Substituted Naphthalenyl-Pyrimidine Compounds

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of death in the United States, exceeded only by heart disease. (Cancer Facts and Figures 2004, American Cancer Society, Inc.). Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors.

Cancer cells are by definition heterogeneous. For example, within a single tissue or cell type, multiple mutational “mechanisms” may lead to the development of cancer. As such, heterogeneity frequently exists between cancer cells taken from tumors of the same tissue and same type that have originated in different individuals. Frequently observed mutational “mechanisms” associated with some cancers may differ between one tissue type and another (e.g., frequently observed mutational “mechanisms” leading to colon cancer may differ from frequently observed “mechanisms” leading to leukemias). It is therefore often difficult to predict whether a particular cancer will respond to a particular chemotherapeutic agent (Cancer Medicine, 5^thedition, Bast et al., B. C. Decker Inc., Hamilton, Ontario).

Components of cellular signal transduction pathways that regulate the growth and differentiation of normal cells can, when dysregulated, lead to the development of cellular proliferative disorders and cancer. Mutations in cellular signaling proteins may cause such proteins to become expressed or activated at inappropriate levels or at inappropriate times during the cell cycle, which in turn may lead to uncontrolled cellular growth or changes in cell-cell attachment properties. For example, dysregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated in the development and progression of human cancers.

AKT protein family, which members are also called protein kinases B (PKB) plays an important role in mammalian cellular signaling. In humans, there are three genes in the AKT family: Akt1, Akt2, and Akt3. These genes code for enzymes that are members of the serine/threonine-specific protein kinase family. Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Akt2 is an important signaling molecule in the Insulin signaling pathway and is required to induce glucose transport. The role of Akt3 is less clear, though it appears to be predominantly expressed in brain.

The AKT family regulates cellular survival and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt1 is known to play a role in the cell cycle. Moreover, activated Akt1 may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes. Akt1 has also been implicated in angiogenesis and tumor development. Studies have shown that deficiency of Akt1 enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels. Since it can block apoptosis, and thereby promote cell survival, Akt1 is a major factor in many types of cancer.

FGFR2 is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting downstream signals, ultimately influencing mitogenesis and differentiation.

Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers. The altered gene expression may enhance several cancer-related events such as cell proliferation, cell movement, and the development of new blood vessels that nourish a growing tumor. The FGFR2 gene is abnormally active (overexpressed) in certain types of stomach cancers, and this amplification is associated with a poorer outcome. Abnormal expression of FGFR2 is also found in patients with prostate cancer. More than 60 percent of women with breast cancer, in the United States, carry at least a single mutation in this gene as well.

The 70-kDa ribosomal protein S6 (p70S6) kinase is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. Its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome. p70S6 kinase is in a signaling pathway that includes mTOR (the mammalian target of rapamycin). p70S6 kinase is known to regulate cell growth by inducing protein synthesis components. p70S6K has been shown to be a dual pathway kinase, signaling cell survival as well as growth through differential substrates which include mitochondrial BAD and the ribosomal subunit S6, respectively.

p70S6 kinase functions in epithelial to mesenchymal transition (EMT) responsible for the acquisition of invasiveness during tumor progression Studies have shown that p70S6 kinase is a downstream effector of PI3 kinase and is frequently activated in human ovarian cancer. Studies have also demonstrated that activation of p70S6 kinase indicates aggressive tumor behavior in patients with clear margin-resected hepatocellular carcinoma (HCC).

Accordingly, new compounds and methods for modulating AKT, FGFR2 and p70S6 genes and treating proliferation disorders, including cancer, are needed. The present invention addresses these needs.

SUMMARY OF THE INVENTION

The present invention provides, in part, substituted naphthalenyl-pyrimidine compounds of Formulae I-IV and methods of preparing the compounds of Formula I-IV:

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wherein:

R₁and R₂are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —C(O)R₆, —C(O)OR₆, —C(O)NR₆R₆′, —S(O)₂R₆, —S(O)₂NR₆R₆′, or C₁-C₆alkyl substituted with halogen, —NR_qR_q′, —C(O)NR_qR_q′, OR_q, or SR_q, provided that at most one of R₁and R₂is H, or R₁and R₂, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 5- or 6-member ring optionally containing from 1 to 4 heteroatoms selected from N, O and S;

R₃and R₄are each independently -T₃-Q₃provided that at most one of R₃and R₄is H;

R₅is halogen, cyano, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₇R₇′, —NR₇′C(O)R₇, —NR₇′C(O)OR₇′, —NHC(O)NR₇R₇′, or —NR₇′S(O)₂R₇;

R_p1and R_p2are each independently H, halogen, cyano, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₇R₇′, —NR₇′C(O)R₇, —NR₇′C(O)OR₇′, —NHC(O)NR₇R₇′, or —NR₇′S(O)₂R₇;

R₆and R₆′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or -T₁-Q₁;

R₇and R₇′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R_qand R_q′ are each independently H, amidinyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R_qand R_q′, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycle or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R₈is unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted phenyl, or -T₁-Q₁;

—Z₁-Z₂— is —CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—NR_z— or —CH₂—NR_z—CH₂—;

—Z₃-Z₄— is —CH₂—NR_z—, —CH₂—CH₂—NR_z— or —CH₂—NR_z—CH₂—;

m is 0, 1, 2, 3, 4, 5, or 6;

T₁, T₂and T₃are each independently unsubstituted or substituted C₁-C₆alkyl linker, or a bond;

Q₁is H, hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or —NR₉R₉′;

R₉and R₉′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R₉and R₉′, together with the nitrogen atom to which they are attached, form a 4- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T₂-Q₂;

Q₂is H, hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₁₀R₁₀′, —C(O)R₁₀, —C(O)OR₁₀, or —C(O)NR₁₀R₁₀′;

R₁₀and R₁₀′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

Q₃is H, hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R_zis H, amidinyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₁R₁₁′; and

R₁₁and R₁₁′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkyl-C₆-C₁₅aryl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

The present invention also provides pharmaceutical compositions comprising one or more compounds of Formulae I-IV and one or more pharmaceutically acceptable carriers.

The present invention also provides methods of treating a cell proliferative disorder by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, such that the disorder is treated.

The present invention also provides methods of treating cancer by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, such that the cancer is treated.

The present invention also provides methods of selectively inducing cell death in precancerous or cancerous cells by contacting a cell with an effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, such that contacting the cell results in selective induction of cell death in the precancerous or cancer cells.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION
1. Substituted Naphthalenyl-Pyrimidine Compounds

The present invention provides novel substituted naphthalenyl-pyrimidine compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.

The present invention provides the compounds of Formula I:

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wherein:

R₁and R₂are each independently H, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —C(O)R₆, —C(O)OR₆, —C(O)NR₆R₆′, —S(O)₂R₆, —S(O)₂NR₆R₆′, or C₁-C₆alkyl substituted with halogen, —NR_qR_q′, —C(O)NR_qR_q′, OR_q, or SR_q, provided that at most one of R₁and R₂is H, or R₁and R₂, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 5- or 6-member ring optionally containing from 1 to 4 heteroatoms selected from N, O and S;

R₃and R₄are each independently -T₃-Q₃provided that at most one of R₃and R₄is H;

T₃is a bond or unsubstituted or substituted C₁-C₆alkyl linker;

each R₅is independently halogen, cyano, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₇R₇′, —NR₇′C(O)R₇, —NR₇′C(O)OR₇′, —NHC(O)NR₇R₇′, or —NR₇′S(O)₂R₇;

T₁is a bond or unsubstituted or substituted C₁-C₆alkyl linker;

T₂is a bond or unsubstituted or substituted C₁-C₆alkyl linker;

m is 0, 1, 2, 3, 4, 5, or 6.

In the examples that follow, where the identity of only one of R₁and R₂is specified (e.g., via the phrase “one of R₁and R₂is”), the other of R₁and R₂may be selected from H, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —C(O)R₆, —C(O)OR₆, —C(O)NR₆R₆′, —S(O)₂R₆, —S(O)₂NR₆R₆′, or C₁-C₆alkyl substituted with halogen, —NR_qR_q′, —C(O)NR_qR_q′, OR_q, or SR_q, provided that at most one of R₁and R₂is H, or R₁and R₂, together with the nitrogen atom to which they are attached, form a 5- or 6-member ring optionally containing from 1 to 4 heteroatoms selected from N, O and S.

For example, where the identity of only one of R₁and R₂is specified, the other of R₁and R₂is H.

In the examples that follow, where the identity of only one of R_qand R_q′ is specified (e.g., via the phrase “one of R_qand R_q′ is”), the other of R_qand R_q′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, where the identity of only one of R_qand R_q′ is specified, the other of R_qand R_q′ is H.

In the examples that follow, where the identity of only one of R₃and R₄is specified (e.g., via the phrase “one of R₃and R₄is”), the other of R₃and R₄may be selected from H or -T₃-Q₃.

For example, where the identity of only one of R₃and R₄is specified, the other of R₃and R₄is H.

For example, one of R₃and R₄is H or methyl.

For example, one of R₃and R₄is H.

In the examples that follow, where the identity of only one of R₆and R₆′ is specified (e.g., via the phrase “one of R₆and R₆′ is”), the other of R₆and R₆′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or -T₁-Q₁.

For example, where the identity of only one of R₆and R₆′ is specified, the other of R₆and R₆′ is H.

In the examples that follow, where the identity of only one of R₇and R₇′ is specified (e.g., via the phrase “one of R₇and R₇′ is”), the other of R₇and R₇′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, where the identity of only one of R₇and R₇′ is specified, the other of R₇and R₇′ is H.

In the examples that follow, where the identity of only one of R₉and R₉′ is specified (e.g., via the phrase “one of R₉and R₉′ is”), the other of R₉and R₉′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R₉and R₉′, together with the nitrogen atom to which they are attached, form a 4- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T₂-Q₂.

For example, where the identity of only one of R₉and R₉′ is specified, the other of R₉and R₉′ is H.

In the examples that follow, where the identity of only one of R₁₁and R₁₁′ is specified (e.g., via the phrase “one of R₁₁and R₁₁′ is”), the other of R₁₁and R₁₁′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkyl-C₆-C₁₅aryl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, where the identity of only one of R₁₁and R₁₁′ is specified, the other of R₁₁and R₁₁′ is H.

In the examples that follow, where the identity of only one of R₁₃and R₁₃′ is specified (e.g., via the phrase “one of R₁₃and R₁₃′ is”), the other of R₁₃and R₁₃′ may be selected from H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, where the identity of only one of R₁₃and R₁₃′ is specified, the other of R₁₃and R₁₃′ is H.

For example, R₁and R₂are each independently H.

For example, at least one of R₁and R₂is substituted straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₁and R₂is straight chain C₁-C₆or branched C₃-C₆alkyl substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, and i-propyloxy), unsubstituted or substituted C₁-C₆alkylthiol (e.g., methylthiol, ethylthiol, propylthiol, and i-propylthiol), or —NR_qR_q′, wherein:

R_qand R_q′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, at least one of R₁and R₂is straight chain C₁-C₆or branched C₃-C₆alkyl substituted with C₁-C₆alkylthiol, wherein the alkylthiol is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), or amidinyl.

For example, at least one of R₁and R₂is straight chain C₁-C₆or branched C₃-C₆C₁-C₆alkyl substituted with —NR_qR_q′ or —C(O)NR_qR_q′, wherein

For example, at least one of R_qand R_q′ is straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, and i-propyloxy), unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), or unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, at least one of R_qand R_q′ is phenyl or naphthyl, and is optionally substituted with hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, and i-propyloxy).

For example, at least one of R_qand R_q′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, pyrazolopyrimidinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), or unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, and i-propyloxy).

For example, at least one of R_qand R_q′ is pyrazolopyrimidinyl optionally substituted with halogen.

For example, together with the N to which they are attached, R_qand R_q′ form heterocycle selected from isoindolinyl, indolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, azetidinyl, and morpholinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, oxo, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₆-C₁₀aryl (e.g., phenyl and naphthyl), unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrimidinonyl, and pyrrolidine-dionyl), amidinyl, —C(O)R₁₂, or —C(O)OR₁₂, wherein:

R₁₂is unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₅aryl-C₁-C₆alkyl, or unsubstituted or substituted C₆-C₁₀aryl

For example, together with the N to which they are attached, R_qand R_q′ form isoindoline-1,3-dione.

For example, at least one of R₁and R₂is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, and the like, and is optionally substituted.

For example, at least one of R₁and R₂is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R₁and R₂is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₆-C₁₀aryl (e.g., phenyl and naphthyl), unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrimidinonyl, and pyrrolidine-dionyl), amidinyl, —C(O)R₁₂, or —C(O)OR₁₂, wherein:

R₁₂is unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₅aryl-C₁-C₆alkyl, or unsubstituted or substituted C₆-C₁₀aryl.

For example, R₁₂is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, R₁₂is unsubstituted or substituted C₆-C₁₅aryl-C₁-C₆alkyl, including but not limited to, benzyl, phenylethyl, phenylpropyl, fluorenylmethyl, fluorenylethyl, and fluorenylpropyl.

For example, at least one of R₁and R₂is heterocycle substituted with heteroaryl selected from pyridinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrimidinonyl, pyrrolidine-dionyl, quinolinyl, thienopyrimidinyl, and pyrazolopyrimidinyl.

For example, at least one of R₁and R₂is heterocycle substituted with heteroaryl, wherein the heteoaryl is substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, amidinyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy and t-butoxy, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkylthiol (e.g., methylthiol, ethylthiol, propylthiol, and i-propylthiol), unsubstituted or substituted C₁-C₆alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl, i-propylcarbonyl, butylcarbonyl, and t-butylcarbonyl), unsubstituted or substituted C₁-C₆alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, i-propyloxycarbonyl, butoxycarbonyl, and t-butoxycarbonyl), carboxyl, amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino), and unsubstituted or substituted C₁-C₆alkylcarbonylamino (e.g., methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, i-propylcarbonylamino, butylcarbonylamino, and t-butylcarbonylamino).

For example, one of R₁and R₂is C(O)R₆, —C(O)OR₆, —C(O)NR₆R₆′, —S(O)₂R₆, or —S(O)₂NR₆R₆′ and the other is H.

For example, R₆and R₆′ are each independently H.

For example, at least one of R₆and R₆′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₆and R₆′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R₆and R₆′ is unsubstituted phenyl.

For example, at least one of R₆and R₆′ is phenyl substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, and methylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, at least one of R₆and R₆′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, and the like, and is optionally substituted.

For example, at least one of R₆and R₆′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R₆and R₆′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, at least one of R₆and R₆′ is -T₁-Q₁.

For example, T₁is a bond.

For example, T₁is straight chain C₁-C₆or branched C₃-C₆alkyl linker, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

For example, T₁is methyl.

For example, Q₁is H.

For example, Q₁is fluorine, chlorine, bromine, or iodine.

For example, Q₁is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, Q₁is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, Q₁is unsubstituted or substituted phenyl or naphthyl.

For example, Q₁is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, and the like, and is optionally substituted.

For example, Q₁is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, Q₁is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, Q₁is —NR₉R₉′.

For example, R₉and R₉′ are each independently H.

For example, at least one of R₉and R₉′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₉and R₉′ is straight chain C₁-C₆or branched C₃-C₆alkyl substituted with hydroxyl, unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, and i-propyloxy), unsubstituted or substituted C₆-C₁₀aryl (e.g., phenyl and naphthyl), unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, and quinoxalinyl, each of which is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl)), unsubstituted or substituted C₃-C₁₀carbocycle (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl)), —NR_rR_r′, or —CO NR_rR_r′ wherein:

R_rand R_r′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted C₆-C₁₀aryl.

For example, R_rand R_r′ are each independently unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, R_rand R_r′ are each independently C₆-C₁₀aryl (e.g., phenyl and naphthyl) optionally substituted with, e.g., halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀carbocycle, aryl, heteroaryl, heterocycle and the like, each of which is optionally further substituted.

For example, at least one of R₉and R₉′ is straight chain C₁-C₆or branched C₃-C₆alkyl substituted with morpholinyl or piperidinyl, each of which is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, at least one of R₉and R₉′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, and quinoxalinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, at least one of R₉and R₉′ is pyridinyl, pyrimidinyl, or benzoimidazolyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, at least one of R₉and R₉′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, at least one of R₉and R₉′ is piperidinyl or piperazinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 4- to 10-member ring selected from pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, triazolidine, piperidine, piperazine, morpholine, and octahydropyrrolopyrazine, and is optionally substituted with -T₂-Q₂.

For example, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 5- to 10-member ring selected from pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, triazolidine, piperidine, piperazine, morpholine, and octahydropyrrolopyrazine, and is optionally substituted with -T₂-Q₂.

For example, R₉and R₉′, together with the nitrogen atom to which they are attached, form a piperidine or piperazine, and is optionally substituted with -T₂-Q₂.

For example, T₂is a bond.

For example, T₂is straight chain C₁-C₆or branched C₃-C₆alkyl linker, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

For example, T₂is methyl, ethyl or propyl.

For example, Q₂is H.

For example, Q₂is hydroxyl.

For example, Q₂is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with hydroxyl or halogen (e.g., fluorine, chlorine, bromine and iodine).

For example, Q₂is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy, each of which is optionally substituted with hydroxyl or halogen (e.g., fluorine, chlorine, bromine and iodine).

For example, Q₂is unsubstituted or substituted phenyl or naphthyl.

For example, Q₂is phenyl and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, Q₂is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), or unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, Q₂is heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, pyrrolyl, and thiophenyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), halogen (e.g., fluorine, chlorine, bromine, and iodine), or cyano.

For example, Q₂is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, Q₂is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), or unsubstituted or substituted amino.

For example, Q₂is heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen).

For example, R₁₀and R₁₀′ are each independently H.

For example, at least of R₁₀and R₁₀′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least of R₁₀and R₁₀′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least of R₁₀and R₁₀′ is phenyl substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, at least of R₁₀and R₁₀′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted.

For example, at least of R₁₀and R₁₀′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least of R₁₀and R₁₀′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, at least of R₁₀and R₁₀′ is heterocycle selected from pyrrolidinyl, piperidinyl, and morpholinyl.

For example, R₁and R₂, together with the nitrogen atom to which they are attached, form a ring selected from pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, triazolidine, piperidine, piperazine, and morpholine, and is optionally substituted with amidinyl, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen, hydroxyl, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy), unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), or unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, di-i-propylamino, methylpropyl amino, ethylmethylamino, and cyclohexylmethylamino), unsubstituted or substituted C₆-C₁₀aryl (e.g., phenyl and naphthyl), unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, pyrazolopyrimidinyl, and pyrrolidinedionyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine), hydroxyl, or unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl)), unsubstituted or substituted C₃-C₁₀carbocycle (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl), —C(O)R₁₃, —C(O)OR₁₃, or —C(O)NR₁₃R₁₃′, wherein:

R₁₃and R₁₃′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, R₁and R₂, together with the nitrogen atom to which they are attached, form a heterocycle ring such as morpholine and piperazine, which is substituted with heteroaryl selected from pyrazolopyrimidinyl and pyrrolidinedionyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine).

For example, R₁and R₂, together with the nitrogen atom to which they are attached, form a ring selected from morpholine and piperazine.

For example, at least one of R₁₃and R₁₃′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₁₃and R₁₃′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R₁₃and R₁₃′ is phenyl and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, at least one of R₁₃and R₁₃′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, and the like, and is optionally substituted.

For example, at least one of R₁₃and R₁₃′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R₁₃and R₁₃′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, T₃is a bond.

For example, T₃is straight chain C₁-C₆or branched C₃-C₆alkyl linker, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and 2,2-dimethylpropyl.

For example, T₃is methyl, ethyl, propyl, or 2,2-dimethylpropyl.

For example, Q₃is H.

For example, Q₃is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, Q₃is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, Q₃is unsubstituted or substituted C₁-C₆alkylamino, including but not limited to, methylamino, ethylamino, propylamino and i-propylamino

For example, Q₃is unsubstituted or substituted di-C₁-C₆alkylamino, including but not limited to, dimethylamino, diethylamino, dipropylamino and di-i-propylamino.

For example, Q₃is unsubstituted or substituted phenyl or naphthyl.

For example, Q₃is phenyl and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, Q₃is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, Q₃is heteroaryl selected from pyridinyl or imidazolyl.

For example, Q₃is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, Q₃is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), unsubstituted or substituted C₆-C₁₀aryl-C₁-C₆alkyl (e.g., benzyl), or unsubstituted or substituted heteroaryl-C₁-C₆alkyl (e.g., pyridylmethyl).

For example, Q₃is heterocycle selected from pyrrolidinyl and piperidinyl.

For example, R₅is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, R₅is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, R₅is methoxy.

For example, R₅is unsubstituted or substituted phenyl or naphthyl.

For example, R₅is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted.

For example, R₅is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, R₅is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, m is 0 or 1.

For example, R_p1and R_p2are each independently H.

For example, one of R_p1and R_p2is H and the other is not H.

For example, at least one of R_p1and R_p2is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R_p1and R_p2is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, at least one of R_p1and R_p2is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R_p1and R_p2is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted.

For example, at least one of R_p1and R_p2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R_p1and R_p2is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, R₇and R₇′ are each independently H.

For example, at least one of R₇and R₇′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₇and R₇′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R₇and R₇′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, triazinyl, and the like, and is optionally substituted.

For example, at least one of R₇and R₇′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R₇and R₇′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, the compound of Formula I is of Formula II, III, or IV:

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in which:

—Z₁-Z₂— is —CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—NR_z— or —CH₂—NR_z—CH₂—;

—Z₃-Z₄— is —CH₂—NR_z—, —CH₂—CH₂—NR_z— or —CH₂—NR_z—CH₂—;

R₈is unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted phenyl, or -T₁-Q₁;

For example, in Formula II, —Z₁-Z₂— is —CH₂—O—CH₂— or —CH₂—NR_z—CH₂— and one of R₃and R₄is H and the other is -T₃-Q₃.

For example, in Formula II, Q₃is H, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, in Formula II, R_zis H, amidinyl, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, in Formula III, R_zis H, —C(O)OR₁₁, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, in Formula III, R_zis heteroaryl optionally substituted with halogen, cyano, amidinyl, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₁-C₆alkylthiol, or unsubstituted or substituted C₁-C₆alkoxycarbonyl.

For example, in formula III, R₃and R₄are each independently H or unsubstituted or substituted C₁-C₆alkyl.

For example, R₈is -T₁-Q₁, T₁is unsubstituted or substituted C₁-C₆alkyl linker and Q₁is —NR₉R₉′.

For example, in Formula IV, T₁is a methyl linker

For example, in Formula IV, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 4- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T₂-Q₂

For example, in Formula IV, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 5- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T₂-Q₂

For example, in Formula IV, R₉and R₉′, together with the nitrogen atom to which they are attached, form

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T₂is a bond or unsubstituted or substituted C₁-C₄alkyl linker, and Q₂is H, hydroxyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or —C(O)R₁₀.

For example, in Formula IV, R₉and R₉′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, provided that at most one of R₉and R₉′ is H.

For example, R₈is phenyl optionally substituted with C₁-C₆alkyl, C₁-C₆alkoxy, or C₁-C₆haloalkyl.

For example, R₈is C₁-C₆alkyl and one of R₃and R₄is H and the other is -T₃-Q₃.

For example, the compound of Formula I is of Formula IIA, MA, or IVA:

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For example, R₅is hydroxyl or unsubstituted or substituted C₁-C₆alkoxy.

For example, in Formula IIIA, R_zis heteroaryl optionally substituted with halogen, cyano, amidinyl, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₁-C₆alkylthiol, or unsubstituted or substituted C₁-C₆alkoxycarbonyl.

For example, in formula IIIA, R₃and R₄are each independently H or unsubstituted or substituted C₁-C₆alkyl.

For example, in Formula IVA, T₁is a methyl linker

For example, in Formula IVA, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 4- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T-Q₂.

For example, in Formula IVA, R₉and R₉′, together with the nitrogen atom to which they are attached, form a 5- to 10-member ring which optionally contains from 1 to 4 heteroatoms selected from N, O and S and is optionally substituted with -T₂-Q₂

For example, in Formula IVA, R₉and R₉′, together with the nitrogen atom to which they are attached, form

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For example, in Formula IVA, R₉and R₉′ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, provided that at most one of R₉and R₉′ is H.

The present invention also provides the compounds of Formula II:

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wherein:

each of R₃and R₄independently is -T₃-Q₃where -T₃-Q₃is not H, and at most one of R₃and R₄is H;

—Z₁-Z₂— is —CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—NR_z— or —CH₂—NR_z—CH₂—;

m is 0, 1, 2, 3, 4, 5, or 6;

T₃is unsubstituted or substituted C₁-C₆alkyl linker, or a bond;

For example, —Z₁-Z₂— is —CH₂—O—CH₂— or —CH₂—NR_z—CH₂— and one of R₃and R₄is H and the other is -T₃-Q₃.

For example, R_zis H, amidinyl, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₃is a bond.

For example, T₃is methyl, ethyl, propyl, or 2,2-dimethylpropyl.

For example, Q₃is H.

For example, Q₃is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, Q₃is unsubstituted or substituted C₁-C₆alkylamino, including but not limited to, methylamino, ethylamino, propylamino and i-propylamino

For example, Q₃is unsubstituted or substituted di-C₁-C₆alkylamino, including but not limited to, dimethylamino, diethylamino, dipropylamino and di-i-propylamino.

For example, Q₃is unsubstituted or substituted phenyl or naphthyl.

For example, Q₃is phenyl and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen such as F), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, Q₃is heteroaryl selected from pyridinyl or imidazolyl which is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, Q₃is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, Q₃is heterocycle selected from pyrrolidinyl and piperidinyl.

For example, R₅is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, R₅is methoxy.

For example, R₅is unsubstituted or substituted phenyl or naphthyl.

For example, R₅is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, m is 0 or 1.

For example, R_p1and R_p2are each independently H.

For example, one of R_p1and R_p2is H and the other is not H.

For example, at least one of R_p1and R_p2is unsubstituted or substituted C₁-C₆alkoxy, including but not limited to, methoxy, ethoxy, propyloxy, and i-propyloxy.

For example, at least one of R_p1and R_p2is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R_p1and R_p2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, R₇and R₇′ are each independently H.

For example, at least one of R₇and R₇′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R₇and R₇′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, R_zis H.

For example, R_zis amidinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl).

For example, R_zis unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine and iodine), hydroxyl, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy), unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), or unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, di-i-propylamino, methylpropyl amino, ethylmethylamino, and cyclohexylmethylamino).

For example, R_zis phenyl or naphthyl, and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, R_zis heteroaryl selected from pyrazolopyrimidinyl and pyrrolidinedionyl, and is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine).

For example, R_zis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, and t-butoxy), or unsubstituted or substituted amino.

For example, R_zis heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted with hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, and t-butoxy), or unsubstituted or substituted amino.

For example, at least one of R₁₁and R₁₁′ is unsubstituted or substituted, straight chain C₁-C₆or branched C₃-C₆alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, at least one of R₁₁and R₁₁′ is unsubstituted or substituted phenyl or naphthyl.

For example, at least one of R₁₁and R₁₁′ is phenyl and is optionally substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), nitro, cyano, unsubstituted or substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionally substituted with halogen), unsubstituted or substituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy, and ethylenedioxy, each of which is optionally substituted with halogen), amino, unsubstituted or substituted C₁-C₆alkylamino (e.g., methylamino, ethylamino, propylamino and i-propylamino), and unsubstituted or substituted di-C₁-C₆alkylamino (e.g., dimethylamino, diethylamino, dipropylamino and di-i-propylamino).

For example, at least one of R₁₁and R₁₁′ is heteroaryl selected from pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, imidazolthiazolyl, quinoxalinyl, and the like, and is optionally substituted.

For example, at least one of R₁₁and R₁₁′ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted.

For example, at least one of R₁₁and R₁₁′ is heterocycle selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the like, and is optionally substituted.

For example, the compound of Formula II is of Formula IIA:

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For example, R₅is hydroxyl or unsubstituted or substituted C₁-C₆alkoxy.

The present invention also provides the compounds of Formula III:

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wherein:

each of R₃and R₄independently is -T₃-Q₃, where -T₃-Q₃is not H, and at most one of R₃and R₄is H;

R₅is halogen, cyano, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₇R₇′, —NR₇′ C(O)R₇, —NR₇′C(O)OR₇′, —NHC(O)NR₇R₇′, or —NR₇′ S(O)₂R₇;

R_p1and R_p2are each independently H, halogen, cyano, hydroxyl, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆alkoxy, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising one or two 4-, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —NR₇R₇′, —NR₇′C(O)R₇, —NR₇C(O)OR₇′, —NHC(O)NR₇R₇′, or —NR₇′S(O)₂R₇;