) and To a stirred mixture of methyl 2-(bromomethyl)acrylate methanol (6 ml) was refluxed overnight. The mixture was (239 ul, 2 mmol) in petroleum ether (3 ml) was added potas 60 filtered through Celite, washed with ethyl acetate. The com sium carbonate (276 mg, 2 mmol), followed by sodium meth bined filtrate was concentrated and the residue was taken into oxide (119 mg, 2.2 mmol) and methanol (450 ul). The result ethyl acetate, washed with Small amount of water. Aqueous ing mixture was stirred overnight, filtered, concentrated to a layer was isolated, extracted with dichloromethane three residue that was purified by column chromatography eluting times. The dichloromethane extracts were combined with with 10% ether in hexanes to provide the title compound (150 65 previous ethyl acetate extracts and dried over MgSO. Evapo mg, 58%). (Reference: J. Med. Chem.: 42; 15: 1999; 2760 ration of solvents provided the title compound as oil (140 mg. 2773.) 57%). US 7,807,672 B2 183 184 Step 4 Step 6 Preparation of 1-tert-butoxycarbonylmethyl-3-meth Preparation of 3-methoxymethyl-1-(2-oxo-2-[4-(4- oxymethyl-pyrrolidine-3-carboxylic acid methyl pyrimidin-2-yl-phenyl)-piperazin-1-yl-ethyl-pyrro ester lidine-3-carboxylic acid ethyl ester

10

97 + 1 () -- MeOOC r Ng -- NH 15 OMe 95 MeOOC O

MeOOC O XOlu r OMe N- N

O OMe n 96 25 O 98

To a stirred mixture of 3-methoxymethyl-pyrrolidine-3- To a solution of 1-carboxymethyl-3-methoxymethyl-pyr carboxylic acid methyl ester (140 mg. 0.81 mmol), triethy rolidine-3-carboxylic acid methyl ester (compound 97) (0.21 lamine (112 ul, 0.82 mmol) and cesium carbonate (263 mg. mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 0.81 mmol) in acetonitrile (2 ml) was added tert-butyl bro 10, see Example 1 Step 7) (0.21 mmol), O-(7-azabenzotria moacetate (119 ul, 0.81 mmol) slowly. The mixture was 35 Zol-1-yl-)-N.N.N',N'-tetramethyluronium hexafluorophos stirred for 15 minutes, filtered and concentrated. The residue phate (HATU) (78 mg, 0.21 mmol) in dry DMF (2 ml) was was purified by column chromatography on silica gel. Elution added N,N-diisopropylethylamine (108 ul, 0.62 mmol). The with a solution of ethyl acetate and hexanes (1:2) provided reaction mixture was stirred for 4 hours, and evaporated to a 118 mg (51%) of the title compound. residue that was partitioned in ethyl acetate and saturated 40 sodium carbonate. Organic layer was isolated, washed with Step 5 water, brine and dried over magnesium sulfate. Evaporation Preparation of 1-carboxymethyl-3-methoxymethyl of solvent provided a crude product which was chromato pyrrolidine-3-carboxylic acid methyl ester graphed with 5% methanol in dichloromethane to furnish the 45 title compound (97 mg). Step 7 MeOOC O Preparation of 3-methoxymethyl-1-(2-oxo-2-[4-(4- N 50 pyrimidin-2-yl-phenyl)-piperazin-1-yl-ethyl-pyrro susO X TFA lidine-3-carboxylic acid OMe 96 MeOOC O 55 NullsOH MeOOC O OMe Null 97 ^ 60 OMe N- N

The 1-tert-butoxycarbonylmethyl-3-methoxymethyl-pyr N rolidine-3-carboxylic acid methyl ester (118 mg) was treated n with trifluoroacetic acid (2 ml), stirred for 20 minutes and O evaporated to a residue that was exchanged with hydrochloric 65 acid (1 ml. 4N) and lyophilized overnight to a gummy title 98 product. US 7,807,672 B2 185 186 PREPARATIVE EXAMPLE 46 -continued Step 1 HOOC O Nulls, Preparation of 2-fluoromethyl-acrylic acid ethyl ester OMe O 10 EtOOC EtOOC n DAST

Na2 HO F 99 15 84 101

The 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3- To a solution of (diethylamino)sulfur trifluoride (DAST) carboxylic acid methyl ester (97 mg, 0.21 mmol) was saponi (363 ul. 2.76 mmol) in dichloromethane (1 ml) was slowly fied with lithium hydroxide monohydrate (27 mg, 0.64 mmol) added at -78 C. a solution of 2-hydroxylmethyl acrylic acid in tetrahydronfuran and water (2:1, 3 ml) for 2 hours. The ethyl ester (300 mg, 2.31 mmol) in dichloromethane (3 ml). reaction mixture was acidified with 4 NHCl and lyophilized The reaction mixture was allowed to warm to room tempera overnight to provide the title compound which was directly ture, re-chilled to -78 C. and additional DAST (100 ul, 0.76 used in the next step synthesis. 25 mmol) was added to ensure complete reaction. The reaction mixture was let to warm to room temperature and quenched PREPARATIVE EXAMPLE 45 with Saturated Sodium carbonate. Organic layer was isolated, washed with water, brine and dried (MgSO). The dichlo Preparation of 3-Methoxymethyl-1-(2-oxo-2-4-(4- 30 romethane Solution was directly passed through a short silica pyrimidin-2-yl-phenyl)-piperazin-1-yl-ethyl-pyrro gel pad, eluted with dichloromethane and the product frac lidine-3-carboxylic acid (4-hydroxy-3-trifluorom tions were collected. The combined fractions (ca. 12 ml) will ethyl-phenyl)-amide be directly used in the next step synthesis without further concentration. 35 Step 2 Preparation of 1-benzyl-3-fluoromethyl-pyrrolidine-3-carboxylic (Clu, 40 acid ethyl ester --

N EtOOC n 45 N s1N1 NoMe -- HeTFA Na2 ls Ph F HO 86 101 HOBt, EDC EtOOC --- 50 FC NH2 N N1 Ph O O F 102 HO -)- NH sul ^ 55 O N N FC / N-(methoxymethyl)-N-(trimethylsilylmethyl)benzy N lamine (548 ul, 2.14 mmol) was dissolved in the dichlo a romethane solution of the 2-fluoromethyl-acrylic acid ethyl O 60 ester from the previous reaction and chilled to 0 C. A solution of trifluoroacetic acid (67 ul, 0.87 mmol) in dichloromethane A mixture of compound 2 (0.058 mmols), HOBt (7.8 mg, (0.5 ml) was added slowly. The reaction mixture was allowed 0.058 mmols), EDC (11 mg, 0.057 mmols) in DMF (1 ml) to warm to room temperature in two hours and directly chro was stirred at r.t. overnight, then 55° C. overnight. The reac 65 matographed on silica gel. Elution with Solutions of ethyl tion mixture was directly purified by HPLC (Gilson) to pro acetate in hexanes (1:5, 1:4, 1:3) obtained the title product vide titled compound. MS found 599.1 (M+H) (143 mg) as oil. US 7,807,672 B2 187 188 PREPARATIVE EXAMPLE 47 -continued MeO N O -(- F r O O MeOC MeOC NBoc -- NBoc n-Butyl lithium (2.5M/Hexanes, 3.83 ml; 9.575 mmol) 10 1D added dropwise to solution of diisopropylamine (1.36 ml; OH 9.62 mmol) at -78° C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to -78°C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2 g, 8.72 mmol) in THF (10 ml) was 15 added dropwise, warmed to -40°C. for 1 hour, then cooled to -70° C. A solution of N-fluorobenzene-sulfonimide (3.02 g, 9.57 mmol) in THF (15 ml) was added dropwise, stirred at To a solution of LDA (33.5 mmol. 16.7 mL, 2 Mintoluene) -78° C. for 1 hour, then stirred at room temperature over in 50 mL THF cooled at -78 deg C. was added a solution of night. Precipitated solid was filtered, washed with EtOAc ID (5.9 g, 25.7 mmol) in 50 mL THF drop wise. The crude (2x150 ml). Organic layer was washed with 1 NHCl (30 ml), was stirred at -78 deg C. for 45 mins. To the crude was brine (100 ml), dried (MgSO), filtered and solvent evapo bubbled formaldehyde gas, freshly generated from cracking rated. The residue was chromatographed on silica gel eluting of para-formaldehyde (12 g, 400 mmol). The crude was with 10% V/v EtOAc/hexanes yielding product as colorless stirred at -78 deg C. for an additional 30 mins. To the crude oil (1.38 g:64% yield). MS (ESMS, MH 249). was added sat NHCl (200 mL). The crude was warmed to rt. 25 The crude was diluted in EtOAc. The organic layer washed PREPARATIVE EXAMPLE SO with brine and dried over MgSO, filtered, and conc. in vacuum. The crude was purified on Biotage using EtOAc/ Preparation of 3-Allyl-pyrrolidine-1,3-dicarboxylic hexane (3:7)->EtOAc/hexane (1:1) to give 6.6 g (57%) of the acid 1-tert-butyl ester 3-methyl ester product as a yellow oil. 30

PREPARATIVE EXAMPLE 48

35

NBoc MeOC NBOC -- HO NBOC 40

OH OH 2D 3D

45

To a solution of ester 2D (2.5g, 9.6 mmol) in MeOH (100 mL) was added 1 N NaOH (48 mL, 48.2 mmol) at rt. The crude was stirred at rt overnight. To the crude was added 1 N Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-me 50 thyl ester 2 (see Example 1, Step 1) (4.58 g. 20 mmol) was HC1 (47.5 mL, 47.5 mmol). The crude was stirred at rt for 5 dissolved in THF (100 mL) and cooled down to -78°C. in a mins. PH of crude is made to 5 using PH paper. The crude was dry ice-acetone bath. LDA (12 mL, 2.0 M, 24 mmol) was then conc in vacuum and azeotropped 2x with toluene and dried added dropwise. The mixture was stirred at -78°C. for 1 hr. under high vacuum for use the next reaction. Allyl bromide (5.3 mL, 61 mmol) was added in neat. The 55 reaction was allowed to warm to rt naturally and stirred for 24 PREPARATIVE EXAMPLE 49 hrs. It was then quenched with sat. NHCl solution, extracted with ethyl acetate 2x150 mL. The organic layer washed with Preparation of 3-Fluoro-pyrrolidine-1,3-dicarboxylic brine, dried (MgSO) and concentrated. The crude was puri acid 1-tert-butyl ester 3-methyl ester fied on silica gel column using 4:1 hexanes/ethyl acetate to 60 get the title compound (3.6 g) as a yellow oil. MS (292, MNa). EXAMPLES 1 TO 14 LDA/PhSONF He The compounds in Table 1 were prepared utilizing Scheme N s THF 65 8 and Preparative example 43-50 substituting the appropriate O O piperazine derivative for the piperazine compound 10, and appropriate pyrrolidine as described in examples 43-50. US 7,807,672 B2 189 190

TABLE 1.

Retention Time EX Compound M+ 1 (Minutes) HO C--O F F - O O- "O-2O (-)-O-( )-()

O) ()-O-(-k)

HO O (Y)-O-O-K)X- N/ \N ) CF; OH

O HO N \ X-O-(){ N N ()\ / CF: OMe Preparative Example 45

O HO N X-O-()4 N\ /N ()\ / CF; F

519.3 3.41

HO or-C-C,O- CH piperazine commercially available US 7,807,672 B2 191 192

TABLE 1-continued

Retention Time EX Compound M' + 1 (Minutes)

511.2 3.51 HO -C-- O

piperazine commercially available DC-2-)-C-O-D

10 O N NJ-y\ HO \U/ N O n NH2 CF

11 O HO N /N C CH2 F N O 2 \U/ F F piperazine commercially available

12 HO O ) ( ) NS N K 4 N\ /N \ / CF; OH

13 O HN N buy- /N C

HO O \U/

CF piperazine commercially available US 7,807,672 B2 193 194

TABLE 1-continued

Retention Time EX Compound M' + 1 (Minutes)

14 CH3 F. F O o/ F N AJ-?\ O

HO O \U/

piperazine commercially available

EXAMPLES 15-107, 109, 110, AND 112-117 20 (de-Boc) piperazine compound 106a in preparative example 19 step 2. If the piperazine derivative is not The compounds in Table 2 were prepared utilizing Scheme described, it is commercially available or prepared by meth 9 and Preparative example 39-42 substituting the appropriate ods similar to procedures described herein and known in the piperazine derivative as described herein for the deprotected art.

TABLE 2

Retention Time EX Compound M' + 1 (minutes)

15

HOu O-O-O-( )

-C-C, ( ) ( ) F C-C-C- C CH US 7,807,672 B2 195 196

TABLE 2-continued

Retention Time EX Compound M + 1 (minutes) 19 N-C -\\ 5334 3.03

Preparative example 42 -C \-/ C-C 21 C. -CU-y NS C \-/ C-C 22 -)--O-O-O-O 23

CH3

24 A 25 N-O-)-. O V -C \-/ C-C - CH3 CH