Compounds that are ERK inhibitors

BACKGROUND

The processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2. When activated, ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of ERK1/2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers. These observations indicate that the ERK1/2 signalling pathway is an attractive pathway for anticancer therapies in a broad spectrum of human tumours.

Therefore, a welcome contribution to the art would be small-molecules (i.e., compounds) that inhibit ERK activity (i.e., ERK1 and ERK2 activity), which small-molecules would be useful for treating a broad spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION

This invention provides compounds that inhibit the activity of ERK1 and/or the activity of ERK2.

The compounds of this invention also inhibit the phosphorylation of ERK1 and ERK2.

Thus, this invention provides compounds that are ERK inhibitors (i.e., ERK1 inhibitors and/or ERK2 inhibitors), said compounds being of the formula 1.0:

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or the pharmaceutically acceptable salts thereof, wherein:

Y¹, Y², and Y³are each independently selected from the group consisting of: C, N and substituted carbon;

Q is selected from the group consisting of: piperidinyl, piperazinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), bridged piperazinyl, bridged piperidinyl, bridged tetrahydropyridinyl, substituted piperidinyl, substituted piperazinyl, substituted tetrahydropyridinyl (e.g., a substituted 1,2,3,6-tetrahydro-pyridinyl), bridged substituted piperazinyl, bridged substituted piperidinyl, and bridged substituted tetrahydropyridinyl;

z is 1 to 3 (and preferably 1); and

R¹, R², R⁸, R³⁵and R³⁶are as defined below.

This invention provides compounds of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) in pure or isolated form.

This invention also provides a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90) and an effective amount of at least one other (e.g., 1, 2 or 3, 1 or 2, and usually 1) pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

This invention also provides a method of inhibiting ERK (i.e., inhibiting the activity of ERK) in a patient in need of such treatment 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method of inhibiting ERK1 (i.e., inhibiting the activity of ERK1) in a patient in need of such treatment 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method of inhibiting ERK2 (i.e., inhibiting the activity of ERK2) in a patient in need of such treatment 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method of inhibiting ERK1 and ERK2 (i.e., inhibiting the activity of ERK1 and ERK2) in a patient in need of such treatment 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method of treating cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90) in combination with at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) signal transduction inhibitor.

This invention also provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90) in combination with at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) signal transduction inhibitor.

This invention also provides a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma, in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer.

This invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer.

This invention also provides a method for treating melanoma in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating pancreatic cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating pancreatic cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating pancreatic cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating thyroid cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating thyroid cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating thyroid cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating colorectal cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating lung cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating breast cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating ovarian cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents).

This invention also provides methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents).

This invention also provides methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

The methods of treating breast cancer described herein include the treatment of hormone-dependent metastatic and advanced breast cancer, adjuvant therapy for hormone-dependent primary and early breast cancer, the treatment of ductal carcinoma in situ, and the treatment of inflammatory breast cancer in situ.

The methods of treating hormone-dependent breast cancer can also be used to prevent breast cancer in patients having a high risk of developing breast cancer.

Thus, this invention also provides methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents).

This invention also provides methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents).

This invention also provides methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective 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 one of Embodiment Nos. 1 to 90) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) a in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of a chemotherapeutic agent, wherein said chemotherapeutic agent is temozolomide.

This invention also provides a method for treating prostate cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating acute myelogenous leukemia (AML) in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating acute myelogenous leukemia (AML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating acute myelogenous leukemia (AML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating bladder cancer in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating multiple myeloma in a patient in need of such treatment, said method 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 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

This invention also provides a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90).

This invention also provides a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective 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 one of Embodiment Nos. 1 to 90), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

In the methods of this invention the compounds of this invention can be administered concurrently or sequentially (i.e., consecutively) with the chemotherapeutic agents or the signal transduction inhibitor.

The methods of treating cancers described herein can optionally include the administration of an effective amount of radiation (i.e., the methods of treating cancers described herein optionally include the administration of radiation therapy).

DETAILED DESCRIPTION OF THE INVENTION

As described herein, unless otherwise indicated, the use of a drug or compound in a specified period is per treatment cycle. For example, once a day means once per day of each day of the treatment cycle. Twice a day means twice per day each day of the treatment cycle. Once a week means one time per week during the treatment cycle. Once every three weeks means once per three weeks during the treatment cycle.

The following abbreviations have the following meanings unless defined otherwise:

- ACN Acetonitrile
- AcOH Acetic acid
- DAST (diethylamino)sulfur trifluoride
- DCC Dicyclohexylcarbodiimide
- DCU Dicyclohexylurea
- DCM Dichloromethane
- DIAD Diisopropylazodicarboxylate
- DIEA Diisopropylethylamine
- DMAP 4-Dimethylaminopyridine
- DME Dimethoxyethane
- DMF Dimethylformamide
- DMFDMA N,N-Dimethylformamide dimethylacetal DMSO Dimethyl sulfoxide
- DTT Dithiothreitol
- EDCl 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride
- EtOAc Ethyl acetate
- EtOH Ethanol
- HATU N,N,N′,N′-Tetramethyl-O-(7-Azabenzotriazol-1-yl)Uronium hexafluorophosphate
- Hex hexanes
- HOBt 1-Hydroxylbenzotriazole
- HPLC High pressure liquid chromatography
- LCMS Liquid chromatography mass spectrometry
- LDA Lithium diisopropylamide
- mCPBA meta-Chloroperoxybenzoic acid
- MeOH Methanol
- MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue)
- NMR Nuclear magnetic resonance
- PFP Pentafluorophenol
- PMB p-methoxybenzyl
- Pyr Pyridine
- RT Room temperature
- SEMCl 2-(Trimethylsily)ethoxy methyl chloride
- TEA Triethylamine
- Tr Triphenyl methane
- TrCl Triphenyl methane chloride
- TFA Trifluoroacetic acid
- THF Tetrahydrofuran
- TLC Thin layer chromatography
- TMS Trimethylsilyl

As used herein, unless otherwise specified, the following terms have the following meanings:

- “anti-cancer agent” means a drug (medicament or pharmaceutically active ingredient) for treating cancer;
- “antineoplastic agent” means a drug (medicament or pharmaceutically active ingredient) for treating cancer (i.e., a chemotherapeutic agent);
- “at least one”, as used in reference to the number of compounds of this invention means for example 1-6, generally 1-4, more generally 1, 2 or 3, and usually one or two, and more usually one;
- “at least one”, as used in reference to the number of chemotherapeutic agents used, means for example 1-6, generally 14, more generally 1, 2 or 3, and usually one or two, or one;
- “chemotherapeutic agent” means a drug (medicament or pharmaceutically active ingredient) for treating cancer (i.e., and antineeoplastic agent);
- “compound” with reference to the antineoplastic agents, includes the agents that are antibodies;
- “concurrently” means (1) simultaneously in time (e.g., at the same time); or (2) at different times during the course of a common treatment schedule;
- “consecutively” means one following the other;
- “different” as used in the phrase “different antineoplastic agents” means that the agents are not the same compound or structure; preferably, “different” as used in the phrase “different antineoplastic agents” means not from the same class of antineoplastic agents; for example, one antineoplastic agent is a taxane, and another antineoplastic agent is a platinum coordinator compound;
- “effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention, or an amount of radiation, effective in treating or inhibiting the diseases or conditions described herein, and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect; thus, for example, in the methods of treating cancer described herein “effective amount” (or “therapeutically effective amount”) means, for example, the amount of the compound (or drug), or radiation, that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor; for example, in the treatment of lung cancer (e.g., non small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain; also, for example, an effective amount, or a therapeutically effective amount of the ERK inhibitor (i.e., a compound of this invention) is that amount which results in the reduction in ERK (ERK1 and/or ERK2) activity and phosphorylation; the reduction in ERK activity may be determined by the analysis of pharmacodynamic markers such as phosphorylated RSK1,2 and phosphorylated ERK1,2, using techniques well known in the art;
- “one or more” has the same meaning as “at least one”;
- “patient” means an animal, such as a mammal (e.g., a human being, and preferably a human being);
- “prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, i.e., to the compounds of formula 1.0 or to a salt and/or to a solvate thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes Prodrugs of the novel compounds of this invention;
- sequentially-represents (1) administration of one component of the method ((a) compound of the invention, or (b) chemotherapeutic agent, signal transduction inhibitor and/or radiation therapy) followed by administration of the other component or components; after administration of one component, the next component can be administered substantially immediately after the first component, or the next component can be administered after an effective time period after the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component; and
- “solvate” means a physical association of a compound of this invention with one or more solvent molecules; this physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding; in certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid; “solvate” encompasses both solution-phase and isolatable solvates; non-limiting examples of suitable solvates include ethanolates, methanolates, and the like; “hydrate” is a solvate wherein the solvent molecule is H₂O.

As used herein, unless otherwise specified, the following terms have the following meanings, and unless otherwise specified, the definitions of each term (i.e., moiety or substituent) apply when that term is used individually or as a component of another term (e.g., the definition of aryl is the same for aryl and for the aryl portion of arylalkyl, alkylaryl, arylalkynyl, and the like):

- “acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, Alkynyl-C(O)—, cycloalkyl-C(O)—, cycloalkenyl-C(O)—, or cycloalkynyl-C(O)— group in which the various groups are as defined below (and as defined below, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties can be substituted); the bond to the parent moiety is through the carbonyl; preferred acyls contain a lower alkyl; Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl;
- “alkenyl” means an aliphatic hydrocarbon group (chain) comprising at least one carbon to carbon double bond, wherein the chain can be straight or branched, and wherein said group comprises about 2 to about 15 carbon atoms; Preferred alkenyl groups comprise about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain; branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, or alkenyl groups are attached to a linear alkenyl chain; “lower alkenyl” means an alkenyl group comprising about 2 to about 6 carbon atoms in the chain, and the chain can be straight or branched; the term “substituted alkenyl” means that the alkenyl group is substituted by one or more independently selected substituents, and each substituent is independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl); non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl;
- “alkoxy” means an alkyl-O— group (i.e., the bond to the parent moiety is through the ether oxygen) in which the alkyl group is unsubstituted or substituted as described below; non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy;
- “alkoxycarbonyl” means an alkyl-O—CO— group (i.e., the bond to the parent moiety is through the carbonyl) wherein the alkyl group is unsubstituted or substituted as previously defined; non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl;
- “alkyl” (including the alkyl portions of other moieties, such as trifluoroalkyl and alkyloxy) means an aliphatic hydrocarbon group (chain) that can be straight or branched wherein said group comprises about 1 to about 20 carbon atoms in the chain; preferred alkyl groups comprise about 1 to about 12 carbon atoms in the chain; more preferred alkyl groups comprise about 1 to about 6 carbon atoms in the chain; branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain; “lower alkyl” means a group comprising about 1 to about 6 carbon atoms in the chain, and said chain can be straight or branched; the term “substituted alkyl” means that the alkyl group is substituted by one or more independently selected substituents, and wherein each substituent is independently selected from the group consisting of: halo, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy, —C(O)O-alkyl and —S(alkyl); non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl;
- “alkylaryl” (or alkaryl) means an alkyl-aryl- group (i.e., the bond to the parent moiety is through the aryl group) wherein the alkyl group is unsubstituted or substituted as defined above, and the aryl group is unsubstituted or substituted as defined below; preferred alkylaryls comprise a lower alkyl group; non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl;
- “alkylheteroaryl” means an alkyl-heteroaryl- group (i.e., the bond to the parent moiety is through the heteroaryl group) wherein the alkyl is unsubstituted or substituted as defined above and the heteroaryl group is unsubstituted or substituted as defined below;
- “alkylsulfinyl” means an alkyl-S(O)— group (i.e., the bond to the parent moiety is through the sulfinyl) wherein the alkyl group is unsubstituted or substituted as previously defined; preferred groups are those in which the alkyl group is lower alkyl;
- “alkylsulfonyl” means an alkyl-S(O₂)— group (i.e., the bond to the parent moiety is through the sulfonyl) wherein the alkyl group is unsubstituted or substituted as previously defined; preferred groups are those in which the alkyl group is lower alkyl;
- “alkylthio” means an alkyl-S— group (i.e., the bond to the parent moiety is through the sulfur) wherein the alkyl group is unsubstituted or substituted as previously described; non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio;
- “alkynyl” means an aliphatic hydrocarbon group (chain) comprising at least one carbon to carbon triple bond, wherein the chain can be straight or branched, and wherein the group comprises about 2 to about 15 carbon atoms in the; preferred alkynyl groups comprise about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain; Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkynyl chain; “lower alkynyl” means an alkynyl group comprising about 2 to about 6 carbon atoms in the chain, and the chain can be straight or branched; non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl; the term “substituted alkynyl” means that the alkynyl group is substituted by one or more independently selected, and each substituent is independently selected from the group consisting of alkyl; aryl and cycloalkyl;
- “amino means a —NH₂group;
- “aralkenyl” (or arylalkenyl) means an aryl-alkenyl- group (i.e., the bond to the parent moiety is through the alkenyl group) wherein the aryl group is unsubstituted or substituted as defined below, and the alkenyl group is unsubstituted or substituted as defined above; preferred aralkenyls contain a lower alkenyl group; non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl;
- “aralkyl” (or arylalkyl) means an aryl-alkyl- group (i.e., the bond to the parent moiety is through the alkyl group) wherein the aryl is unsubstituted or substituted as defined below and the alkyl is unsubstituted or substituted as defined above; preferred aralkyls comprise a lower alkyl group; non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl;
- “aralkyloxy” (or arylalkyloxy) means an aralkyl-O— group (i.e., the bond to the parent moiety is through the ether oxygen) wherein the aralkyl group is unsubstituted or substituted as previously described; non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy;
- “aralkoxycarbonyl” means an aralkyl-O—C(O)— group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aralkyl group is unsubstituted or substituted as previously defined; a non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl;
- “aralkylthio” means an aralkyl-S— group (i.e., the bond to the parent moiety is through the sulfur) wherein the aralkyl group is unsubstituted or substituted as previously described; a non-limiting example of a suitable aralkylthio group is benzylthio;
- “aroyl” means an aryl-C(O)— group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aryl group is unsubstituted or substituted as defined below; non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl;
- “aryl” (sometimes abbreviated “ar”) means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms; the aryl group can be optionally substituted with one or more independently selected “ring system substituents” (defined below). Non-limiting examples of suitable aryl groups include phenyl and naphthyl;
- “arylalkynyl” means an aryl-alkynyl- group (i.e., the bond to the parent moiety is through the alkynyl group) wherein the aryl group is unsubstituted or substituted as defined above, and the alkynyl group is unsubstituted or substituted as defined above;
- “arylaminoheteroaryl” means an aryl-amino-heteroaryl group (i.e., the bond to the parent moiety is through the heteroaryl group) wherein the aryl group is unsubstituted or substituted as defined above, the amino group is as defined above (i.e., a —NH— here), and the heteroaryl group is unsubstituted or substituted as defined below;
- “arylheteroaryl” means an aryl-heteroaryl group—(i.e., the bond to the parent moiety is through the heteroaryl group) wherein the aryl group is unsubstituted or substituted as defined above, and the heteroaryl group is unsubstituted or substituted as defined below;
- “aryloxy” means an aryl-O— group (i.e., the bond to the parent moiety is through the ether oxygen) wherein the aryl group is unsubstituted or substituted as defined above; non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy;
- “aryloxycarbonyl” means an aryl-O—C(O)— group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aryl group is unsubstituted or substituted as previously defined; non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl;
- “arylsulfinyl” means an aryl-S(O)— group (i.e., the bond to the parent moiety is through the sulfinyl) wherein aryl is unsubstituted or substituted as previously defined;
- “arylsulfonyl” means an aryl-S(O₂)— group (i.e., the bond to the parent moiety is through the sulfonyl) wherein aryl is unsubstituted or substituted as previously defined;
- “arylthio” means an aryl-S— group (i.e., the bond to the parent moiety is through the sulfur) wherein the aryl group is unsubstituted or substituted as previously described; non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio;
- “cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms that contains at least one carbon-carbon double bond; preferred cycloalkenyl rings contain about 5 to about 7 ring atoms; the cycloalkenyl can be optionally substituted with one or more independently selected “ring system substituents” (defined below); Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like; a non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl;
- “cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 7 carbon atoms, preferably about 3 to about 6 carbon atoms; the cycloalkyl can be optionally substituted with one or more independently selected “ring system substituents” (defined below); non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like;
- “cycloalkylalkyl” means a cycloalkyl-alkyl-group (i.e., the bond to the parent moiety is through the alkyl group) wherein the cycloalkyl moiety is unsubstituted or substituted as defined above, and the alkyl moiety is unsubstituted or substituted as defined above;
- “halo” means fluoro, chloro, bromo, or iodo groups; preferred halos are fluoro, chloro or bromo, and more preferred are fluoro and chloro;
- “halogen” means fluorine, chlorine, bromine, or iodine; preferred halogens are fluorine, chlorine and bromine;
- “haloalkyl” means an alkyl, as defined above, wherein one or more hydrogen atoms on the alkyl is replaced by a halo group, as defined above;
- “heteroaralkenyl” means a heteroaryl-alkenyl- group (i.e., the bond to the parent moiety is through the alkenyl group) wherein the heteroaryl group is unsubstituted or substituted as defined below, and the alkenyl group is unsubstituted or substituted as defined above;
- “heteroaralkyl” (or heteroarylalkyl) means a heteroaryl-alkyl- group (i.e., the bond to the parent moiety is through the alkyl group) in which the heteroaryl is unsubstituted or substituted as defined below, and the alkyl group is unsubstituted or substituted as defined above; preferred heteroaralkyls comprise an alkyl group that is a lower alkyl group; non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl;
- “heteroaralkylthio” means a heteroaralkyl-S— group wherein the heteroaralkyl group is unsubstituted or substituted as defined above;
- “heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination; preferred heteroaryls comprise about 5 to about 6 ring atoms; the “heteroaryl” can be optionally substituted by one or more independently selected “ring system substituents” (defined below); the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom; a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide; non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like;
- “heteroarylalkynyl” (or heteroaralkynyl) means a heteroaryl-alkynyl- group (i.e., the bond to the parent moiety is through the alkynyl group) wherein the heteroaryl group is unsubstituted or substituted as defined above, and the alkynyl group is unsubstituted or substituted as defined above;
- “heteroarylaryl” (or heteroararyl) means a heteroaryl-aryl- group (i.e., the bond to the parent moiety is through the aryl group) wherein the heteroaryl group is unsubstituted or substituted as defined above, and the aryl group is unsubstituted or substituted as defined above;
- “heteroarylheteroarylaryl” means a heteroaryl-heteroaryl- group (i.e., the bond to the parent moiety is through the last heteroaryl group) wherein each heteroaryl group is independently unsubstituted or substituted as defined above;
- “heteroarylsulfinyl” means a heteroaryl-SO— group wherein the heteroaryl group is unsubstituted or substituted as defined above;
- “heteroarylsulfonyl” means a heteroaryl-SO₂— group wherein the heteroaryl group is unsubstituted or substituted as defined above;
- “heteroarylthio” means a heteroaryl-S— group wherein the heteroaryl group is unsubstituted or substituted as defined above;
- “heterocyclenyl” (or heterocycloalkenyl) means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon (for example one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atom), and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond; there are no adjacent oxygen and/or sulfur atoms present in the ring system; Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms; the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom; the heterocyclenyl can be optionally substituted by one or more independently selected “Ring system substituents” (defined below); the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like; Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like; A non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl; non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like;
- “heterocycloalkylalkyl” (or heterocyclylalkyl) means a heterocycloalkyl-alkyl-group (i.e., the bond to the parent moiety is through the alkyl group) wherein the heterocycloalkyl group (i.e., the heterocyclyl group) is unsubstituted or substituted as defined below, and the alkyl group is unsubstituted or substituted as defined above;
- “heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination; there are no adjacent oxygen and/or sulfur atoms present in the ring system; preferred heterocyclyls contain about 5 to about 6 ring atoms; the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom; the heterocyclyl can be optionally substituted by one or more independently selected “ring system substituents” (defined below); the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like;
- “hydroxyalkyl” means a HO-alkyl- group wherein the alkyl group is substituted or unsubstituted as defined above; preferred hydroxyalkyls comprise a lower alkyl; Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl; and
- “ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces an available hydrogen on the ring system; ring system substituents are each independently selected from the group consisting of: alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, R⁶⁰R⁶⁵N—, R⁶⁰R⁶⁵N-alkyl-, R⁶⁰R⁶⁵NC(O)— and R⁶⁰R⁶⁵NSO₂—, wherein R⁶⁰and R⁶⁵are each independently selected from the group consisting of: hydrogen, alkyl, aryl, and aralkyl; “Ring system substituent” also means a cyclic ring of 3 to 7 ring atoms, wherein 1-2 ring atoms can be heteroatoms, attached to an aryl, heteroaryl, heterocyclyl or heterocyclenyl ring by simultaneously substituting two ring hydrogen atoms on said aryl, heteroaryl, heterocyclyl or heterocyclenyl ring; Non-limiting examples include:

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and the like

Lines drawn into a ring mean that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Any carbon or heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.

One or more compounds of the invention may also exist as, or optionally converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, capsules, pills and the like. Similarly, the herein-described methods of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

Prodrugs of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula 1.0 or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

For example, if a compound of formula 1.0, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxy-methyl, 1-(alkanoyloxy)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, 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)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of formula 1.0 contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyl-oxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of formula 1.0 incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R⁷⁰-carbonyl, R⁷⁰O-carbonyl, NR⁷⁰R⁷⁵-carbonyl where R⁷⁰and R⁷⁵are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R⁷⁰-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY⁸⁰wherein Y⁸⁰is H, (C₁-C₆)alkyl or benzyl, —C(OY⁸²)Y⁸⁴wherein Y⁸²is (C₁-C₄) alkyl and Y⁸⁴is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁸⁶)Y⁸⁸wherein Y⁸⁶is H or methyl and Y⁸⁸is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

This invention also includes the compounds of this invention in isolated and purified form.

Polymorphic forms of the compounds of formula 1.0, and of the salts, solvates and prodrugs of the compounds of formula 1.0, are intended to be included in the present invention.

Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

The compounds of formula 1.0 form salts that are also within the scope of this invention. Reference to a compound of formula 1.0 herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula 1.0 contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable salts) are preferred. Salts of the compounds of the formula 1.0 may be 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 formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Compounds of formula 1.0, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

In hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

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there is no —OH attached directly to carbons marked 2 and 5.

The compounds of formula 1.0 may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

Tautomeric forms such as, for example, the moieties:

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are considered equivalent in certain embodiments of this invention.

The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

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 natural source or combination thereof. Thus, 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 obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R³, etc.) occurs more than one time in any moiety or in any compound of formula 1.0, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of formula 1.0 (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of formula 1.0 can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

This invention provides compounds of formula 1.0:

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or the pharmaceutically acceptable salts thereof, wherein:

Y¹, Y², and Y³are each independently selected from the group consisting of: —CH═, —N═ and —CR⁹═ (preferably Y¹, Y², and Y³are each —CH═);

z is 1 to 3 (i.e., 1, 2 or 3, and preferably 1);

Q is a substituent selected from the group consisting of:

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Each Q¹represents a ring independently selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of: the R¹⁰moieties; provided that when Q¹is aryl, heteroaryl, substituted aryl or substituted heteroaryl then the carbon atoms at the ring junction (i.e., the two carbon atoms common to the fused rings) are not substituted;

Q²represents a ring selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of: the R¹⁰moieties;

Z¹represents —(C(R²⁴)₂)_w— wherein each R²⁴is independently selected from the group consisting of: H, alkyl (e.g., C₁to C₆alkyl, 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 wherein in one example each R²⁴is H, and in another example w is 1, and in another example each R²⁴is H and w is 1, preferably w is 1 and each R²⁴is H (i.e., preferably Z¹is —CH₂—);

Z²is selected from the group consisting of: —N(R⁴⁴)—, —O— and —C(R⁴⁶)₂— (e.g., Z²is —NH—, —O— or —CH₂—);

m is 1 to 6;

n is 1 to 6;

p is 0 to 6;

t is 0, 1, or 2;

R¹is selected from the group consisting of:

- (1) —CN,
- (2) —NO₂,
- (3) —OR¹⁰,
- (4) —SR¹⁰,
- (5) —N(R¹⁰)₂,
- (6) R¹⁰,
- (7) halo (e.g., Cl, Br, and F),
- (8) —CF₃;
- (9) alkenyl (e.g., —CH═CHCH₃);
- (10) —C(O)N(R¹⁰)₂wherein each R¹⁰is independently selected, and preferably each R¹⁰is independently 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 R¹⁰is selected from the group consisting of: H, methyl, butyl, i-propyl, pyridyl, phenyl and cyclopropyl, wherein, for example, said —C(O)N(R¹⁰)₂moiety is selected from the group consisting of: —C(O)NH₂, —C(O)NH(CH₃), —C(O)NH(CH)(CH₃)₂(i.e., —C(O)NH(i-propyl)), —C(O)NH(C₄H₉), —C(O)NH(C₆H₅) (i.e., —C(O)NH(phenyl)), —C(O)NH(C₃H₅) (i.e., —C(O)NH(cyclopropyl), and —C(O)NH(C₅H₄N) (i.e., —C(O)NH(pyridyl), such as

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- (11) arylalkenyl- (aralkenyl-), for example, aryl(C₂to C₆)alkenyl-, such as for example, —CH═CH-phenyl;

R²is selected from the group consisting of:

- (1) H,
- (2) —CN,
- (3) halo (e.g., F),
- (4) alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl, ethyl and propyl, and in another example, methyl and ethyl),
- (5) substituted alkyl (e.g., substituted C₁to C6 alkyl, such as, for example, substituted methyl and substituted ethyl) wherein said substituted alkyl is substituted with 1 to 3 substituents (e.g., 1 substituent) selected from the group consisting of: (a) —OH, (b) —O-alkyl (e.g., —O—(C₁-C₃alkyl), (c) —O-alkyl (e.g., —O—(C₁-C₃alkyl)) substituted with 1 to 3 F atoms, and (d) —N(R⁴⁰)₂wherein each R⁴⁰is independently selected from the group consisting of: (i) H, (ii) C₁-C₃alkyl (e.g., methyl) and (iii) —CF₃, (examples of said substituted alkyl groups described in (5) include but are not limited to —CH₂OCH₃),
- (6) alkynyl (e.g., ethynyl),
- (7) alkenyl (e.g., —CH₂—CH═CH₂),
- (8) —(CH₂)_mR¹¹,
- (9) —N(R²⁶)₂,
- (10) —OR²³(e.g., —OH, —OCH₃and —O-phenyl),
- (11) —N(R²⁶)C(O)R⁴²wherein in one example R²⁶is H or C₁to C₆alkyl (e.g., methyl) and R⁴²is alkyl (e.g., methyl), and in another example —N(R²⁶)C(O)R⁴²is —NHC(O)CH₃,
- (12) cycloalkyl (e.g., C₃to C₆cycloalkyl, such as, for example, cyclopropyl and cyclohexyl),
- (13) cycloalkylalkyl (e.g., C₃to C₆cycloalkyl-(C₁to C₃)alkyl-, such as, for example, cyclopropyl-CH₂— and cyclohexyl-CH₂—),
- (14)

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wherein:

- (a) in one example said (12) moiety is

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and n is 1,

- (b) in another example said (12) moiety is

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(i.e., n is 1, and each R³⁰is H),

- (c) in another example Z²is —NH— in (a),
- (d) in another example Z²is —NH— in (b),
- (e) in another example Z²is —O— in (a),
- (f) in another example Z²is —O— in (b),
- (g) in another example Z²is —CH₂— in (a),
- (h) in another example Z²is —CH₂— in (b),
- (i) in another example R²is —(CH₂)—R¹and m is 1,
- (j) in another example R²is —N(R²⁶)₂,
- (k) in another example R²is —N(R²⁶)₂, and each R²⁶is H (i.e., R²is —NH₂),
- (l) in another example R²is —OR²³, and
- (m) in another example R²is —OH (i.e., R²¹is H);

each R³, R⁴, R⁵, R⁶and R⁷is independently selected from the group consisting of:

- (1) H,
- (2) alkenyl (e.g., —CH₂CH═CH₂),
- (3) substituted alkenyl,
- (4) alkyl (e.g., methyl and ethyl),
- (5) substituted alkyl,
- (6) cycloalkyl (e.g., cyclohexyl),
- (7) substituted cycloalkyl,
- (8) cycloalkylalkyl-,
- (9) substituted cycloalkylalkyl-,
- (10) heterocycloalkyl,
- (11) substituted heterocycloalkyl,
- (12) heterocycloalkylalkyl-,
- (13) substituted heterocycloalkylalkyl-,
- (14) —C(O)R¹⁰wherein in one example R¹⁰is selected from the group consisting of: alkyl (e.g., C₁to C₆, e.g., methyl), in another example R¹⁰is aryl (e.g., phenyl), in another example R¹⁰is substituted aryl (e.g., substituted phenyl, such as, for example, fluorophenyl-), in another example R¹⁰is heteroaryl (e.g., furanyl), and in another example R¹⁰is heterocycloalkyl (e.g., tetrahydrofuranyl-)
- (15) arylheteroaryl- (e.g., phenylthiadiazolyl-, and phenylthienyl-),
- (16) substituted arylheteroaryl- (e.g., substituted phenylthiadiazolyl-),
- (17) heteroarylaryl-, such as, for example, pyrimidinylphenyl-, pyrazinylphenyl-, pyridinylphenyl- (i.e., pyridylphenyl-), furanylphenyl-, thienylphenyl-, thiazolylphenyl-, benzofuranylphenyl-, oxazolylphenyl-, pyrazolylphenyl-, pyrrolylphenyl, and triazolylphenyl,
- (18) substituted heteroarylaryl-, such as, for example, substituted pyrimidinylphenyl-, substituted pyrazinylphenyl-, substituted pyridinylphenyl- (i.e., substituted pyridylphenyl-), substituted furanylphenyl-, substituted thienylphenyl-, substituted thiazolylphenyl-, substituted pyrimidinylphenyl, substituted pyridazinylphenyl, and substituted pyrrolylphenyl-,
- (19) aryl (e.g., phenyl and naphthyl),
- (20) substituted aryl (e.g., substituted phenyl and substituted naphthyl),
- (21) heteroaryl (e.g., thiazolyl, thienyl, pyridyl, pyrimidinyl, bonzoimidazolyl, benzotriazolyl, benzooxazolyl, benzothiazolyl, benzofuranyl, and pyrazinyl),
- (22) substituted heteroaryl (e.g., substituted thiazolyl, substituted pyridyl, substituted pyrimidinyl, substituted benzoimidazolyl, and substituted pyrazinyl), examples of substituted heteroaryl groups include, for example bromothiazolyl-, bromopyrimidinyl-, fluoropyrimidinyl-, ethenylpyrimidinyl-, chloropyrazinyl-, cyanobenzoimidazolyl, cyanopyridyl-, nitropyridyl-, methylpyridyl-, CH₃C(O)-pyrimidyl-, and N-cyclopropylmethyl-benzoimidazolyl-,
- (23) heteroarylheteroaryl- (e.g., pyrimidinylpyridyl-, and pyrimidinylthiazolyl-),
- (24) substituted heteroarylheteroaryl- (e.g., substituted pyrimidinyl- pyridyl-)
- (25) arylaminoheteroaryl- (e.g., phenyl-NH-oxadiazolyl-),
- (26) substituted arylaminoheteroaryl- (e.g., substituted phenyl-NH-oxadiazolyl-),
- (27) arylalkynyl- (e.g., aryl(C₂to C₄)alkynyl such as, for example phenylethynyl-),
- (28) substituted arylalkynyl- (e.g., substituted aryl(C₂to C₄)alkynyl-, such as, for example, substituted phenylethynyl-),
- (29) heteroarylalkynyl- (e.g., heteroaryl(C₂to C₄)alkynyl-, such as, for example, pyrimidinylethynyl-),
- (30) substituted heteroarylalkynyl- (e.g., substituted heteroaryl(C₂to C₄)alkynyl-, such as, for example substituted pyrimidinylethynyl-),
- (31) —C(O)NHR²⁸(e.g., —C(O)NHCH₃),
- (32) cycloalkylheteroarylaryl- (e.g., cyclopropylpyrimidylphenyl-).
- (33) substituted arylaryl- (e.g., HOCH₂-phenyl-phenyl-, Cl-phenyl-phenyl-, F-phenyl-phenyl-, and CH₃O-phenyl-phenyl-),
- (34) arylalkenylaryl- (e.g., aryl(C₂-C₄)alkenylaryl, such as, for example, phenylethenylphenyl-),
- (35) arylaryl- (e.g., phenyl-phenyl-),
- (36) substituted arylalkyl- (e.g., Br-phenyl-CH(CH₃)—, and 1-phenyl-CH(CH₃)—),
- (37) arylalkyl- (e.g., benzyl),
- (38) —SO₂aryl (e.g., —SO₂-phenyl),
- (39) benzoheteroaryl-C(O)-(substituted heterocycloalkyl)- (e.g., benzopyridazinyl-C(O)-(substituted piperidinyl)-, such as, for example, benzopyridazinyl-C(O)-(methyl substituted piperidinyl)-),
- (40) substituted heterocycloalkyl (e.g., N—CH₃C(O)-piperidinyl-, N—CH₃C(O)-methyl substituted piperidinyl, N-(t-butylC(O)O)-methyl substituted piperidinyl, and N-benzyl-piperidinyl), and
- (41) heterocycloalkyl-C(O)-alkyl- (e.g., morpholinyl-C(O)—CH₂—),
- (42) benzo[1,3]dioxolyl,

wherein said R³, R⁴, R⁵, R⁶and R⁷substituted groups (7), (9), (11), (13), (16), (18), (20), (22), (24), (26), (28), (30), (33), (36), (39) and (40), are substituted with 1 to 3 substituents independently selected from the group consisting of: —CH₂OH, CN, —OH, —NH₂, alkyl (e.g., C₁to C₆alkyl, e.g., methyl, ethyl, and i-propyl), alkenyl (e.g., C₂to C₆alkenyl, such as, for example —CH═CH₂), halo (e.g., I, F, Cl and Br, and in one example said halo is selected from the group consisting of: F, Cl and Br, and in another example said halo is F, and in another example said halo is Br, and in another example said halo is Cl), —C(O)—NH—R²⁸(e.g., —C(O)—NH—CH₃), —C(O)—NH₂, —C(O)OR²⁸(e.g., —C(O)OC₂H₅), —C(O)R²⁸(e.g., —C(O)CH₃), —C(alkyl)=NOH (e.g., —C(CH₃)═NOH), —C(alkyl)=NO(alkyl) (e.g., —C(CH₃)═NOCH₃), alkoxy (e.g., methoxy and t-butoxy), hydroxyl substituted alkyl (e.g., —CH(CH₃)OH), dialkylamine wherein each alkyl group is independently selected (e.g., —N(CH₃)₂), —CF₃, —SO₂alkyl (e.g., —SO₂CH₃), and —NHC(O)H,

wherein said R³, R⁴, R⁵, R⁶and R⁷substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of: —NH₂, halo (e.g., F, Cl and Br, and in another example F), —C(O)—NH—R²⁸(e.g., —C(O)—NH—CH₃), —C(O)OR²⁸(e.g., —C(O)OC₂H₅), and —C(O)R²⁸(e.g., —C(O)CH₃), and

wherein:

- in one example said substituted heteroarylaryl (moiety (18) above) is substituted with 1 to 3 substituents independently selected from the group consisting of: —NH₂, alkyl (e.g., C¹to C₆alkyl, e.g., methyl), halo (e.g., F, Cl and Br, such as, for example F),
- in another example said substituted aryl (moiety (20) above) is substituted with 1 to 3 substituents independently selected from the group consisting of halo (e.g., F, Cl and Br), —C(O)—NH—R²⁸(e.g., —C(O)—NH—CH₃), —C(O)OR²⁸(e.g., —C(O)O—C₂H₅), and —C(O)R²⁸(e.g., —C(O)CH₃), and
- in another example said substituted heteroaryl (moiety (22) above) is substituted with 1 to 3 substituents selected from the group consisting of: halo (e.g., Br, F, and Cl), alkenyl (e.g., C₂to C₆alkenyl, such as, for example, —CH═CH₂);

R⁸is selected from the group consisting of: H, —OH, alkyl (e.g., methyl), aryl (e.g., phenyl), —N(R¹⁰)₂(e.g., —NH₂) and —NR¹⁰C(O)R¹²(e.g., —NHC(O)CH₃);

each R⁹is independently selected from the group consisting of: halogen, —CN, —NO₂, —OR¹⁰, —SR¹⁰, —N(R¹⁰)₂, and R¹⁰;

each R¹⁰is independently selected from the group consisting of: H, alkyl (e.g., i-propyl, t-butyl, and methyl), aryl (e.g., phenyl), arylalkyl, heteroaryl (e.g., pyridyl, such as o-pyridyl, and pyrazolyl), heteroarylalkyl, cycloalkyl (e.g., cyclopropyl), cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein:

said R¹⁰substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: —NH₂, —NHR²⁰, —NO₂, —CN, —OR²⁶, halo (e.g., F, Cl and Br, and in another example F), —C(O)—NH—R²⁶(e.g., —C(O)—NH—CH₃, i.e., R²⁶is alkyl, such as methyl), —C(O)OR²⁶(e.g., —C(O)OC₂H₅, i.e., R²⁶is alkyl, such as ethyl), and —C(O)R²⁶(e.g., —C(O)CH₃, i.e., R²⁶is alkyl, such as methyl), and

said R¹⁰substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) —NH₂, (2) —NO₂, (3) —CN, (4) —OH, (5) —OR²⁰, (6)—OCF₃, (7) —CF₃, (8) —C(O)R³⁸(e.g., R³⁸is H or alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl or ethyl), for example, R³⁸is alkyl (e.g., methyl), thus, an example of —C(O)R³⁸is —C(O)CH₃), (9) alkyl (e.g., C₁to C₆alkyl, e.g., methyl, ethyl, and i-propyl), (10) alkenyl (e.g., C₂to C₆alkenyl, such as, for example —CH═CH₂), (11) halo (e.g., F, Cl and Br, and in another example F), (12) —C(O)—NH—R²⁶(e.g., —C(O)—NH—CH₃), (13) —C(O)OR³⁸(e.g., R³⁸is H or alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl or ethyl), for example, R³⁸is alkyl (e.g., methyl or ethyl), thus, for example, —C(O)OR³is —C(O)OC₂H₅), (14) —C(O)—NR³²—(C(R³⁰)₂)_n—N(R⁸)₂(e.g., —C(O)—NH—(CH₂)_n—N(R³⁸)₂) (wherein (a) in one example R³²is H, (b) in another example each R³⁰is H, (c) in another example n is 2, (d) in another example each R³⁸is independently selected, (e) in another example each R³⁸is independently selected from the group consisting of: H and alkyl (e.g., methyl), (f) in another example R³²is H, each R³⁰is H, and each R³⁸is independently selected, (g) in another example R³²is H, each R³⁰is H, and each R³⁸is independently selected from the group consisting of: H and alkyl (e.g., methyl), (15) —S(O)_tR³⁸(wherein in one example t is 2, and in another example R³⁸is alkyl (e.g., methyl), and in another example t is 2 and R³⁸is alkyl (e.g., methyl)), (16) —C(O)—NR³²—R³⁸(e.g., —C(O)—NR³²—R³⁸) (wherein one example R³²is H, in another example R³⁸is alkyl (e.g., propyl), and in another example R³²is H and R³⁸is alkyl (e.g., propyl)), (17) —NR³²—C(O)—R³⁸(e.g., —NH—C(O)—R³⁸) (wherein in one example R³²is H, in another example R³⁸is alkyl (e.g., methyl), and in another example R³²is H and R³⁸is alkyl (e.g., methyl)),

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(wherein in one example R³²is H, in another example R³⁸is H, and in another example R³²is H and R³⁸is H); and (19) —NHR²⁰;

R¹¹is selected from the group consisting of: F, —OH, —CN, —OR¹⁰, —NHNR¹R¹⁰, —SR¹⁰and heteroaryl (e.g., triazolyl, such as, for example,

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R¹²is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl;

R¹⁴is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;

R¹⁵is selected from the group consisting of: H, —OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;

R²⁰represents alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl or ethyl);

R²³is selected from the group consisting of: H, alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl and i-propyl), aryl (e.g., phenyl), cycloalkyl (e.g., C₃to C₆cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl- (e.g., C₃to C₆cycloalkylalkyl-, such as —(CH₂)_n-cycloalkyl, such as —(CH₂)_n—(C₃to C₆)cycloalkyl, wherein each H of each —(CH₂)_n— moiety can independently be substituted with an alkyl group (e.g., C₁to C₆alkyl, such as, for example, methyl), and wherein in one example n is 1 and the —CH₂— moiety is not substituted, that is, —CH₂-cycloalkyl, such as, —CH₂-cyclopropyl, is an example of said cycloalkylalkyl-moiety);

each R²⁶is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl and ethyl);

R²⁸is alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl or ethyl);

each R³⁰is independently selected from the group consisting of: H, alkyl (e.g., C₁to C₆alkyl, such as, for example methyl, ethyl and i-propyl), and F, and wherein in one example each R³⁰is H;

each R³²is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl, ethyl and propyl), and wherein each R³²is generally H;

each R³⁵is independently selected from the group consisting of: H and C₁to C₆alkyl (e.g., methyl, ethyl, i-propyl, and propyl), and wherein in one example both R³⁵substituents are the same or different alkyl groups (e.g., both R³⁵groups are the same alkyl group, such as methyl), and in another example one R³⁵group is H and the other R³⁵group is alkyl, such as methyl), and in another example each R³⁵is preferably H;

R³⁶is selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl, ethyl and propyl), and preferably R³⁶is selected from the group consisting of H and methyl, and more preferably R³⁶is H;

each R³⁸is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein:

said R³⁸substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: —NH₂, —NO₂, —CN, —OR²⁶, halo (e.g., F, Cl and Br, and in another example F), —C(O)—NH—R²⁸(e.g., —C(O)—NH—CH₃), —C(O)OR²⁸(e.g., —C(O)OC₂H₅), and —C(O)R²⁸(e.g., —C(O)CH₃), and

said R³⁸substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) —NH₂, (2) —NO₂, (3) —CN, (4) —OH, (5) —OR²⁰, (6) —OCF₃, (7) —CF₃, (8) —C(O)R²⁶(e.g., R²⁶is H or C₁to C₆alkyl, such as, for example, methyl or ethyl, for example, R²⁶is alkyl (e.g., methyl), thus, an example of —C(O)R²⁶is —C(O)CH₃), (9) alkyl (e.g., C₁to C₆alkyl, e.g., methyl, ethyl, and i-propyl), (10) alkenyl (e.g., C₂to C₆alkenyl, such as, for example —CH═CH₂), (11) halo (e.g., F, Cl and Br, and in another example F), (12) —C(O)—NH—R²⁶(e.g., —C(O)—NH—CH₃), (13) —C(O)OR²⁶(e.g., R²⁶is H or e.g., C₁to C₆alkyl, such as, for example, methyl or ethyl, for example, R²⁶is alkyl (e.g., methyl or ethyl), thus, for example, —C(O)OR²⁶is —C(O)OC₂H₅); (14) —C(O)—NR³²(C(R³)₂)_n—N(R²⁶)₂(e.g., —C(O)—NH—(CH₂)_n—N(R²⁶)₂) (wherein (a) in one example R³²is H, (b) in another example each R³⁰is H, (c) in another example n is 2, (d) in another example each R²⁶is independently selected, (e) in another example each R²⁶is independently selected from the group consisting of: H and methyl), (f) in another example R³²is H, each R³⁰is H, and each R²⁶is independently selected, (g) in another example R³²is H, each R³⁰is H, and each R²⁶is independently selected from the group consisting of: H and methyl), (15) —S(O)_tR²⁶(wherein in one example t is 2, and in another example R²⁶is methyl, and in another example t is 2 and R²⁶is methyl), (16) —C(O)N(R³²)(R²⁶) (wherein in one example R³²is H, in another example R²⁶is alkyl (e.g., propyl), and in another example R³²is H and R²⁶is alkyl (e.g., propyl)), (17) —NR³²C(O)R²⁶(e.g., —NHC(O)R²⁶) (wherein in one example R³²is H, in another example R²⁶is alkyl (e.g., methyl), and in another example R³²is H and R²⁶is alkyl (e.g., methyl)),

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(wherein in one example R³²is H, in another example R²⁶is H, and in another example R³²is H and R²⁶is H); and (19) —NHR²⁰;

R⁴²is selected from the group consisting of: alkyl (e.g., C₁to C₆alkyl, such as, for example —CH₃), aryl (e.g., phenyl), heteroaryl (e.g., thiazolyl and pyridyl), and cycloalkyl (e.g., C₃to C₆cycloalkyl, such as, for example, cyclopropyl);

R⁴⁴is selected from the group consisting of: H, alkyl (e.g., C₁to C₆alkyl, such as, for example, C₁to C₃alkyl, such as, for example, methyl, ethyl and i-propyl), cycloalkyl (e.g., C₃to C₆cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl (e.g., (C₃to C₆)cycloalkyl(C₁to C₆)alkyl, such as, for example, (C₃to C₆)cycloalkyl(C₁to C₃)alkyl, such as, for example, (C₃to C₆)cycloalkyl-methyl-, such as, for example, cyclopropyl-methyl- and cyclohexyl-methyl-), and in one example, R⁴⁴is H; and

Each R⁴⁶is independently selected from the group consisting of: H, alkyl (e.g., C₁to C₆alkyl, such as, for example, C₁to C₃alkyl, such as, for example, methyl, ethyl and i-propyl), cycloalkyl (e.g., C₃to C₆cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl (e.g., (C₃to C₆)cycloalkyl(C₁to C₆)alkyl, such as, for example, (C₃to C₆)cycloalkyl(C₁to C₃)alkyl, such as, for example, (C₃to C₆)cycloalkyl-methyl-, such as, for example, cyclopropyl-methyl- and cyclohexyl-methyl-), and in one example, each R⁴⁶is H.

When R¹is a cycloalkyl group (i.e., R¹is R¹⁰wherein R¹⁰is cycloalkyl), examples of said cycloalkyl group include, but are limited to, cyclopropyl and cyclobutyl.

When R¹is a heterocycloalkyl group (i.e., R¹is R¹⁰wherein R¹⁰is heterocycloalkyl), examples of said heterocycloalkyl group include, but are limited to, morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl.

When R¹is a heteroaryl group (i.e., R¹is R¹⁰and R¹⁰is heteroaryl), examples of said heteroaryl group include, but are not limited to,

- (a) unsubstituted heteroaryl,
- (b) heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of: —C(O)R³⁸(e.g., R³⁸is alkyl such as methyl), —NHR²⁰(e.g., —NHCH₃), —OR²⁰(e.g., —OCH₃), and halo (e.g., Cl),
- (c) heteroaryl selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridyl N—O, and pyrimidinyl,
- (d) heteroaryl selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridyl N—O, and pyrimidinyl, wherein said heteroaryl is substituted with 1 to 3 substituents independently selected from the group consisting of: —C(O)R³⁸(e.g., R³⁸is alkyl such as methyl), —NHR²⁰(e.g., —NHCH₃), —OR²⁰(e.g., —OCH₃), and halo (e.g., Cl), and
- (e) heteroaryl selected from the group consisting of: thienyl substituted with —C(O)R³⁸(such as, for example, thienyl substituted with —C(O)CH₃), thiazolyl substituted with —NHR²⁰such as, for example (thazolyl substituted with —NHCH₃), pyridyl substituted with halo (such as, for example, pyridyl substituted with —Cl), pyridyl substituted with —OR²⁰(such as, for example, pyridyl substituted with methyl), and pyrimidinyl substituted with —OR²⁰(such as, for example, pyrimidinyl substituted with —OCH₃).

When R¹is a heteroarylalkyl group (i.e., R¹is R¹⁰and R¹⁰is heteroarylalkyl), examples of said heteroarylalkyl group include, but are not limited to,

- (a) unsubstituted heteroarylalkyl-
- (b) heteroarylalkyl-substituted with 1 to 3 substituents independently selected from the group consisting of: —C(O)R³⁸(e.g., R³⁸is alkyl such as methyl), —NHR²⁰(e.g., —NHCH₃), —OR²⁰(e.g., —OCH₃), and halo (e.g., Cl),
- (c) heteroarylalkyl-selected from the group consisting of: pyrrolylalkyl- (e.g., pyrrolylCH₂—), pyrazolylalkyl- (e.g., pyrazolylCH₂—), imidazolylalkyl- (e.g., imdazolyl-CH₂—), furanylalkyl- (e.g., furanylCH₂—), thienylalkyl- (e.g., thienylCH₂—), thiazolylalkyl- (e.g., thiazolylCH₂—), pyridylalkyl- (e.g., pyridylCH₂—), pyridyl N—O alkyl- (e.g., pyridyl(N—O)CH₂—), and pyrimidinylalkyl- (e.g., pyrimidinylCH₂—),
- (d) heteroarylalkyl-selected from the group consisting of: pyrrolylalkyl- (e.g., pyrrolylCH₂—), pyrazolylalkyl- (e.g., pyrazolylCH₂—), imidazolylalkyl- (e.g., imdazolylCH₂—), furanylalkyl- (e.g., furanylCH₂—), thienylalkyl- (e.g., thienylCH₂—), thiazolylalkyl- (e.g., thiazolylCH₂—), pyridylalkyl- (e.g., pyridylCH₂—), pyridyl N—O alkyl- (e.g., pyridyl(N—O)CH₂—), and pyrimidinylalkyl- (e.g., pyrimidinylCH₂—), wherein said heteroaryl is substituted with 1 to 3 substituents independently selected from the group consisting of: —C(O)R³⁸(e.g., R³⁸is alkyl such as methyl), —NHR²⁰(e.g., —NHCH₃), —OR²⁰(e.g., —OCH₃), and halo (e.g., Cl), and
- (e) heteroarylalkyl-selected from the group consisting of: thienylalkyl-substituted with a —C(O)R²⁰group (such as, for example, thienylCH₂— substituted with —C(O)CH₃), thiazolylalkyl-substituted with —NHR²⁰such as, for example (thazolylCH₂-substituted with —NHCH₃), pyridylalkyl-substituted with halo (such as, for example, pyridylCH₂-substituted with —Cl), pyridylalkyl-substituted with —OR²⁰(such as, for example, pyridylCH₂— substituted with methyl), and pyrimidinylalkyl-substituted with —OR²⁰(such as, for example, pyrimidinylCH₂— substituted with —OCH₃).

When R¹is an aryl group (i.e., R¹is R¹⁰and R¹⁰is aryl), examples of said aryl group include, but are not limited to, phenyl and naphthyl, and preferably phenyl.

When R¹is an arylalkyl group (i.e., R¹is R¹⁰and R¹⁰is arylalkyl), examples of said arylalkyl group include, but are not limited to, —(C(R³⁰)₂)_nphenyl (e.g., —(CH₂)_nphenyl), wherein in one example said arylalkyl- is —(C(R³⁰)₂)_nphenyl wherein n is 1, and in another example said arylalkyl- is —(CH₂)_nphenyl wherein n is 1 (i.e., said arylalkyl- is benzyl).

When R¹is a substituted arylalkyl group (i.e., R¹is R¹⁰and R¹⁰is a substituted arylalkyl), examples of said substituted arylalkyl group include, but are not limited to, —(C(R³)₂)_nsubstituted phenyl (e.g., —(CH₂)_nsubstituted phenyl), wherein in one example said substituted arylalkyl- is —(C(R³⁰)₂)_nsubstituted phenyl wherein n is 1, and in another example said substituted arylalkyl- is —(CH₂)_nsubstituted phenyl wherein n is 1 (i.e., said substituted arylalkyl- is substituted benzyl), wherein the aryl moiety of said substituted arylalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: halo (e.g., F, Cl and Br), —CF₃, and —OR²⁰(e.g., —OCH₃).

In one embodiment the invention R¹is selected from the group consisting of: H, alkyl (e.g., methyl, i-propyl, and t-butyl), cycloalkyl (e.g., cyclopropyl), aryl (e.g., phenyl), substituted aryl (e.g., halo substituted aryl, such as for example, fluorophenyl), halo (e.g., Cl, Br, and F), heteroaryl (e.g., pyridyl and pyrazolyl), —CF₃, —C(O)NH₂, and —CH₂OH.

Those skilled in the art will appreciate that when Q¹is aryl, substituted aryl, heteroaryl or substituted heteroaryl the two carbon atoms common to the two fused rings are not substituted. Thus, there is no R³and no R⁴groups in 2.9 when Q¹is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R³and no R⁴groups in 2.10 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R⁶and no R⁷groups in 2.10 when Q¹, fused to the R⁶and R⁷positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R³and no R⁴groups in 2.11 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R³and no R⁴groups in 2.13 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R³and no R⁴groups in 2.14 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R³and no R⁴groups in 2.15 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R⁶and no R⁷groups in 2.15 when Q¹fused to the R³and R⁴positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

In one embodiment of the compounds of formula 1.0, z is 1. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0A1:

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In another embodiment of the compounds of formula 1.0, z is 1 and R³⁶is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0A:

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In another embodiment of the compounds of formula 1.0, z is 1, and each R³⁵is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R³⁵is H and the other is methyl, or both R³⁵substituents are methyl, or preferably both R³⁵substituents are H).

In another embodiment of the compounds of formula 1.0, z is 1, each R³⁵is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R³⁵is H and the other is methyl, or both R³⁵substituents are methyl, or preferably both R³⁵substituents are H), and R³⁶is selected from the group consisting of: H, methyl, ethyl and propyl.

In another embodiment of the compounds of formula 1.0, each R³⁵is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0B1:

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In another embodiment of the compounds of formula 1.0, each R³⁵is H and R³⁶is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0B:

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In another embodiment of the compounds of formula 1.0, z is preferably 1 and each R³⁵is preferably H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0C1:

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In another embodiment of the compounds of formula 1.0, z is preferably 1, each R³⁵is preferably H, and R³⁶is H. Thus, preferably the compounds of formula 1.0 have the formula 1.0C:

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Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.1A:

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Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.1:

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wherein all substituents are as defined for formula 1.0.

Another embodiment of this invention is directed to compounds of formulas 1.0 and 1.1A wherein Y¹, Y², and Y³are —CH═. Thus, one embodiment of this invention is directed to compounds of formula 1.2A:

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Another embodiment of this invention is directed to compounds of formulas 1.0 and 1.1 wherein Y¹, Y², and Y³are —CH═. Thus, one embodiment of this invention is directed to compounds of formula 1.2:

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wherein all substituents are as defined for formula 1.0.

Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.3A:

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Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.3:

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wherein all substituents are as defined for formula 1.0.

Examples of Q include, but are not limited to: moieties 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 2.15 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

Examples of Q also include, but are not limited to: moieties 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 2.15 wherein each R³, R⁴, R⁶, and R⁷is H.

Examples of Q include, but are not limited to: moieties 2.12, 2.13, or 2.16 wherein each R³, R⁴, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

Examples of Q also include, but are not limited to: moieties 2.12, 2.13, or 2.16 wherein each R³, R⁴, and R⁷is H.

Thus, in one example of Q, Q is moiety 2.1 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.1 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.1 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.2 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.2 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.2 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.3 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.3 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.3 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.4 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.4 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.4 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.5 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.5 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.5 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.6 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.6 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.7 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.7 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.7 wherein each R³R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.8 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.8 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.8 wherein each R³, R⁴, R⁶and R⁷is H.

In another example of Q, Q is moiety 2.9 or 2.10 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.9 or 2.10 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.9 or 2.10 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.11 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.11 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.11 wherein each R³, R⁴, R⁶, and R⁷is H.

In another example of Q, Q is moiety 2.12 or 2.13 wherein each R³, R⁴, and R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.12 or 2.13 wherein each R³, R⁴, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.12 or 2.13 wherein each R³, R⁴, and R⁷is H.

In another example of Q, Q is moiety 2.14 or 2.15 wherein each R³, R⁴, R⁶, and

R⁷is independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example methyl).

In another example of Q, Q is moiety 2.14 or 2.15 wherein each R³, R⁴, R⁶, and R⁷is independently selected from the group consisting of: H and methyl.

In another example of Q, Q is moiety 2.14 or 2.15 wherein each R³, R⁴, R⁶, and ⁷is H.

In another example of Q, Q is moiety 2.16 wherein each R³, R⁴, and R⁷is H.

Another example of the Q substituent 2.3 is: