PYRAZOLE AND IMIDAZOLE COMPOUNDS FOR INHIBITING IL-17 AND RORgamma

Abstract

Disclosed herein are compounds of the formula: # imgabs0 # and analogs thereof, wherein the variables are as defined herein. Also provided are pharmaceutical compositions thereof. In certain aspects, the compounds and compositions provided herein can be used to modulate the activity of IL-17 and ROR [gamma]. Also provided are methods of administering the compounds and compositions provided herein to a patient in need thereof, for example, in order to treat or prevent a disease or disorder associated with inflammation or an autoimmune disorder.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980052795.1, application date June 17, 2019, and invention name “Pyrazole and Imidazole Compounds for Inhibiting IL-17 and RORγ” after the PCT international application with PCT application number PCT / US2019 / 037543 entered the Chinese national phase.

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 685,742, filed June 15, 2018, and U.S. Provisional Application No. 62 / 687,602, filed June 20, 2018, both of which are hereby incorporated by reference in their entireties. Technical Field

[0003] The present invention relates generally to the fields of biology and medicine. More specifically, the present invention relates to compounds, compositions and methods for treating and preventing diseases such as those associated with overproduction of RAR-related orphan receptor gamma (RORγ) and IL-17. Background Art

[0004] Inflammatory diseases, particularly autoimmune diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and multiple sclerosis, often have serious and long-term adverse effects on physical health and quality of life. In many patients, these diseases can cause severe disability, and in some cases (e.g., lupus and multiple sclerosis), they can be life-threatening. Recent advances in treatment options, such as the development of therapeutic antibodies against tumor necrosis factor (TNF), have improved efficacy and quality of life for many patients. However, a large number of patients cannot fully relieve symptoms with these therapies or cannot tolerate these therapies. Even in patients who do respond, side effects can be significant and potentially life-threatening due to immunosuppression or other complications.

[0005] Recent research on chronic inflammation and autoimmunity has revealed the important role played by a subset of T lymphocytes called Th17 cells. These cells produce the inflammatory cytokine interleukin 17 (IL-17). It has been shown to play a role in many autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, vitiligo, Sjögren's disease, and inflammatory bowel disease. Excessive levels of IL-17 have been reported in patients with schizophrenia, ankylosing spondylitis, and myasthenia gravis (Miossec and Kolls, 2012; Yang et al., 2014; Gaffen et al., 2014). There is evidence that IL-17 also plays an important role in the pathology of vasculitis, atherosclerosis, and inflammatory lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease (COPD). IL-17 has also been implicated in the pathophysiology of epilepsy and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and ALS. Elevated levels of IL-17 or Th17 cells have been reported in patients with psychiatric and neuropsychiatric disorders, including schizophrenia, obsessive-compulsive disorder, bipolar disorder, post-traumatic stress disorder, major depression, and autism. Elevated levels of IL-17 have been implicated in other disorders involving dysregulated inflammatory signaling, including obesity, insulin resistance, and fatty liver disease.

[0006] Although Th17 cells are not the only source of IL-17, they have been reported to be the main source of this cytokine in tissues damaged by autoimmune diseases (such as arthritic joints). Elevated IL-17 levels have also been reported to promote tissue degradation, for example, by stimulating the production of matrix metalloproteinases (which are a source of damage to connective tissue and cartilage) and increasing the expression of receptor activator of NF-κB ligand (RANKL), which stimulates osteoclast activity and promotes bone damage.

[0007] Inappropriate activity of Th17 cells, including excessive production of IL-17, has also been implicated in pathologies associated with certain viral and parasitic infections. For example, IL-17 has been implicated in the development of severe neuroinflammation associated with Toxoplasma gondii infection, as well as in increased severity of lesions associated with Leishmania infection. In these and other cases, IL-17 appears to play a role in perpetuating infection, promoting excessive inflammatory responses, and inhibiting clearance of infectious agents (Waite and Skokos, 2011). Therefore, therapies that prevent or inhibit excessive production of IL-17 or otherwise reduce circulating levels of IL-17 have significant potential in a variety of diseases or disorders, including those with inflammatory and autoimmune components.

[0008] The differentiation of Th17 cells and their production of IL-17 are largely regulated by the retinoid orphan receptor RORγt (a member of the nuclear hormone receptor family). RORγt expression is common to all types of Th17 cells and plays an important role in their differentiation and activity. RORγ also regulates IL-17 production in other cell types, including γδT cells, innate lymphoid cells, and lymphoid tissue induction cells (Bronner et al., 2017). It has been shown that inhibition of RORγt activity leads to reduced IL-17 expression. Therefore, the identification of small molecule inhibitors of RORγt is of great interest. Summary of the Invention

[0009] The present disclosure provides novel compounds, including pyrazole and imidazole derivatives having anti-inflammatory and / or antioxidant properties, pharmaceutical compositions thereof, methods for their preparation, and methods of their use. In certain embodiments, the compound is further defined as:

[0010]

[0011] in:

[0012] n is 0, 1, or 2;

[0013] R1 is cyano, fluorine, -CF3 or -C(O)R a ,in:

[0014] R a is hydroxy or amino; or

[0015] Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups;

[0016] R2 and R2' are each independently hydrogen; or

[0017] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0018] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0019] R3 is an alkyl group(C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups;

[0020] R4 and R5 are each independently absent or hydrogen; or

[0021] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0022] A group of the formula:

[0023]

[0024] Wherein l and m are each 0, 1, 2 or 3;

[0025] R6 is absent or is hydrogen or amino; or

[0026] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12), arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and

[0027] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0028] or a pharmaceutically acceptable salt thereof.

[0029] In certain embodiments, the compound is further defined as:

[0030]

[0031] in:

[0032] n is 0, 1, or 2;

[0033] R1 is cyano, fluorine, -CF3 or -C(O)R a ,in

[0034] R a is hydroxy or amino; or

[0035] Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups;

[0036] R2 and R2' are each independently hydrogen; or

[0037] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0038] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0039] R3 is an alkyl group (C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups;

[0040] R4 and R5 are each independently absent or hydrogen; or

[0041] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12)-heteroaryl (C≤12) or a substituted form of any of these groups; or

[0042] A group of the formula:

[0043]

[0044] Wherein l and m are each 0, 1, 2 or 3;

[0045] R6 is absent or is hydrogen or amino; or

[0046] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups;

[0047] and

[0048] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0049] or a pharmaceutically acceptable salt thereof.

[0050] In certain embodiments, the compound is further defined as:

[0051]

[0052] in:

[0053] R1 is cyano, fluorine, -CF3 or -C(O)R a ,in

[0054] R a is hydroxy or amino; or

[0055] Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups;

[0056] R2 and R2' are each independently hydrogen; or

[0057] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0058] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0059] R3 is an alkyl group (C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups;

[0060] R4 and R5 are each independently absent or hydrogen; or

[0061] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl(C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0062] A group of the formula:

[0063]

[0064] Wherein l and m are each 0, 1, 2 or 3;

[0065] R6 is absent or is hydrogen or amino; or

[0066] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy(C≤12) or a substituted form of any of these groups; and

[0067] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0068] or a pharmaceutically acceptable salt thereof.

[0069] In certain embodiments, the compound is further defined as:

[0070]

[0071] in:

[0072] R1 is cyano, fluorine, -CF3 or -C(O)R a ,in

[0073] R a is hydroxy or amino; or

[0074] Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups;

[0075] R2 and R2' are each independently hydrogen; or

[0076] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0077] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0078] R4 and R5 are each independently absent or hydrogen; or

[0079] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl(C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0080] A group of the formula:

[0081]

[0082] in:

[0083] l and m are each 0, 1, 2, or 3;

[0084] R6 is absent or is hydrogen or amino; or

[0085] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic(C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and

[0086] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0087] or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the compound is further defined as:

[0089]

[0090] in:

[0091] R2 and R2' are each independently hydrogen; or

[0092] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0093] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0094] R4 and R5 are each independently absent or hydrogen; or

[0095] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic(C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0096] A group of the formula:

[0097]

[0098] Wherein l and m are each 0, 1, 2 or 3;

[0099] R6 is absent or is hydrogen or amino; or

[0100] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl(C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and

[0101] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0102] or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments, the compound is further defined as:

[0104]

[0105] in:

[0106] R2 and R2' are each independently hydrogen; or

[0107] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0108] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0109] R4 and R5 are each independently absent or hydrogen; or

[0110] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl(C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0111] A group of the formula:

[0112]

[0113] Wherein l and m are each 0, 1, 2 or 3;

[0114] R6 is absent or is hydrogen; or

[0115] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18)-Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups;

[0116] or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the compound is further defined as:

[0118]

[0119] in:

[0120] R2 and R2' are each independently hydrogen; or

[0121] alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; or

[0122] R2 and R2' together, and is an alkanediyl (C≤8) , olefin diyl (C≤8) or a substituted form of any of these groups;

[0123] R4 and R5 are each independently absent or hydrogen; or

[0124] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12),-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0125] A group of the formula:

[0126]

[0127] wherein l and m are each 0, 1, 2 or 3; and

[0128] R6 is absent or is hydrogen; or

[0129] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; wherein:

[0130] or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, the compound is further defined as:

[0132]

[0133] in:

[0134] R4 and R5 are each independently absent or hydrogen; or

[0135] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0136] A group of the formula:

[0137]

[0138] wherein l and m are each 0, 1, 2 or 3; and

[0139] R6 is absent or is hydrogen; or

[0140] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino(C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and

[0141] X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C;

[0142] or a pharmaceutically acceptable salt thereof.

[0143] In other embodiments, the compound is further defined as:

[0144]

[0145] in:

[0146] R4 and R5 are each independently absent or hydrogen; or

[0147] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12),-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0148] A group of the formula:

[0149]

[0150] wherein l and m are each 0, 1, 2 or 3; and

[0151] R6 is absent or is hydrogen; or

[0152] Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12)or a substituted form of any of these groups; wherein:

[0153] or a pharmaceutically acceptable salt thereof.

[0154] In other embodiments, the compound is further defined as:

[0155]

[0156] in:

[0157] R4 and R5 are each independently absent or hydrogen; or

[0158] alkyl (C≤12) , cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) ,-arene diyl (C≤12) -alkyl (C≤12) ,-arene diyl (C≤12) -Aryl (C≤12) ,-arene diyl (C≤12) -heteroaryl (C≤12) ,-arene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-arene diyl (C≤12) -cycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -cycloalkyl (C≤12) ,-heterocycloalkanediyl (C≤12) -Aryl (C≤12) ,-heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) or a substituted form of any of these groups; or

[0159] A group of the formula:

[0160]

[0161] wherein l and m are each 0, 1, 2 or 3; and

[0162] R6 is absent or is hydrogen; or

[0163] Alkylamino(C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) ,-alkanediyl (C≤12) -cycloalkyl (C≤12) ,-alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) ,-arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) ,-arene diyl (C≤18) -Heterocycloalkyl (C≤12) , heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups;

[0164] or a pharmaceutically acceptable salt thereof.

[0165] In certain embodiments, X1 and X2 are both N. In other embodiments, X1 and X2 are not both N. In other embodiments, X1 or X2 is N. In certain embodiments, X1 is N. In certain embodiments, X2 is N.

[0166] In certain embodiments, R3 is alkyl (C≤12) or substituted alkyl (C≤12) In certain embodiments, R3 is alkyl (C≤12) In certain embodiments, R1 is cyano. In other embodiments, R1 is -C(O)R a In certain embodiments, R a Alkoxy (C≤6) In other embodiments, R a It's amino.

[0167] In certain embodiments, R2′ is hydrogen. In certain embodiments, R2 is hydrogen. In other embodiments, R2′ and R2 are both hydrogen. In other embodiments, R2 is alkyl. (C≤12) or substituted alkyl (C≤12) In certain embodiments, R2 is alkyl (C≤12)In certain embodiments, R4 is absent. In other embodiments, R4 is hydrogen. In other embodiments, R4 is alkyl. (C≤12) or substituted alkyl (C≤12) In certain embodiments, R4 is substituted alkyl (C≤12) Such as 2,2,2-trifluoroethyl. In other embodiments, R4 is cycloalkyl (C≤12) or substituted cycloalkyl (C≤12) In certain embodiments, R4 is cycloalkyl (C≤12) Such as cyclohexyl. In other embodiments, R4 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) In certain embodiments, R4 is heterocycloalkyl (C≤12) Such as tetrahydro-2H-pyran-4-yl or 1,1-dioxotetrahydrothiophen-3-yl. In other embodiments, R4 is:

[0168]

[0169] wherein l and m are each 0, 1, 2, or 3. In certain embodiments, l is 1 or 2. In certain embodiments, m is 1 or 2.

[0170] In other embodiments, R4 is aryl (C≤18) or substituted aryl (C≤18) In certain embodiments, R4 is aryl (C≤18) , such as phenyl, o-tolyl, p-tolyl, [1,1′-biphenyl]-4-yl, 4-isopropylphenyl, naphth-1-yl, 4′-methyl-[1,1′-biphenyl]-4-yl or 2′-methyl-[1,1′-biphenyl]-4-yl. In other embodiments, R4 is substituted aryl (C≤18) , such as 4-(trifluoromethyl)phenyl, 4-cyanophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl, 4-carboxyphenyl, 4′-methoxy-[1,1′-biphenyl]-4-yl, 4′-(dimethylamino)-[1,1′-biphenyl]-4-yl, 2′-fluoro-[1,1′-biphenyl]-4-yl, 3′-fluoro-[1,1′-biphenyl]-4-yl, 2′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl, 3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl, 4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl, or 5-(3-(hydroxymethyl)phenyl. In other embodiments, R4 is aralkyl (C≤18) or substituted aralkyl (C≤18) In certain embodiments, R4 is aralkyl (C≤18)In other embodiments, R4 is -arenediyl (C≤12) -Heterocycloalkyl (C≤12) or substituted arene diyl (C≤12) -Heterocycloalkyl (C≤12) In certain embodiments, R4 is -arenediyl (C≤12) -Heterocycloalkyl (C≤12) Such as 4-morpholinophenyl. In other embodiments, R4 is heteroaryl (C≤18) or substituted heteroaryl (C≤18) In certain embodiments, R4 is heteroaryl (C≤18) , such as pyridin-4-yl, quinolin-4-yl, 5-methylpyridin-2-yl, 6-methylpyridin-3-yl, (pyridin-3-yl)phenyl, (pyridin-4-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-phenylpyridin-2-yl, [3,3′-bipyridyl]-6-yl, 5-cyclopropylpyridin-2-yl, 6-phenylpyridin-3-yl, 4-(6-methylpyridazin-4-yl)phenyl, 5-methyl-1,2,4-oxadiazole-3-yl, In other embodiments, R4 is substituted heteroaryl. (C≤18) , such as 2-fluoro-4-(pyridin-3-yl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 5-(3-fluorophenyl)pyridin-2-yl, 5-(4-fluorophenyl)pyridin-2-yl, 4-(2-(hydroxymethyl)pyridin-4-yl)phenyl, 4-(2-(fluoromethyl)pyridin-4-yl)phenyl, 5-(trifluoromethyl)benzo[d]oxazol-2-yl, 6-chlorobenzo[d]thiazol-2-yl, or 4-(5-fluoropyridin-3-yl)phenyl.

[0171] In certain embodiments, R5 is hydrogen. In other embodiments, R5 is alkyl (C≤12) or substituted alkyl (C≤12) In certain embodiments, R5 is alkyl (C≤12) In other embodiments, R5 is cycloalkyl.(C≤12) or substituted cycloalkyl (C≤12) In certain embodiments, R5 is cycloalkyl (C≤12) Such as cyclohexyl. In other embodiments, R5 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) In certain embodiments, R5 is heterocycloalkyl (C≤12) Such as tetrahydro-2H-pyran-4-yl. In other embodiments, R5 is aryl (C≤18) or substituted aryl (C≤18) In certain embodiments, R5 is aryl (C≤18) , such as phenyl, o-tolyl, p-tolyl, [1,1′-biphenyl]-4-yl, 4-isopropylphenyl, naphth-1-yl, [1,1′-biphenyl]-3-yl or 3-isopropylphenyl. In other embodiments, R5 is substituted aryl (C≤18) , such as 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl, 3-bromophenyl, 3-chlorophenyl, 4-(dimethylamino)phenyl. In other embodiments, R5 is aralkyl (C≤18) or substituted aralkyl (C≤18) In certain embodiments, R5 is aralkyl (C≤18) In other embodiments, R5 is -arenediyl (C≤12) -Heterocycloalkyl (C≤12) or substituted arene diyl (C≤12) -Heterocycloalkyl (C≤12) In certain embodiments, R5 is -arenediyl (C≤12) -Heterocycloalkyl (C≤12) Such as 3-morpholinophenyl. In other embodiments, R5 is heteroaryl (C≤18) or substituted heteroaryl (C≤18) In certain embodiments, R5 is heteroaryl (C≤18) , such as pyridin-4-yl, quinolin-4-yl, quinolin-3-yl, quinolin-5-yl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 2-isopropylpyrimidin-5-yl, 6-cyclopropylpyridin-3-yl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 1-methyl-1H-pyrazol-4-yl, 3-(3,5-dimethylisoxazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-5-yl)phenyl or 2-cyclopropylpyridin-4-yl. In other embodiments, R5 is substituted heteroaryl. (C≤18) , such as 2-(trifluoromethyl)pyridin-4-yl or 3-(5-fluoropyridin-3-yl)phenyl. In other embodiments, R5 is -heteroarenediyl (C≤12) -Heterocycloalkyl (C≤12)or substituted-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) In certain embodiments, R5 is -heteroarenediyl (C≤12) -Heterocycloalkyl (C≤12) Such as 2-morpholinopyridin-4-yl.

[0172] In certain embodiments, R6 is hydrogen. In other embodiments, R6 is amino. In other embodiments, R6 is alkylamino. (C≤12) or substituted alkylamino (C≤12) In certain embodiments, R6 is alkylamino (C≤12) Such as methylamino. In other embodiments, R6 is cycloalkylamino (C≤12) or substituted cycloalkylamino (C≤12) In certain embodiments, R6 is cycloalkylamino (C≤12) Such as cyclobutylamino. In other embodiments, R6 is alkyl (cycloalkyl) amino (C≤12) or substituted alkyl(cycloalkyl)amino (C≤12) In certain embodiments, R6 is alkyl(cycloalkyl)amino (C≤12) Such as methyl(cyclobutyl)amino. In other embodiments, R6 is arylamino (C≤12) or substituted arylamino (C≤12) In certain embodiments, R6 is arylamino (C≤12) Such as phenylamino. In other embodiments, R6 is alkyl (C≤12) or substituted alkyl (C≤12) In certain embodiments, R6 is alkyl (C≤12) In other embodiments, R6 is substituted alkyl. (C≤12) Such as 2-hydroxyethyl or 2-methoxyethyl. In other embodiments, R6 is acyl (C≤6) or substituted acyl (C≤6) In certain embodiments, R6 is acyl (C≤6) Such as -C(O)CH3. In other embodiments, R6 is cycloalkyl (C≤12) or substituted cycloalkyl (C≤12) In certain embodiments, R6 is cycloalkyl (C≤12) Such as cyclopropyl or cyclohexyl. In other embodiments, R6 is -alkanediyl (C≤18) -cycloalkyl (C≤18) or substituted-alkanediyl (C≤18) -cycloalkyl (C≤18) In certain embodiments, R6 is -alkanediyl (C≤18) -cycloalkyl (C≤18) Such as cyclobutylmethyl. In other embodiments, R6 is aryl(C≤18) or substituted aryl (C≤18) In certain embodiments, R6 is aryl (C≤18) , such as phenyl, o-tolyl, p-tolyl or 3-isopropylphenyl. In other embodiments, R6 is substituted aryl (C≤18) , such as 2-fluorophenyl, 4-fluorophenyl, 4-(hydroxymethyl)phenyl, 3-fluorophenyl or 4-(fluoromethyl)phenyl. In other embodiments, R6 is aralkyl (C≤18) or substituted aralkyl (C≤18) In certain embodiments, R6 is aralkyl (C≤18) In other embodiments, R6 is a substituted aralkyl (C≤18) , such as 2-fluorobenzyl, 4-fluorobenzyl or 4-chlorobenzyl. In other embodiments, R6 is -arenediyl (C≤18) -Heterocycloalkyl (C≤12) or substituted arene diyl (C≤18) -Heterocycloalkyl (C≤12) In certain embodiments, R6 is -arenediyl (C≤18) -Heterocycloalkyl (C≤12) Such as 4-morpholinophenyl. In other embodiments, R6 is heteroaryl (C≤18) or substituted heteroaryl (C≤18) In certain embodiments, R6 is heteroaryl (C≤18) , such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methyl-2H-tetrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl)phenyl, pyridin-2-ylmethyl, 3-methyl-1,2,4-oxadiazol-5-yl or 5-methyl-1,2,4-oxadiazol-3-yl. In other embodiments, R6 is heteroarylalkyl (C≤18) or heteroarylalkyl (C≤18) In certain embodiments, R6 is heteroarylalkyl (C≤18) , such as 2-pyridylmethyl or 4-pyridylmethyl. In other embodiments, R6 is -alkanediyl (C≤18) -Aralkyloxy (C≤18) or substituted-alkanediyl (C≤18) -Aralkyloxy (C≤18) In certain embodiments, R6 is -alkanediyl (C≤18) -Aralkyloxy (C≤18) Such as 2-(benzyloxy)ethyl.

[0173] In certain embodiments, the compound is further defined as:

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] or a pharmaceutically acceptable salt of any one of the above formulae.

[0189] In certain embodiments, the compound can be further defined as:

[0190]

[0191]

[0192] or a pharmaceutically acceptable salt of any one of the above formulae.

[0193] In certain aspects, the present disclosure provides compounds of the formula:

[0194] (5aR,6R,9aS)-2-cyclohexyl-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0195] (5aR,6R,9aS)-1-cyclohexyl-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0196] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(2,2,2-trifluoroethyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0197] (5aR,6R,9aS)-2-Benzyl-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0198] (5aR,6R,9aS)-1-benzyl-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0199] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(4-(trifluoromethyl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0200] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0201] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(quinolin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0202] (5aR,6R,9aS)-1-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0203] (5aR,6R,9aS)-1-(3,4-dichlorophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0204] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-1,3-diphenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0205] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(p-tolyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0206] (5aR,6R,9aS)-1-(4-chlorophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0207] (5aR,6R,9aS)-1-(4-methoxyphenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0208] (5aR,9aS)-1-(4-cyanophenyl)-9a-methyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0209] (5aR,9aS)-1-(4-fluorophenyl)-9a-methyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0210] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(o-tolyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0211] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-2-(o-tolyl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0212] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(4-(trifluoromethoxy)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0213] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-2-(4-(trifluoromethoxy)phenyl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0214] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0215] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0216] (5aR,6R,9aS)-6,9a-dimethyl-1-(naphthalen-1-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0217] (5aR,6R,9aS)-6,9a-dimethyl-2-(naphthalen-1-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0218] (5aR,6R,9aS)-1-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0219] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0220] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0221] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-2-(tetrahydro-2H-pyran-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0222] (5aR,6R,9aS)-1-(1,1-dioxotetrahydrothiophen-3-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0223] (5aR,6R,9aS)-2-(1,1-dioxotetrahydrothiophen-3-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0224] (5aR,6R,9aS)-6,9a-dimethyl-1-(5-methylpyridin-2-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0225] (5aR,6R,9aS)-6,9a-dimethyl-1-(6-methylpyridin-3-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0226] (5aR,6R,9aS)-1-(3-bromophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0227] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(3-(pyridin-3-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0228] (5aR,6R,9aS)-1-([1,1′-biphenyl]-3-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0229] (5aR,6R,9aS)-1-(2′-fluoro-[1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0230] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(4-(pyridin-3-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0231] (5aR,6R,9aS)-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0232] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(4-(pyridin-4-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0233] (5aR,6R,9aS)-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0234] (5aR,6R,9aS)-6,9a-dimethyl-1-(4'-methyl-[1,1'-biphenyl]-4-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0235] (5aR,6R,9aS)-1-(4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0236] (5aR,6R,9aS)-1-(2'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0237] (5aR,6R,9aS)-6,9a-dimethyl-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0238] (5aR,6R,9aS)-1-(3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0239] (5aR,6R,9aS)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0240] (5aR,6R,9aS)-1-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0241] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0242] (5aR,6R,9aS)-1-(4-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0243] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-1-(4-(pyrimidin-5-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0244] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-1-(4-(pyridin-3-yl)phenyl)-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0245] 4-((5aR,6R,9aS)-8-cyano-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazol-1-yl)benzoic acid;

[0246] (5aR,6R,9aS)-1-(2-fluoro-4-(pyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0247] (5aR,6R,9aS)-1-(4-(2-(fluoromethyl)pyridin-4-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0248] (5aR,6R,9aS)-1-(4-(2-(hydroxymethyl)pyridin-4-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0249] (5aR,6R,9aS)-1-(5-(4-fluorophenyl)pyridin-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0250] (5aR,6R,9aS)-1-([3,3′-bipyridyl]-6-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0251] (5aR,6R,9aS)-1-(5-(3-fluorophenyl)pyridin-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0252] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-1-(5-phenylpyridin-2-yl)-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0253] (5aR,6R,9aS)-1-(5-(3-(hydroxymethyl)phenyl)pyridin-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0254] (5aR,6R,9aS)-1-(5-(3-(fluoromethyl)phenyl)pyridin-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0255] (5aR,6R,9aS)-1-(5-cyclopropylpyridin-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0256] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0257] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-1-(6-phenylpyridin-3-yl)-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0258] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(4-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0259] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0260] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0261] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0262] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(p-tolyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0263] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-5-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0264] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(3-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0265] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(o-tolyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0266] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(4-(hydroxymethyl)phenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0267] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(4-(fluoromethyl)phenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0268] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-cyclopropyl-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0269] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-cyclohexyl-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0270] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-3-morpholino-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0271] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(cyclobutylamino)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0272] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-3-(methylamino)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0273] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-3-(cyclobutyl(methyl)amino)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0274] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-2-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0275] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(4-(pyrimidin-5-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0276] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0277] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(4-(pyridin-4-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0278] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-1-(4-morpholinophenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0279] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-1-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0280] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(4-phenylthiazol-2-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0281] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0282] (5aR,6R,9aS)-1-(6-chlorobenzo[d]thiazol-2-yl)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0283] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0284] (5aR,6R,9aS)-1-(1H-benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0285] (5aR,6R,9aS)-1-(Benzo[d]thiazol-2-yl)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0286] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(4-(pyrimidin-4-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0287] (5aR,6R,9aS)-3-(2-Fluorophenyl)-6,9a-dimethyl-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile

[0288] (5aR,6R,9aS)-3-(2-Fluorophenyl)-6,9a-dimethyl-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile

[0289] (5aR,6R,9aS)-1-([1,1'-biphenyl]-4-yl)-6,9a-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile

[0290] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-1-(5-phenylpyridin-2-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0291] (5aR,6R,9aS)-1-(Benzo[d]thiazol-2-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0292] (5aR,6R,9aS)-1-(Benzo[d]thiazol-2-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0293] (5aR,6R,9aS)-1-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(phenylamino)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0294] (5aR,6R,9aS)-1-(4-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0295] (5aR,6R,9aS)-6,9a-dimethyl-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0296] (5aR,6R,9aS)-1-(4-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0297] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(quinolin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0298] (5aR,6R,9aS)-3-(4-fluorophenyl)-1-(4-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0299] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0300] (5aR,6R,9aS)-6,9a-dimethyl-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0301] (5aR,6R,9aS)-6,9a-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0302] (5aR,6R,9aS)-6,9a-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo-1-(4-(pyridin-3-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0303] (5aR,6R,9aS)-6,9a-dimethyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0304] (5aR,6R,9aS)-6,9a-dimethyl-3-(2-methyl-2H-tetrazol-5-yl)-7-oxo-2-phenyl-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0305] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-2-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0306] (5aR,6R,9aS)-2-cyclohexyl-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0307] (5aR,6R,9aS)-2-(4-chlorophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0308] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-2,3-diphenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0309] (5aR,6R,9aS)-2-(4-methoxyphenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0310] (5aR,6R,9aS)-2-(3,4-dichlorophenyl)-6,9a-dimethyl-7-oxo-3-phenyl-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0311] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-phenyl-2-(p-tolyl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0312] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-3-(cyclobutylmethyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0313] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0314] (5aR,6R,9aS)-2-([1,1′-biphenyl]-3-yl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0315] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0316] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0317] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0318] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0319] (5aR,6R,9aS)-2-([1,1′-biphenyl]-3-yl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0320] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0321] (5aR,6R,9aS)-2-([1,1′-biphenyl]-3-yl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0322] (5aR,6R,9aS)-3-(3-fluorophenyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0323] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(tetrahydro-2H-pyran-4-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0324] (5aR,6R,9aS)-3-(3-fluorophenyl)-2-(2-isopropylpyrimidin-5-yl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0325] (5aR,6R,9aS)-2-(4-(dimethylamino)phenyl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0326] (5aR,6R,9aS)-3-(3-fluorophenyl)-2,6,9a-trimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0327] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-phenyl-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0328] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(quinolin-4-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0329] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(quinolin-5-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0330] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(quinolin-3-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0331] (5aR,6R,9aS)-3-(3-fluorophenyl)-2-(3-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0332] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-2-(2-morpholinopyridin-4-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0333] (5aR,6R,9aS)-2-benzyl-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0334] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(2-(trifluoromethyl)pyridin-4-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0335] (5aR,6R,9aS)-2-(6-cyclopropylpyridin-3-yl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0336] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-2-(3-morpholinophenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0337] (5aR,6R,9aS)-2-(2-cyclopropylpyridin-4-yl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0338] (5aR,6R,9aS)-2-(3-bromophenyl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0339] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(3-(pyridin-4-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0340] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(3-(pyrimidin-5-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0341] (5aR,6R,9aS)-3-(3-fluorophenyl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0342] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-2-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0343] (5aR,6R,9aS)-2-(3-(3,5-dimethylisoxazol-4-yl)phenyl)-3-(3-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0344] (5aR,6R,9aS)-3-(3-fluorophenyl)-6,9a-dimethyl-2-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0345] (5aR,6R,9aS)-2-([1,1′-biphenyl]-4-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0346] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0347] (5aR,6R,9aS)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-2-(quinolin-4-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0348] (5aR,6R,9aS)-2-([1,1′-biphenyl]-3-yl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0349] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0350] (5aR,6R,9aS)-2-(3-chlorophenyl)-6,9a-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0351] (5aR,6R,9aS)-2-(3,4-dichlorophenyl)-6,9a-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0352] (5aR,6R,9aS)-6,9a-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-7-oxo-2-(3-(pyridin-4-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0353] (5aR,6R,9aS)-6,9a-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-2-(2-morpholinopyridin-4-yl)-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0354] (5aR,6R,9aS)-3-cyclopropyl-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0355] (5aR,6R,9aS)-3-isopropyl-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0356] (5aR,6R,9aS)-2-(4-isopropylphenyl)-3,6,9a-trimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0357] (5aR,6R,9aS)-2-(4-isopropylphenyl)-3-(2-methoxyethyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0358] (5aR,6R,9aS)-3-(2-(benzyloxy)ethyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0359] (5aR,6R,9aS)-3-benzyl-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0360] (5aR,6R,9aS)-3-(4-fluorobenzyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0361] (5aR,6R,9aS)-3-(2-fluorobenzyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0362] (5aR,6R,9aS)-3-(4-chlorobenzyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0363] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-2-ylmethyl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0364] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-4-ylmethyl)-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0365] (5aR,6R,9aS)-3-(2-hydroxyethyl)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0366] (5aR,6R,9aS)-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0367] (5aR,6R,9aS)-3-acetyl-2-(4-isopropylphenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-3H-naphtho[1,2-d]imidazole-8-carbonitrile;

[0368] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(1-phenylpiperidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0369] (5aR,6R,9aS)-3-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(1-phenylpiperidin-4-yl)-4,5,5a,6,7,9a-hexahydro-2H-benzo[g]indazole-8-carbonitrile;

[0370] (5aR,6R,9aS)-6,9a-dimethyl-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0371] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0372] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-7-oxo-1-(4-(pyridazin-3-yl)phenyl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0373] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-1-(4-(5-methylpyridazin-3-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0374] (5aR,6R,9aS)-1-(4-(2-(fluoromethyl)pyridin-4-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0375] (5aR,6R,9aS)-1-(4-(2-(fluoromethyl)pyridin-4-yl)phenyl)-3-(4-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0376] (5aR,6R,9aS)-3-(4-fluorophenyl)-6,9a-dimethyl-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0377] (5aR,6R,9aS)-1-(4-(1,2,4-oxadiazol-3-yl)phenyl)-3-(4-fluorophenyl)-6,9a-dimethyl-7-oxo-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0378] (5aR,6R,9aS)-6,9a-dimethyl-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-7-oxo-3-(pyridin-3-yl)-4,5,5a,6,7,9a-hexahydro-1H-benzo[g]indazole-8-carbonitrile;

[0379] (5aR,6R,9aS)-1-(4-(5-fluoropyridin-3-yl)phenyl)-6,9a-dimethyl-7-oxo-3-(pyrimidin-4-yl)-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[g]indazole-8-carbonitrile; or

[0380] (5aR,6R,9aR)-3-(2-fluorophenyl)-6,9a-dimethyl-1-(4-(6-methylpyridazin-4-yl)phenyl)-7-oxo-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[g]indazole-8-carbonitrile;

[0381] or a pharmaceutically acceptable salt thereof.

[0382] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising:

[0383] (A) a compound described herein or shown above; and

[0384] (B) Excipients.

[0385] In certain embodiments, the pharmaceutical composition is formulated for oral administration, intraadipose, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesical, intravitreal, in the form of liposomes, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, buccally, transdermally, vaginally, in the form of creams, in the form of lipid compositions, via catheter, via lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via local perfusion. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for administration via injection. In certain embodiments, the pharmaceutical composition is formulated for intra-arterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration. In other embodiments, the pharmaceutical composition is formulated for topical administration. In certain embodiments, the pharmaceutical composition is formulated for topical administration to the skin or eye. In certain embodiments, the pharmaceutical composition is formulated as a unit dose.

[0386] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutically effective amount of a compound or composition described herein. In certain embodiments, the patient is a mammal, such as a human. In certain embodiments, the disease or disorder is associated with increased production of the cytokine IL-17. In certain embodiments, the disease or disorder is associated with dysregulated angiogenesis.

[0387] In certain embodiments, the disease or disorder is an autoimmune disease, organ rejection, asthma, cancer, neurological disorder, psychiatric disorder, neuropsychiatric disorder, chronic pain syndrome, inflammatory condition, retinal disorder or cardiovascular disease. In certain embodiments, the disease or disorder is cancer. In other embodiments, the autoimmune disease is psoriasis, multiple sclerosis, scleroderma, rheumatoid arthritis, lupus, psoriatic arthritis, ankylosing spondylitis, Sjögren's syndrome, vitiligo, uveitis, dry eye syndrome, systemic sclerosis, type I diabetes, myasthenia gravis and inflammatory bowel disease. In other embodiments, the cardiovascular disease is vasculitis, atherosclerosis, myocardial infarction, myocarditis, heart failure, pulmonary hypertension or stroke. In other embodiments, the neurological disorder is epilepsy, multiple sclerosis, spinal cord injury, Guillain-Barre syndrome, or another neurological disorder involving inflammatory signaling or oxidative stress of imbalance. In other embodiments, the neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or Huntington's disease. In other embodiments, the inflammatory condition is pancreatitis, hepatitis, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, asthma, dermatitis, gastritis, esophagitis, irritable bowel syndrome, inflammatory bowel disease, nephritis, amyotrophic lateral sclerosis or osteoarthritis. In other embodiments, the chronic pain syndrome is fibromyalgia or neuropathic pain. In certain embodiments, the disease or disorder is a severe inflammatory response to a pathogen (such as from encephalitis, meningitis, Helicobacter pylori (H.pylori), Toxoplasma gondii or Leishmania spp). In other embodiments, the disease or disorder is obesity or a disorder related to obesity. In certain embodiments, the disorder related to obesity is insulin resistance or fatty liver disease. In certain embodiments, the retinal disorder is macular degeneration or other disorders of the retina.

[0388] In certain embodiments, the disease or disorder is relevant to inflammation. In certain embodiments, the disease or disorder relevant to inflammation is obesity, type II diabetes, or a complication of type I or type II diabetes. In certain embodiments, the complication of type I or type II diabetes is neuropathy, reduced renal function or chronic kidney disease, retinopathy, diabetic ulcer or cardiovascular disease. In other embodiments, the disease or disorder relevant to inflammation is chronic kidney disease. In certain embodiments, the chronic kidney disease is hereditary. In other embodiments, the chronic kidney disease is due to non-hereditary reasons. In certain embodiments, the method includes administering the compound once. In other embodiments, the method includes administering the compound twice or more.

[0389] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments of the present invention, are given by way of illustration only, as various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. It should be noted that just because a particular compound is assigned to a particular general formula does not mean that it may not also belong to another general formula. DETAILED DESCRIPTION

[0390] Description of Exemplary Embodiments

[0391] Disclosed herein are novel compounds and compositions that can be used to inhibit the activity of the RORγ nuclear receptor and / or IL-17, thereby being useful in treating a variety of different indications, such as autoimmune diseases, metabolic diseases, cancer, and infections. In certain embodiments, these compounds are used to modulate the expression of one or more downstream compounds, such as interleukin-17 (IL-17).

[0392] I. Compounds and Synthesis Methods

[0393] The compounds of the present invention (also referred to as "compounds of the present disclosure") are shown, for example, in the Summary of the Invention section above and in the claims below. They can be prepared using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught in, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2013), which is incorporated herein by reference. In addition, the synthetic methods can be further modified and optimized using the principles and techniques of process chemistry applied by those skilled in the art for batch or continuous preparation, pilot- or large-scale production. Such principles and techniques are taught in, for example, Anderson, Practical Process Research & Development-A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0394] All compounds of the present invention can be used for preventing and treating one or more diseases or disorders discussed herein or elsewhere in certain embodiments. In certain embodiments, one or more compounds characterized or illustrated herein, as intermediates, metabolites and / or prodrugs, can still be used for preventing and treating one or more diseases or disorders. Thus, unless explicitly stated to the contrary, all compounds of the present invention are considered to be "active compounds" and "therapeutic compounds" used as active pharmaceutical ingredients (APIs). A combination of clinical trial protocols and prescribed procedures (such as those promulgated by the Food and Drug Administration (FDA)) is typically used to determine actual suitability for human or veterinary applications. In the U.S., FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality and reliability of human and veterinary drugs, vaccines and other biological products and medical devices.

[0395] In certain embodiments, the compounds of the present invention have advantages over compounds known in the prior art in that they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, be more readily absorbed, be metabolically more stable, more lipophilic, more hydrophilic, and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical or chemical properties, whether for the indications described herein or otherwise.

[0396] The compounds of the present invention may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be separated in optically active or racemic form. Therefore, unless otherwise specified, all chiral, diastereoisomerism, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended. Compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and each diastereomer. In certain embodiments, single diastereomers are obtained. The chiral center of the compounds of the present invention may have an S or R configuration. In certain embodiments, the compounds of the present invention may contain two or more atoms with a determined stereochemical orientation.

[0397] Chemical formulae used to represent compounds of the present invention generally show only one of several possible tautomers. For example, many types of keto groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which is most prevalent, all tautomers of a given formula are intended.

[0398] In addition, the atoms comprising the compounds of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0399] In certain embodiments, the compounds of the present invention act as prodrugs, or can be derivatized to act as prodrugs. Since it is known that prodrugs enhance the numerous desired properties of a drug (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in certain methods of the present invention can be delivered in prodrug form if desired. Thus, the present invention contemplates prodrugs of the compounds of the present invention and methods for delivering prodrugs. The prodrugs of the compounds used in the present invention can be prepared by modifying the functional groups present in the compound in such a way that the modification is cleaved in conventional operation or in vivo to form the parent compound. Therefore, prodrugs include, for example, compounds described herein: wherein a hydroxyl, amino, or carboxyl group is bonded to any group, and when the prodrug is administered to a patient, the cleavage of any group forms a hydroxyl, amino, or carboxylic acid, respectively.

[0400] In certain embodiments, the compounds of the present invention exist in salt or non-salt form. With regard to salt forms, in certain embodiments, the specific anion or cation that forms part of any salt form of the compounds provided herein is not critical, as long as the salt is pharmacologically acceptable as a whole. Other examples of pharmaceutically acceptable salts and their preparation methods and methods of use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0401] It should be understood that many organic compounds can form complexes with the solvents in which they are reacted or precipitated or crystallized. These complexes are referred to as "solvates." Where the solvent is water, the complex is referred to as a "hydrate." It should also be understood that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof, are within the scope of the present invention.

[0402] II. Diseases associated with the inflammatory cytokine IL-17

[0403] Various reports have suggested that the inflammatory cytokine IL-17 is involved in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis, psoriasis and psoriatic arthritis, inflammatory bowel disease (including, but not limited to Crohn's disease), multiple sclerosis, autoimmune nephritis, autoimmune uveitis, type I diabetes and ankylosing spondylitis. In certain embodiments, the compounds provided herein can be administered to patients to treat or prevent one or more of these diseases or disorders. A type of T lymphocyte known as Th17 cells is the main source of IL-17. The IL-17 family has multiple members. The first member identified, IL-17A, is commonly referred to as IL-17. IL-17 consists of two monomers, which are linked by a disulfide bond to form a homodimer (Miossec and Kolls, 2012). In addition to IL-17A, another major family member is IL-17F. Some evidence suggests that, although IL-17F and IL-17A share many common actions, they may have distinct roles in certain settings, such as lung inflammation. The IL-17 cytokine binds to the IL-17 receptor (IL-17R), which is located on the cell membrane of select cell types. Although there are multiple IL-17 receptor isoforms, the IL-17RA / IL-17RC complex is essential for the activity of both IL-17A and IL-17F. IL-17RA has unique signaling properties, signaling through a pathway involving an adaptor protein (ACT1) rather than the Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway used by most interleukin receptors. Binding of IL-17A to IL-17RA activates the proinflammatory nuclear factor-κB (NF-κB) pathway and proinflammatory components of the mitogen-activated protein kinase (MAPK) pathway, such as JNK N-terminal kinase (JNK), p38, and extracellular signal-related kinase (ERK). IL-17 activity stimulates mesenchymal cells to secrete IL-6 and IL-8, resulting in fever and the accumulation of neutrophils in blood and tissues. In certain embodiments, provided herein is a compound that can be used to suppress the IL-6 and IL-8 secretion of mesenchymal cells. In certain embodiments, provided herein is a compound that can be administered to a patient in order to prevent or suppress fever in a patient. In certain embodiments, provided herein is a compound that can be administered to a patient in order to prevent the accumulation of neutrophils in the patient's blood or tissues.

[0404] In addition to its contribution to acute inflammation, IL-17 also contributes to chronic inflammation (Miossec and Kolls, 2012). In certain embodiments, the compounds provided herein can be administered to patients to prevent or treat chronic inflammation. IL-17 stimulates the production of matrix metalloproteinases (MMPs), which, among other effects, can also degrade cartilage in joints. In certain embodiments, the compounds provided herein can be administered to patients to prevent or treat the degradation of cartilage in patients. IL-17 also increases the expression of receptor activator of NF-κB ligand (RANKL) in osteoblasts, thereby leading to differentiation and activation of osteoclasts and bone degradation. In certain embodiments, the compounds provided herein can be administered to patients to prevent or treat the degradation of bones in patients. Depending on the target cells exposed to IL-17, IL-17 may stimulate the production of IL-6, IL-8, IL-1, tumor necrosis factor (TNF), MMPs, nitric oxide, or several other proteins (e.g., tissue factor, CCL20, G-CSF, and GM-CSF) implicated in inflammatory conditions. In certain embodiments, the compounds provided herein can be administered to a patient to inhibit the production of IL-6, IL-8, IL-1, tumor necrosis factor (TNF), MMPs, nitric oxide, or several other proteins implicated in inflammatory disorders (e.g., tissue factor, CCL20, G-CSF, and GM-CSF).

[0405] Although IL-17 plays a role in the immune response to invading pathogens, excessive IL-17 activity is involved in the pathology related to the excessive immune response to infection. In certain embodiments, the compounds provided herein can be administered to patients to prevent or treat excessive immune responses to infection. For example, IL-17 has been involved in the increase in the severity of severe neuroinflammation associated with Toxoplasma gondii infection and lesions associated with Leishmania infection. In certain embodiments, the compounds provided herein can be administered to patients to treat or prevent neuroinflammation, such as neuroinflammation associated with Toxoplasma gondii infection. In certain embodiments, the compounds provided herein can be administered to patients to treat or prevent lesions associated with Leishmania infection. In these and other cases, IL-17 seems to play a role in continuing infection, promoting excessive inflammatory response and inhibiting the removal of infectious pathogens (Waite and Skokos, 2012). In certain embodiments, the compounds provided herein can be administered to patients to prevent excessive inflammatory response and / or promote the removal of infectious pathogens.

[0406] Drugs targeting IL-17 have entered clinical trials for a variety of inflammatory conditions, including psoriasis, rheumatoid arthritis, ankylosing spondylitis, uveitis, Behcet's disease, psoriatic arthritis, Crohn's disease, polymyalgia rheumatica, dry eye syndrome, multiple sclerosis, graft-versus-host disease, and asthma. In certain embodiments, provided herein are compounds administered to patients to treat or prevent one or more of these diseases or disorders. Preclinical evidence also implicates IL-17 in the pathology of type I diabetes, and Th17 cells increase in patients with adult-onset Still's disorder (another autoimmune disease). In certain embodiments, provided herein are compounds administered to patients to treat type I diabetes. In certain embodiments, provided herein are compounds administered to patients to treat or prevent adult-onset Still's disorder. The activity of Th17 cells has been implicated in the development of graft-versus-host disease after allogeneic stem cell (e.g., bone marrow) transplantation (Fujiwara, et al., 2014). In certain embodiments, provided herein is a compound administered to a patient in order to treat or prevent graft-versus-host disease, for example, after allogeneic stem cell (e.g., bone marrow) transplantation. In view of a large amount of evidence to date, reducing the expression of IL-17 or otherwise reducing its level in circulation or target tissue therapy (e.g., anti-IL17 monoclonal antibodies) may be widely used in the treatment of autoimmune diseases and other inflammatory conditions. In certain embodiments, provided herein is a compound administered to a patient in order to reduce the expression of IL-17 or its level in circulation or target tissue (e.g., anti-IL17 monoclonal antibodies). In certain embodiments, provided herein is a compound administered to a patient in order to treat autoimmune diseases or other inflammatory conditions.

[0407] Overproduction of IL-17 or elevated numbers of Th17 cells have been reported in patient studies or animal models of a number of conditions, including autoimmune diseases, neurological disorders, cardiovascular diseases, cancer, psychiatric and neuropsychiatric disorders, acute and chronic inflammatory conditions, chronic pain syndromes, organ rejection or graft-versus-host disease, or asthma and other allergic conditions. In certain embodiments, the compounds provided herein can be administered to a patient to treat or prevent one or more of these diseases or disorders.

[0408] The differentiation of Th17 cells and the production of IL-17 thereof are largely regulated by the retinoid orphan receptor RORγt (a member of the nuclear hormone receptor family). The expression of RORγt is common to all types of Th17 cells. RORγ also regulates the production of IL-17 in other cell types (including γδT cells, innate lymphoid cells and lymphoid tissue induction cells) (Bronner et al., 2017). The inhibition of RORγt activity can lead to reduced IL-17 expression. In certain embodiments, the compounds provided herein can be administered to patients in order to inhibit RORγt activity.

[0409] Provided herein are compounds and compositions that can be used to suppress IL-17 production in human T cell cultures, wherein human T cells are exposed to a mixture of cytokines known to induce differentiation into Th17 cells. In certain embodiments, the ability to act as a RORγt inverse agonist has also been demonstrated. Without wishing to be bound by any theory, it is believed that, for example, a mechanism independent of RORγt appears to contribute to the suppression of IL-17 production. Thus, provided herein are compounds and compositions that can be used to suppress T cell differentiation into Th17 cells, and suppress mature Th17 cells from producing IL-17. In some of these embodiments, the net result is a reduction in the level of IL-17. In certain embodiments, provided herein are compounds that can be administered to a patient to suppress IL-17 production in one or more tissues or organs of the patient.

[0410] III. Pharmaceutical Formulations and Administration Routes

[0411] In another aspect, in order to administer to the patient who needs such treatment, pharmaceutical preparations (also referred to as pharmaceutical products, pharmaceutical compositions, pharmaceutical products, medical products, medicines, drugs or medicaments) include a therapeutically effective amount of a compound disclosed herein, which is formulated together with one or more excipients and / or pharmaceutical carriers suitable for the indicated route of administration. In certain embodiments, the compound disclosed herein is formulated in a manner suitable for treating humans and / or veterinary patients. In certain embodiments, formulation includes mixing or combining one or more compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, silicon dioxide, sodium salts and calcium salts of phosphoric acid and sulfuric acid, sodium lauryl sulfate, gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol. In certain embodiments, for example, for oral administration, pharmaceutical preparations can be made into tablets or capsules. In certain embodiments, the compound can be dissolved in or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In certain embodiments, the pharmaceutical preparations can be subjected to pharmaceutical operations such as sterilization and / or can contain pharmaceutical carriers and / or excipients, such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0412] Pharmaceutical preparations can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, and intraperitoneally). Depending on the route of administration, the compounds disclosed herein can be encapsulated in materials to protect the compounds from the effects of acid and other natural conditions that may inactivate the compounds. In order to administer the active compound in a manner other than parenteral administration, it may be necessary to coat the compound with a substance that prevents its inactivation, or to co-administer it with the compound. In certain embodiments, the active compound can be administered to the patient in an appropriate carrier, such as a liposome or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0413] The compounds disclosed herein can also be administered parenterally, intraperitoneally, intraspinal or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms.

[0414] The pharmaceutical composition that is suitable for injection includes sterile aqueous solution (when water-soluble) or dispersion, and the sterile powder for instant preparation of sterile injectable solution or dispersion.Described carrier can be solvent or dispersion medium, and it contains for example water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol etc.), its suitable mixture and vegetable oil.Suitable fluidity can, for example, by using coating agent such as lecithin, by maintaining required particle size (when dispersion) and by using surfactant to maintain.The effect of stopping microorganism can be realized by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal etc. In many cases, preferably include isotonic agent in described composition, for example, sugar, sodium chloride or polyol such as mannitol and sorbitol.The extended absorption of injectable composition can be realized by including the reagent (for example, aluminum monostearate or gelatin) that delays absorption in composition.

[0415] Compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compound and other ingredients can also be encapsulated in a hard or soft shell gelatin capsule, encapsulated in an HPMC capsule, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, compounds disclosed herein can be combined with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. The percentage of the therapeutic compound in the composition and preparation can certainly vary. The amount of the therapeutic compound in such a pharmaceutical preparation makes it possible to obtain a suitable dosage.

[0416] The therapeutic compound can also be applied topically to the skin, eyes, ears, or mucous membranes. Topical application of the therapeutic compound can include compound formulations as topical solutions, lotions, creams, ointments, gels, foams, transdermal patches, or tinctures. When the therapeutic compound is formulated for topical application, the compound can be combined with one or more agents that increase the permeability of the compound through the tissue to which it is applied. In other embodiments, it is contemplated that topical application is to the eye. Such application can be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by any theory, it is believed that application to the surface of the eye allows the therapeutic compound to reach the back of the eye. Ophthalmic topical application can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical application can also include application to mucous membranes such as the inside of the mouth. Such application can be applied directly to specific locations within the mucous membrane, such as teeth, sores, or ulcers. Alternatively, if local delivery to the lungs is desired, the therapeutic compound can be administered by inhalation in the form of a dry powder or aerosol formulation.

[0417] In certain embodiments, it may be advantageous to formulate a parenteral composition in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit dosages for a patient to be treated; each unit contains a predetermined amount of a therapeutic compound calculated to produce the desired therapeutic effect in association with a desired pharmaceutical carrier. In certain embodiments, the specifications of the dosage unit forms of the present invention are determined by and directly dependent on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of formulating such therapeutic compounds for the treatment of a selected condition in a patient. In certain embodiments, the active compound is administered in a therapeutically effective dose sufficient to treat a condition associated with the patient's condition. For example, the efficacy of a compound can be evaluated in an animal model system that is predictive of efficacy in treating a disease in a human or another animal.

[0418] In certain embodiments, the effective dose range of a therapeutic compound can be extrapolated based on the effective doses determined in animal studies of a variety of different animals. In certain embodiments, the human equivalent dose (HED) in mg / kg can be calculated according to the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference):

[0419] HED (mg / kg) = animal dose (mg / kg) × (animal K m / personK m )

[0420] Using K in the transformation m Factors that produce HED values ​​based on body surface area (BSA) rather than just weight. K in humans and various animals m The values ​​are well known. For example, the average 60 kg person (BSA is 1.6 m 2 ) of K m is 37, while a 20 kg child (BSA is 0.8 m 2 ) has a K of 25 m K in some related animal models m Also well known, including: mouse K m is 3 (given weight is 0.02kg, BSA is 0.007); hamster K m 5 (given weight of 0.08 kg and BSA of 0.02); rat K m 6 (given a weight of 0.15 kg and a BSA of 0.025) and monkey K m is 12 (given a weight of 3 kg and a BSA of 0.24).

[0421] The exact amount of the therapeutic composition depends on the judgment of the practitioner and is specific to each individual. Nevertheless, the calculated HED dosage can provide a general guide. Other factors affecting dosage include the patient's physical and clinical state, the route of administration, the intended therapeutic goal, and the efficacy, stability, and toxicity of the specific therapeutic formulation.

[0422] The amount of the actual dose of the compound of the present invention or the composition comprising the compound of the present invention administered to the patient can depend on physical and physiological factors, such as the type of animal being treated, age, sex, weight, severity of the disease, type of disease being treated, previous or concurrent therapeutic interventions, idiopathic conditions of the patient, and route of administration. These factors can be determined by a technician. The practitioner responsible for administration generally determines the concentration of the active ingredient in the composition and the appropriate dose for the individual patient. In the case of any complication, the dosage can be adjusted by an individual physician.

[0423] In certain embodiments, the therapeutically effective amount is typically between about 0.001 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 750 mg / kg, about 100 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, about 10 mg / kg to about 150 mg / kg, administered in one or more doses per day for one or more days (depending, of course, on the mode of administration and the factors discussed above). Other suitable dosage ranges include 1 mg to 10,000 mg / day, 100 mg to 10,000 mg / day, 500 mg to 10,000 mg / day, and 500 mg to 1,000 mg / day. In certain embodiments, the amount is less than 10,000 mg / day, with a range of 750 mg to 9,000 mg / day.

[0424] In certain embodiments, the amount of active compound in the pharmaceutical preparation is about 1 to about 100 weight %. In certain embodiments, the amount of active compound in the pharmaceutical preparation is about 10 to about 90 weight %, about 25 to about 75 weight %, or about 50 weight %.

[0425] Consider single dose or multiple doses of the agent. The desired time interval for delivering multiple doses can be determined by one of ordinary skill in the art using no more than routine experimentation. As an example, two doses can be administered to the patient at intervals of approximately 12 hours per day. In certain embodiments, the agent is administered once per day.

[0426] The medicament can be used according to the conventional schedule. The conventional schedule used herein represents a predetermined specified time period. The conventional schedule can cover the same time period, or the time period of different lengths, as long as the schedule is predetermined. For example, the conventional schedule can include 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 1 time per week, 1 time per month, or use with the number of days or weeks of any setting therebetween. Or, the predetermined conventional schedule can include that the first week is pressed and used twice a day, and several months are pressed and used once a day etc. afterwards. In other embodiments, the present invention stipulates that the medicament can be orally administered, and the opportunity of using depends on or does not depend on food intake. Therefore, for example, the medicament can be taken in the morning and / or at night every day, and no matter whether the patient has eaten or will eat.

[0427] IV. Combination Therapy

[0428] In addition to being used as a monotherapy, the compounds of the present invention can also be used in combination therapy. Effective combination therapy can be achieved with a single composition or pharmacological formulation comprising both agents, or with two different compositions or formulations administered simultaneously, one of which comprises a compound of the present invention and the other comprises a second agent. Alternatively, the therapy can precede or follow treatment with the other agent, with intervals ranging from minutes to months.

[0429] Non-limiting examples of such combination therapies include one or more compounds of the present invention in combination with the following agents or therapies: another anti-inflammatory agent, a chemotherapeutic agent, radiation therapy, an antidepressant, an antipsychotic, an anticonvulsant, a mood stabilizer, an anti-infective agent, an antihypertensive agent, a cholesterol-lowering agent or other regulator of blood lipids, an agent for promoting weight loss, an antithrombotic agent, an agent for treating or preventing cardiovascular events such as myocardial infarction or stroke, an antidiabetic agent, an agent for reducing transplant rejection or graft-versus-host disease, an antiarthritis agent, an analgesic, an antiasthmatic or other treatment for respiratory diseases, or an agent for treating or preventing skin disorders. The compounds of the present invention can be combined with agents designed to improve the patient's immune response to cancer (including, but not limited to, cancer vaccines). See Lu et al. (2011), which is incorporated herein by reference.

[0430] V. Definitions

[0431] When used in the context of chemical groups: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxyl" means -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently means -F, -Cl, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; " "Cyano" refers to -CN; "isonitrile" refers to -N=C=O; "azide" refers to -N3; ​​in a monovalent context, "phosphate" refers to -OP(O)(OH)2 or a deprotonated form thereof; in a divalent context, "phosphate" refers to -OP(O)(OH)O- or a deprotonated form thereof; "thiol" refers to -SH; and "thio" refers to =S; "sulfonyl" refers to -S(O)2-; and "sulfinyl" refers to -S(O)-.

[0432] In the context of chemical formulae, the symbol "-" refers to a single bond, "=" refers to a double bond, and "≡" refers to a triple bond. represents an optional bond, which if present is a single bond or a double bond. represents a single bond or a double bond. Covering, for example, It is understood that no such ring atom forms part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when connecting one or two stereogenic atoms. Rather, it encompasses all stereoisomers and mixtures thereof. When drawn vertically through a bond (e.g., for a methyl group, ),symbol Indicates the point of attachment for this group. It should be noted that the point of attachment is usually only identified in this way for larger groups to help the reader clearly identify the point of attachment. refers to a single bond where the group attached to the thick end of the wedge is "coming out of the page". refers to a single bond where the group attached to the thick end of the wedge is "into the paper". =Referring to single bonds, the geometry around double bonds (e.g., E or Z) is undefined. Therefore, both options and their combinations are contemplated. Any undefined valence on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. Bold dots on carbon atoms indicate that the hydrogen attached to that carbon is facing out of the page.

[0433] When a variable is described as a "floating group" on a ring system, for example, the group "R" in the formula:

[0434]

[0435] The variable may replace any hydrogen atom attached to any of the ring atoms, including depicted, implied, or explicitly defined hydrogens, so long as a stable structure results. When a variable is described as a "floating group" on a fused ring system, for example, the group "R" in the formula:

[0436]

[0437] The variable can replace any hydrogen connected to any ring atom of any ring in the fused ring, unless otherwise stated. Replaceable hydrogen includes depicted hydrogen (e.g., hydrogen connected to nitrogen in the above formula), implicit hydrogen (e.g., not shown but understood to be hydrogen in the above formula), well-defined hydrogen, and its presence depends on the optional hydrogen of the identity of the ring atom (e.g., when X equals -CH-, hydrogen connected to group X), as long as a stable structure is formed. In the example shown, R can be located on a 5-membered or 6-membered ring of the fused ring system. In the above formula, the subscript "y" following the R in brackets represents a numerical variable. Unless otherwise stated, this variable can be 0, 1, 2 or any integer greater than 2, subject only to the maximum number of replaceable hydrogen atoms of the ring or ring system.

[0438] For chemical groups and compound classes, the number of carbon atoms in the group or class is indicated as follows: "Cn" defines the exact number of carbon atoms (n) in the group / class. "C≤n" defines the maximum number of carbon atoms (n) that can be in the group / class, while the minimum number is as small as possible for the group / class in question. For example, it is understood that in the group "alkyl" (C≤8) ", "Cycloalkanediyl (C≤8) ", "heteroaryl (C≤8) ” and “acyl (C≤8) The minimum number of carbon atoms in the group "alkenyl" is 1. (C≤8) ", "Alkynyl (C≤8) " and "heterocycloalkyl (C≤8) The minimum number of carbon atoms in the group "cycloalkyl" is 2. (C≤8) The minimum number of carbon atoms in the group "aryl" is 3. (C≤8) ” and “aromatic diyl (C≤8) The minimum number of carbon atoms in a group is 6. "Cn-n'" defines the minimum number (n) and maximum number (n') of carbon atoms in a group. Thus, "alkyl" (C2-10) ” denotes those alkyl groups having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and they may or may not be enclosed in parentheses without indicating any change in meaning. Thus, the terms “C5 olefins,” “C5-olefins,” “olefins” (C5) ” and “olefins C5When any chemical group or compound class defined herein is modified by the term "substituted", any carbon atoms that replace hydrogen atoms are not counted. Thus, a methoxyhexyl group having a total of seven carbon atoms is a substituted alkyl group. (C1-6) Unless otherwise indicated, any chemical group or class of compounds listed in the claims without a carbon atom limitation has a carbon atom limitation of less than or equal to 12.

[0439] When used to modify a compound or chemical group, the term "saturated" means that the compound or chemical group does not have carbon-carbon double bonds and carbon-carbon triple bonds, except as described below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And when such bonds are present, carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, it means that no more of the substance can be dissolved in the solution.

[0440] The term "aliphatic" means that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In an aliphatic compound / group, the carbon atoms can be linked together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, i.e., linked by single carbon-carbon bonds (alkanes / alkyls), or unsaturated, having one or more carbon-carbon double bonds (alkenes / alkenyls) or one or more carbon-carbon triple bonds (alkynes / alkynyls).

[0441] The term "aromatic" means that the compound or chemical group so modified has a planar unsaturated ring of atoms containing 4n+2 electrons in a completely conjugated cyclic π system.

[0442] The term "alkyl" refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, having a straight or branched acyclic structure, and having no atoms other than carbon and hydrogen. The groups -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), -CH(CH3)2(i-Pr, i Pr or isopropyl), -CH2CH2CH2CH3(n-Bu), -CH(CH3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C(CH3)3(tert-butyl, t-butyl, t-Bu or tBu) and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as points of attachment, having a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH2-(methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylene" refers to a divalent group =CRR', where R and R' are independently hydrogen, alkyl, aryl, or heteroaryl. Non-limiting examples of alkylene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkanes" refers to the class of compounds having the formula HR, where R is alkyl, as that term is defined above.

[0443] The term "cycloalkyl" refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl or cyclohexyl (Cy). As used herein, the term does not exclude the presence of one or more alkyl groups attached to a carbon atom of a non-aromatic ring structure (carbon number limitations permitting). The term "cycloalkanediyl" refers to a divalent saturated aliphatic group having 2 carbon atoms as the point of attachment, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Group is a non-limiting example of a cycloalkanediyl group. "Cycloalkanes" refers to the class of compounds having the formula HR, in which R is cycloalkyl, as that term is defined above.

[0444] The term "alkenyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, having a straight or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenediyl" refers to a divalent unsaturated aliphatic group having two carbon atoms as the point of attachment, having a straight or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It should be noted that although the alkene diyl group is aliphatic, this does not preclude the group from forming part of an aromatic structure once attached at both ends. The terms "alkene" and "alkene" are synonymous and refer to the class of compounds having the formula HR, where R is an alkenyl group, as defined above. Similarly, the terms "terminal olefin" and "α-olefin" are synonymous and refer to an olefin having exactly one carbon-carbon double bond, where the bond is part of a vinyl group at the end of the molecule.

[0445] The term "alkynyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, having a straight or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The term alkynyl as used herein does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkynes" refers to the class of compounds having the formula HR, where R is an alkynyl group. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have independently been replaced with -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -C02H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0446] The term "aryl" refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as a point of attachment, wherein the carbon atom forms a part for one or more aromatic ring structures, each of which has 6 ring atoms that are all carbon, and wherein the group is not composed of the atoms except carbon and hydrogen. If there is more than one ring, the ring can be fused or not fused. Unfused rings are connected by covalent bonds. The term aryl used herein does not exclude the presence of one or more alkyl groups (carbon number restrictions allow) that are connected to the first aromatic ring or any additional aromatic rings present. The non-limiting example of an aryl group includes phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and the monovalent group (for example, 4-phenylphenyl) derived from biphenyl. The term "arene diyl" refers to a divalent aromatic group having two aromatic carbon atoms as attachment points, wherein the carbon atoms form a part of one or more 6-membered aromatic ring structures, each of which has 6 ring atoms that are all carbon, and wherein the divalent group is not composed of atoms other than carbon and hydrogen. The term "arene diyl" as used herein does not exclude the presence of one or more alkyl groups connected to the first aromatic ring or any additional aromatic ring present (carbon number restrictions allow). If there is more than one ring, the ring can be fused or unfused. Unfused rings are connected by covalent bonds. The non-limiting examples of arene diyl groups include:

[0447]

[0448] "Aromatic hydrocarbons" refers to the class of compounds having the formula HR, wherein R is an aryl group, as that term is defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons.

[0449] The term "aralkyl" refers to the monovalent group -alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0450] The term "heteroaryl" refers to a monovalent aromatic group having an aromatic carbon atom or nitrogen atom as a point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each of which has 3 to 8 ring atoms, wherein at least one ring atom of said aromatic ring structure is nitrogen, oxygen or sulfur, and wherein said heteroaryl group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, said rings are fused. The term heteroaryl does not exclude the presence of one or more alkyl or aryl groups attached to one or more ring atoms (carbon number limitations permitting). Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl(Im), indolyl, indazolyl(Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl(pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl.

[0451] The term "heteroarenediyl" refers to a divalent aromatic group having two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two points of attachment, said atoms forming part of one or more aromatic ring structures, each aromatic ring structure having from 3 to 8 ring atoms, wherein at least one ring atom of said aromatic ring structure is nitrogen, oxygen, or sulfur, and wherein the divalent group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroarenediyl does not exclude the presence of one or more alkyl or aryl groups attached to one or more ring atoms (carbon number limitations permitting). Non-limiting examples of heteroarenediyl groups include:

[0452]

[0453] The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the point of attachment. "Heteroarene" refers to the class of compounds having the formula HR, where R is a heteroaryl group. Pyridine and quinoline are non-limiting examples of heteroarenes.

[0454] The term "heteroaralkyl" refers to the monovalent group -alkanediyl-heteroaryl, wherein the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridylmethyl and 2-quinolinyl-ethyl.

[0455] The term "heterocycloalkyl" refers to a monovalent non-aromatic group having a carbon atom or a nitrogen atom as a point of attachment, the carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each non-aromatic ring structure having 3 to 8 ring atoms, wherein at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group does not consist of atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings are fused. As used herein, the term does not exclude the presence of one or more alkyl groups attached to one or more ring atoms (carbon number restrictions permitting). Furthermore, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group is still non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyranyl, oxirane and oxetanyl.

[0456] The term "heterocycloalkanediyl" refers to a divalent cyclic group having 2 carbon atoms, 2 nitrogen atoms, or 1 carbon atom and 1 nitrogen atom as 2 points of attachment, wherein the atoms form a part of one or more ring structures, wherein at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the divalent group is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If there is more than one ring, the ring is fused. The term heterocycloalkanediyl as used herein does not exclude the presence of one or more alkyl groups connected to one or more ring atoms (carbon number restrictions permitting). Furthermore, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group is still non-aromatic. Non-limiting examples of heterocycloalkanediyl include:

[0457]

[0458] The term "N-heterocycloalkyl" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group.

[0459] The term "acyl" refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl or aryl, as defined above. The groups -CHO, -C(O)CH (acetyl, Ac), -C(O)CHCH, -C(O)CH(CH), -C(O)CH(CH), -C(O)C6H5 and -C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, but the oxygen atom of the group -C(O)R has been replaced by a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkyl group as defined above that is connected to a -CHO group.

[0460] The term "alkoxy" refers to the group -OR, where R is alkyl, as that term is defined above. Non-limiting examples include: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropyloxy), or -OC(CH3)3 (tert-butyloxy). When used without the "substituted" modifier, the terms "cycloalkoxy," "alkenyloxy," "alkynyloxy," "aryloxy," "aralkyloxy," "heteroaryloxy," "heterocycloalkyloxy," and "acyloxy" refer to the group defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkylthio" and "acylthio" refer to the group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, where at least one hydrogen atom has been replaced by a hydroxy group. The term "ether" corresponds to an alkane as defined above, where at least one hydrogen atom has been replaced by an alkoxy group.

[0461] The term "alkylamino" refers to the group -NHR, where R is alkyl, as that term is defined above. Non-limiting examples include: -NHCH3 and -NHCH2CH3. The term "dialkylamino" refers to the group -NRR', where R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N(CH3)2 and -N(CH3)(CH2CH3). When used without the "substituted" modifier, the terms "cycloalkylamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino", and "alkoxyamino" refer to the group defined as -NHR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is -NHC6H5. The terms "dicycloalkylamino," "dialkenylamino," "dialkynylamino," "diarylamino," "diaralkylamino," "diheteroarylamino," "diheterocycloalkylamino," and "dialkoxyamino" refer to a group defined as -NRR', in which R and R' are each cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. Similarly, the term alkyl(cycloalkyl)amino refers to a group defined as -NRR', in which R is alkyl and R' is cycloalkyl. The term "acylamino," when used without the "substituted" modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A non-limiting example of an acylamino group is -NHC(O)CH3.

[0462] When a chemical group is used with the "substituted" modifier, at each occurrence one or more hydrogen atoms has been independently replaced with -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -C02H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl groups in which the hydrogen atom replacement is limited to halo (i.e., -F, -Cl, -Br, or -I) such that no atoms other than carbon, hydrogen, and halogen are present. The group -CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyl groups in which the hydrogen atom replacement is limited to fluoro such that no atoms other than carbon, hydrogen, and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl. The groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are non-limiting examples of substituted amido groups.

[0463] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" or "an" can mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more".

[0464] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device or method being employed to determine the value or the variation that exists among study subjects or patients.

[0465] An "active ingredient" (AI) or active pharmaceutical ingredient (API) (also referred to as active compound, active substance, active agent, pharmaceutical agent, reagent, bioactive molecule, or therapeutic compound) is the biologically active component of a drug.

[0466] The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," are also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other, unlisted steps.

[0467] As used in this specification and / or claims, the term "effective" means sufficient to achieve a desired, expected, or intended result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" means an amount of a compound that, when administered to a subject or patient for the purpose of treating or preventing a disease, is sufficient to achieve such treatment or prevention of the disease.

[0468] " Excipient " is a pharmaceutically acceptable substance formulated together with the active ingredient of a medicine, pharmaceutical composition, preparation or drug delivery system. Excipient can be used, for example, to stabilize the composition, to expand the composition (when used for this purpose, therefore often referred to as " extender ", " filler " or " diluent "), or to give therapeutic enhancement to the active ingredient in the final dosage form, for example, to promote drug absorption, reduce viscosity or improve solubility. Excipients include pharmaceutically acceptable forms of anti-adherents, adhesives, coatings, pigments, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners and vehicles. The main excipient that serves as a medium for transporting active ingredients is generally referred to as a vehicle. In addition to assisting in vitro stability, such as preventing denaturation or aggregation within the expected shelf life, excipients can also be used in manufacturing processes, for example, to assist the processing of active substances, such as by promoting powder flowability or non-stick performance to achieve. The suitability of an excipient will typically vary depending on route of administration, dosage form, active ingredient and other factors.

[0469] The term "hydrate," when used as a modifier of a compound, means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) molecule of water associated with each molecule of the compound (e.g., a solid form of the compound).

[0470] The term "IC 50 ” represents the inhibitory dose that obtains 50% of the maximal response. This quantitative measure indicates the amount of a particular drug or other substance (inhibitor) required to inhibit a given biological, biochemical, or chemical process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half.

[0471] An "isomer" of a first compound is an individual compound wherein each molecule contains the same constituent atoms as the first compound, but wherein the three-dimensional configuration of those atoms is different.

[0472] As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, adolescents, infants, and fetuses.

[0473] As used generally herein, "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs and / or body fluids of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio. An example of a pharmaceutically acceptable compound includes those compounds, materials, compositions and / or dosage forms that have been designated as having Generally Recognized as Safe (GRAS) status by the U.S. Food and Drug Administration (US FDA).

[0474] "Pharmaceutically acceptable salts" refers to salts of the compounds disclosed herein that are pharmaceutically acceptable as defined above and possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, Pharmaceutically acceptable salts include hydroxybenzoic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, enanthic acid, caproic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl) benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts, which can be formed when the acidic protons present can react with inorganic bases or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It will be appreciated that the particular anion or cation forming part of any salt of the invention is not critical so long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable salts and methods for their preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P.H. Stahl & C.G. Wermuth, eds., Verlag Helvetica Chimica Acta, 2002).

[0475] A "pharmaceutically acceptable carrier," "drug carrier," or simply "carrier" is a pharmaceutically acceptable substance formulated with an active ingredient drug that participates in the carriage, delivery, and / or transport of a chemical agent. Drug carriers can be used to improve the delivery and effectiveness of drugs, including, for example, controlled-release technologies to modulate drug bioavailability, reduce drug metabolism, and / or reduce drug toxicity. Some drug carriers may improve the effectiveness of drug delivery to a specific target site. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic acid) copolymers), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, red blood cells, virosomes, and dendrimers.

[0476] A "pharmaceutical drug" (also known as a drug, drug product, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medicament, or simply drug, medicament, or formulation) is a composition used for the diagnosis, cure, treatment, or prevention of disease, which comprises an active pharmaceutical ingredient (API) (as defined above) and, optionally, one or more inactive ingredients, also known as excipients (as defined above).

[0477] "Prevention" or "preventing" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but who does not yet experience or display any or all of the symptoms or signs of the disease; and / or (2) slowing the onset of symptoms or signs of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but who does not yet experience or display any or all of the symptoms or signs of the disease.

[0478] " prodrug " refers to the compound that can be converted into the inhibitor according to the present invention by metabolism in vivo. Prodrug itself also may have or not have activity to given target protein. For example, the compound comprising hydroxyl can be used as ester, and this ester is converted into hydroxy compound by hydrolysis in vivo. The non-limiting example of the suitable ester that can be converted into hydroxy compound in vivo comprises acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxy naphthoate, gentisate, isethionate, di-toluoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl aminosulfonate, quinate, and amino acid ester. Similarly, the compound comprising amine can be used as amide, and this amide is converted into amine compound by hydrolysis in vivo.

[0479] "Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to the same other atoms, but in which the three-dimensional configurations of these atoms are different. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain chiral centers (also called stereocenters or stereocenters), which are any points (but not necessarily atoms) in a molecule that carry multiple groups such that the interchange of any two groups will produce stereoisomers. In organic compounds, chiral centers are usually carbon, phosphorus, or sulfur atoms, but other atoms can also serve as stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving rise to its many stereoisomers. In compounds whose stereoisomerism is attributable to tetrahedral stereocenters (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2. n , where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a smaller number than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Generally, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is expected that for any stereocenter or chiral axis whose stereochemistry has not yet been defined, the stereocenter or chiral axis can exist in its R form, S form, or as a mixture of R and S forms (including racemic mixtures and non-racemic mixtures). As used herein, the phrase "substantially free of other stereoisomers" means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of one or more other stereoisomers.

[0480] "Treatment" or "treating" includes (1) inhibiting the disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., arresting further development of the symptoms and / or signs), (2) ameliorating the disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., reversing the symptoms and / or signs), and / or (3) achieving any measurable reduction in the disease or its symptoms in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease.

[0481] The term "unit dose" refers to a formulation of a compound or composition that is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that can be used include, but are not limited to, a single tablet, capsule, or other oral formulation, or a single vial of a liquid or other injectable formulation that can be injected with a syringe.

[0482] The above definitions supersede any conflicting definitions in any references incorporated herein by reference. However, the fact that certain terms are defined should not be construed as indicating that any undefined term is undefined. Rather, all terms used are intended to describe the present invention in a manner that enables one of ordinary skill in the art to understand the scope of the present invention and to practice the present invention.

[0483] VI. Examples

[0484] The following examples are included to demonstrate preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the present invention and, thus, can be considered to constitute preferred modes for its practice. However, it will be appreciated by those skilled in the art, in view of this disclosure, that many changes can be made in the disclosed specific embodiments and still obtain similar or similar results without departing from the spirit and scope of the present invention.

[0485] Example 1: Synthesis and characterization

[0486] i. Synthetic routes of compounds

[0487] Solution 1

[0488]

[0489] Reagents and conditions: a) i) HCO2Et, NaOMe, MeOH, 0°C to room temperature; ii) NH2OH·HCl, EtOH, H2O, 55°C; b) Jones' reagent, acetone, 0°C; c) MgBr2·Et2O, DIPEA, PhCOCl, CH2Cl2, room temperature; d) cyclohexylhydrazine hydrochloride, EtOH, microwave, 110°C; e) NaOMe, MeOH, 55°C; f) DDQ, toluene, 85°C (for T1); or DBDMH, DMF, 0°C; pyridine, 55°C (for T2).

[0490]

[0491] Option 4

[0492]

[0493] Reagents and conditions: a) ArNHNH2 and aqueous HCl (for 15a and 15c) or ArNHNH2·HCl (for 15B), EtOH, microwave; b) NaOMe, MeOH, 55°C; c) Condition A (for T6 and T7): DBDMH, DMF, 0°C; pyridine, 55°C; or Condition B (for T8): DDQ, benzene, reflux.

[0494] Option 5

[0495]

[0496] Reagents and conditions: a) ArNHNH2·HCl, EtOH, microwave; b) K2CO3, MeOH, room temperature; c) DBDMH, DMF, 0°C; pyridine, 60°C.

[0497] Option 6

[0498]

[0499] Reagents and conditions: a) i) HCO2Et, NaOMe, MeOH, 0℃ to room temperature; ii) NH2OH·HCl, EtOH, H2O, 55℃; b) MgBr2·Et2O, DIPEA, PhCOCl, CH2Cl2, room temperature; c) ArNHNH2·HCl, 12N aqueous HCl, EtOH, microwave; d) NaOMe, MeOH, 55℃; e) DBDMH, DMF, 0℃; pyridine, 55℃.

[0500] Option 7

[0501]

[0502] Reagents and conditions: a) ArNHNH2·xHCl, EtOH, microwave; b) Condition A: K2CO3, MeOH, room temperature; or Condition B: NaOMe, MeOH, 55°C; c) Condition A: DBDMH, DMF, 0°C; pyridine, 55°C; or Condition B: DDQ, toluene, 85°C.

[0503] Option 8

[0504]

[0505] Reagents and conditions: a) 3-Hydrazinotetrahydrothiophene 1,1-dioxide dihydrochloride, EtOH, microwave, 120°C; b) K2CO3, MeOH, THF, room temperature; c) DBDMH, DMF, 0°C; pyridine, 55°C.

[0506] Option 9

[0507]

[0508] Reagents and conditions: a) ArNHNH2·HCl, EtOH, microwave; b) Condition A (for 32a): NaOMe, MeOH, 55°C; or Condition B (for 32b): K2CO3, MeOH, room temperature; c) DBDMH, DMF, 0°C; pyridine, 55°C.

[0509] Plan 10

[0510]

[0511] Reagents and conditions: a) 3-BrPhNHNH2·HCl, EtOH, microwave, 120°C; b) NaOMe, MeOH, 55°C; c) DBDMH, DMF, 0°C; pyridine, 55°C; d) 3-pyridylboronic acid, K3PO4, Pd(PPh3)4, 1,4-dioxane, DMF, 90°C.

[0512] Plan 11

[0513]

[0514] Reagents and conditions: a) PhB(OH)2, K3PO4, Pd(PPh3)4, 1,4-dioxane, DMF, 90°C; b) DBDMH, DMF, 0°C; pyridine, 55°C.

[0515]

[0516]

[0517]

[0518]

[0519] Plan 17

[0520]

[0521] Reagents and conditions: a) 4-Br-2-F-PhNHNH2·HCl, EtOH, 100°C; b) K2CO3, MeOH, room temperature; c) pyridine-3-boronic acid, K3PO4, Pd(PPh3)4, 1,4-dioxane, DMF, microwave, 90°C; d) DBDMH, DMF, 0°C; pyridine, 55°C.

[0522] Plan 18

[0523]

[0524] Reagents and conditions: a) divaleryl diboron, KOAc, Pd(dppf)Cl2, 1,4-dioxane, 100°C; b) ArBr, K3PO4, Pd(PPh3)4, 1,4-dioxane, DMF, 100°C; c) DBDMH, DMF, 0°C; pyridine, 60°C.

[0525]

[0526] Plan 20

[0527]

[0528] Reagents and conditions: a) DAST, CH2Cl2, -78°C.

[0529] Plan 21

[0530]

[0531] Reagents and conditions: a) potassium cyclopropyltrifluoroborate, K3PO4, RuPhos, toluene, water, Pd(OAc)2, 95°C; b) DBDMH, DMF, 0°C; pyridine, 60°C.

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] Plan 33

[0543]

[0544] Reagents and conditions: a) morpholine, t-BuXPhosPd-G3, XPhos, NaOBu t , 1,4-dioxane, 120°C; b) DDQ, toluene, room temperature.

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] Plan 55

[0567]

[0568] Reagents and conditions: a) DCC, 1,4-dioxane, room temperature.

[0569] Plan 56

[0570]

[0571] Reagents and conditions: a) 202, MgBr2·Et2O, DIPEA, CH2Cl2, room temperature; b) hydrazine monohydrate, EtOH, 60°C; c) 4-biphenylboronic acid, molecular sieves, copper(II) acetate, pyridine, CH2Cl2, room temperature; d) K2CO3, MeOH, room temperature to 50°C; e) DBDMH, DMF, 0°C; pyridine, 60°C.

[0572] Plan 57

[0573]

[0574] Reagents and conditions: a) hydrazine monohydrate, EtOH, 60°C; b) arylboronic acid, molecular sieves, copper(II) acetate, pyridine, CH2Cl2, room temperature; c) K2CO3, MeOH; d) DBDMH, DMF, 0°C; pyridine, 60°C.

[0575] Plan 58

[0576]

[0577] Reagents and conditions: a) hydrazine monohydrate, EtOH, 60°C; b) pyridine-4-boronic acid, molecular sieves, copper(II) acetate, pyridine, DMF, 85°C; c) K2CO3, MeOH, room temperature; d) DBDMH, DMF, 0°C; pyridine, 60°C.

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595] Plan 76

[0596]

[0597] Reagents and conditions: a) NaOAc, Ac2O, 100°C.

[0598] Plan 77

[0599]

[0600] Reagents and conditions: a) Boc-hydrazide, HOAc, MeOH, room temperature; NaBH3CN, room temperature; b) HCl, i-PrOH, 45°C.

[0601]

[0602] Plan 79

[0603]

[0604] Reagents and conditions: a) 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine, K2CO3, Pd(dppf)Cl2, 1,4-dioxane, DMF, 100°C; b) DBDMH, DMF, 0°C; pyridine, 60°C.

[0605] Plan 80

[0606]

[0607] Reagents and conditions: a) 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine, K2CO3, Pd(dppf)Cl2, 1,4-dioxane, DMF, 100°C; b) DBDMH, DMF, 0°C; pyridine, 60°C.

[0608]

[0609] Plan 83

[0610]

[0611] Reagents and conditions: a) 298, Pd(PPh3)4, 1,4-dioxane, 120°C; b) DBDMH, DMF, 0°C; pyridine, 60°C.

[0612] Plan 84

[0613]

[0614] Reagents and conditions: a) 298, Pd(PPh3)4, 1,4-dioxane, 120°C; b) DBDMH, DMF, 0°C; pyridine, 60°C.

[0615] Plan 85

[0616]

[0617] Reagents and conditions: a) NH2OH aqueous solution, EtOH, 80°C; b) dimethylacetamide dimethyl acetal, 1,4-dioxane, 60°C; c) K2CO3, MeOH, room temperature; d) DBDMH, DMF, 0°C; pyridine, 60°C.

[0618]

[0619]

[0620] Indicative Plan 1

[0621]

[0622] Reagents and conditions: a) hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum, H2O.

[0623] Indicative Plan 2

[0624]

[0625] Reagents and conditions: a) i) HCO2Et, NaOMe; ii) NH2OH·HCl; iii) aqueous HCl solution; b) perfluorophenyl pyrimidine-4-carboxylate, MgBr2·OEt2, DIPEA; c) (4-bromophenyl)hydrazine hydrochloride; d) K2CO3; e) (5-fluoropyridin-3-yl)boronic acid, Suzuki coupling reaction; f) DBDMH; Py.

[0626] Indicative Plan 3

[0627]

[0628] Reagents and conditions: a) perfluorophenyl 4-fluorobenzoate, MgBr2·OEt2, DIPEA; b) (4-bromophenyl)hydrazine hydrochloride; c) K2CO3; d) 6-methylpyridazin-4-ylboronic acid pinacol ester, Suzuki coupling reaction; e) DBDMH; Py.

[0629] Prospective Scenario 4

[0630]

[0631] Reagents and conditions: a) MOMCl, DIPEA; b) HCO2Et, NaOMe; c) ozone; Me2S; d) 3-fluoroaniline; e) 3-pyridin-4-yl-benzaldehyde, NH4OAc; f) i) aqueous HCl; ii) oxidation; g) i) HCO2Et, NaOMe; ii) NH2OH·HCl; h) K2CO3; i) DBDMH; Py.

[0632] ii. Synthesis Procedure and Characterization Data

[0633] General information

[0634] Unless otherwise stated, commercial reagents were used as received and all reactions were performed under nitrogen. All solvents were HPLC or ACS grade. Spectrometers were run on a Varian Inova-400 spectrometer at 400 MHz ( 1 H NMR) or 100 MHz ( 13 C NMR) operating frequency, record nuclear magnetic resonance (NMR) spectra. Chemical shifts (δ) are expressed relative to the residual solvent (usually chloroform, for 1H NMR is given in ppm (δ 7.26 ppm), and coupling constants (J) are given in Hz. Multiplicities are tabulated as: s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet. Mass spectra were recorded on a Waters Micromass ZQ or Agilent 6120 mass spectrometer.

[0635] Compound 2: To a stirred solution of compound 1 (5.0 g, 25.47 mmol) in ethyl formate (62 mL, 0.76 mol) at 0°C was added sodium methoxide (25 wt% solution in MeOH, 43.7 mL, 190.97 mmol). The reaction mixture was stirred at room temperature for 1 h and cooled to 0°C. Aqueous HCl (6N, 31.84 mL, 191.04 mmol) was added to adjust the pH to <7. The mixture was stirred at 0°C for 20 min and then extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was dissolved in EtOH (250 mL) and water (25 mL) and cooled to 0°C. Hydroxylamine hydrochloride (2.6 g, 37.42 mmol) was added. The mixture was heated at 55°C for 2 h and then cooled to room temperature. After concentration, the residue was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0% to 50% EtOAc in hexanes) to give Compound 2 (4.0 mg, 71% yield) as a white solid. m / z = 222 (M+1).

[0636] Compound 3: A solution of compound 2 (4.0 g, 18.08 mmol) in acetone (90 mL) was cooled to 0° C. and treated dropwise with Jones reagent until the orange color persisted. The mixture was stirred at 0° C. for 30 min, then i-PrOH was added until the reaction mixture turned green. The mixture was concentrated. The residue was diluted with EtOAc, and the mixture was washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated to give compound 3 (3.78 g, 95% yield) as a white solid. m / z=220 (M+1).

[0637] Compound 4: Compound 3 (246 mg, 1.12 mmol) was dissolved in CHCl (12 mL). At room temperature, magnesium bromide ethyl etherate (738 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.597 mL, 3.42 mmol) were added sequentially. The mixture was stirred at room temperature for 5 min, and benzoyl chloride (0.173 mL, 1.49 mmol) was added. The mixture was stirred at room temperature for 2 h, and saturated NaHPO aqueous solution (5 mL) was added. The mixture was extracted with EtOAc. The organic extract was washed with water; dried over NaSO; filtered; and concentrated to obtain crude compound 4 (400 mg, quantitative yield) as a solid, which was used in the next step without further purification. m / z=324 (M+1).

[0638] Compound 5 and compound 6: reaction A: compound 4 (100mg, 0.31mmol) and cyclohexyl hydrazine hydrochloride (100mg, 0.66mmol) in EtOH (1mL) are heated at 110 ℃ for 5h in a Biotage microwave. Reaction B: compound 4 (16mg, 0.049mmol) and cyclohexyl hydrazine hydrochloride (15mg, 0.10mmol) in EtOH (0.5mL) are heated at 110 ℃ for 5h in a Biotage microwave. The reaction mixture from reactions A and B is merged and concentrated. The residue is dissolved in EtOAc and washed with 1N HCl aqueous solution and saturated NaHCO aqueous solution. The organic extract is dried with Na SO , filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 15% EtOAc in hexanes) to give Compound 5 (50 mg, 35% yield) and Compound 6 (15 mg, 10% yield) as white solids. Compound 5: m / z = 402 (M+1); Compound 6: m / z = 402 (M+1).

[0639] Compound 7: Compound 5 (48 mg, 0.12 mmol) was dissolved in MeOH (1.2 mL). Sodium methoxide (25 wt % in methanol, 42 μL, 0.18 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. EtOAc was added, followed by a 10% aqueous solution of NaH2PO4 to adjust the pH <7. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 15% acetone in hexanes) to obtain compound 7 (38 mg, 79% yield) as a white solid. m / z=402 (M+1).

[0640] T1: Compound 7 (38 mg, 0.095 mmol) was dissolved in toluene (1 mL). DDQ (24 mg, 0.11 mmol) was added. The mixture was heated at 85° C. for 2 h and cooled to room temperature. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3 and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 20% EtOAc in hexanes) to give a partially purified product, which was again purified by column chromatography (silica gel, eluted with 0% to 15% acetone in hexanes) to give Compound T1 (15 mg, 31% yield) as a yellow solid. m / z=400 (M+1); 1 HNMR (400MHz, CDCl3) δ8.57(s,1H),7.45(m,3H),7.27(m,2H),3.98(tt,J=3.9,11.5Hz,1H),2.55( m,3H),2.13(dt,J=2.3,12.8Hz,1H),1.84(m,9H),1.46(s,3H),1.29(d,J=6.8Hz,3H),1.26(m,3H).

[0641] Compound 8: Compound 8 (white solid, 10 mg, 67% yield) was synthesized from compound 6 (15 mg, 0.037 mmol) using the same procedure as described for the synthesis of compound 7. m / z = 402 (M+1).

[0642] T2: Compound 8 (10 mg, 0.025 mmol) was dissolved in anhydrous DMF (0.25 mL) and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (3.6 mg, 0.013 mmol) in DMF (0.1 mL) was added. The reactants were stirred at 0 ° C for 1 h. Pyridine (10 μL, 0.12 mmol) was added. The reactants were heated at 55 ° C for 2 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N HCl aqueous solution and water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 20% EtOAc in hexanes) to give a partially purified product, which was again purified by column chromatography (silica gel, eluted with 0% to 15% acetone in hexanes) to give Compound T2 (5 mg, 50% yield) as a white solid. m / z = 400 (M+1); 1H NMR (400MHz, CDCl3) δ8.13(s,1H),7.67(m,2H),7.39(m,2H),7.30(m,1H),4.00(tt,J=3.8,11.4Hz,1H),2.81(ddd,J=2.0,6.0,16.0Hz,1H),2. 74(m,1H),2.65(qd,J=6.8,13.6Hz,1H),2.24(m,3H),2.00(m,5H),1.7 9(m,1H),1.62(m,1H),1.54(s,3H),1.45(m,3H),1.36(d,J=6.8Hz,3H).

[0643] Compound 9: A mixture of compound 4 (100 mg, 0.25 mmol), (2,2,2-trifluoroethyl)hydrazine (70 wt% in H2O, 62 μL, 0.49 mmol), and 12N aqueous HCl (40 μL, 0.048 mmol) in EtOH (2.5 mL) was heated at 120°C for 3 h in a Biotage microwave and cooled to room temperature. The mixture was concentrated. The residue was dissolved in EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 20% acetone in hexanes) to obtain a partially purified product, which was further purified by column chromatography (silica gel, eluted with 0% to 10% EtOAc in C2Cl2) to obtain compound 9 (48 mg, 48% yield) as a white solid. m / z = 402 (M+1).

[0644] Compound 10: Compound 10 (white solid) was synthesized from compound 9 (45 mg, 0.11 mmol) using the same procedure as described for the synthesis of compound 7. m / z = 402 (M+1).

[0645] T3: Compound T3 (light yellow solid, 6 mg, 13% yield from compound 9) was synthesized from compound 10 (all from the last step, ≤ 0.11 mmol) using the same procedure as described for the synthesis of compound T1. m / z = 400 (M+1); 1HNMR (400MHz, CDCl3) δ8.17(s,1H),7.67(m,2H),7.42(m,2H),7.36(m,1H),4.84(dq,J=2.2,7.7Hz,2H),2.84(ddd,J=1.9,6.0,16.0Hz,1H ),2.77(m,1H),2.64(td,J=6.7,13.5Hz,1H),2.31(dt,J=2.0,12.6Hz,1H),2.10(m,1H),1.67(m,1H),1.54(s,3H),1.37(d,J=6.8Hz,3H).

[0646] Compound 11 and compound 12: reaction A: compound 4 (108mg, 0.33mmol) and benzyl hydrazine dihydrochloride (130mg, 0.67mmol) in EtOH (2.7mL) are heated at 110 ℃ for 4h in Biotage microwave. Reaction B: compound 4 (80mg, 0.25mmol) and benzyl hydrazine dihydrochloride (97mg, 0.50mmol) in EtOH (2mL) are heated at 110 ℃ for 4h in Biotage microwave. The reaction mixture from reaction A and B is merged and concentrated. The residue is dissolved in EtOAc and washed with 1N HCl aqueous solution and saturated NaHCO3 aqueous solution. The organic extract is dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to give Compound 11 (68 mg, 29% yield) and Compound 12 (65 mg, 27% yield) as white solids. Compound 11: m / z = 410 (M+1); Compound 12: m / z = 410 (M+1).

[0647] Compound 13: Compound 11 (68 mg, 0.17 mmol) was dissolved in MeOH (2 mL). Sodium methoxide (25 wt % in methanol, 57 μL, 0.25 mmol) was added. The reaction mixture was stirred at 55 ° C for 2 h and cooled to room temperature. The mixture was concentrated. The residue was distributed between EtOAc and 10% NaH2PO4 aqueous solution. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 13 (65 mg, 96% yield) as a yellow solid. m / z=410 (M+1).

[0648] T4: Compound 13 (68 mg, 0.17 mmol) was dissolved in anhydrous DMF (2 mL), and the solution was cooled to 0°C. 1,3-Dibromo-5,5-dimethylhydantoin (24 mg, 0.084 mmol) in DMF (1 mL) was added. The reaction was stirred at 0°C for 1 h. Pyridine (60 μL, 0.74 mmol) was added. The reaction was heated at 55°C for 2 h and at 40°C overnight. The mixture was cooled to room temperature; diluted with EtOAc; and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T4 (35 mg, 52% yield) as a light yellow solid. m / z=408 (M+1); 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),7.40(m,3H),7.27(m,3H),7.21(m,2H),7.00(m,2H),5.27(d,J=15.6Hz,1H),5.22(d, J=16.0Hz,1H),2.60(m,3H),2.17(dt,J=2.3,12.8Hz,1H),2.01(m,1H),1.74(m,1H),1.50(s,3H),1.30(d,J=6.7Hz,3H).

[0649] Compound 14: Compound 14 (65 mg, quantitative yield) was synthesized from compound 12 (65 mg, 0.16 mmol) using the same procedure as described for the synthesis of compound 13. m / z = 410 (M+1).

[0650] T5: Compound T5 (31 mg, 48% yield) was synthesized from compound 14 (65 mg, 0.16 mmol) using the same procedure as described for the synthesis of compound T4. m / z = 408 (M+1); 8.05 (s, 1H), 7.72 (m, 2H), 7.43 (m, 2H), 7.35 (m, 4H), 7.09 (m, 2H), 5.73 (d, J = 16.8 Hz, 1H), 5.44 (d, J = 16.8 Hz, 1H), 2.85 (m, 2H), 2.57 (qd, J = 6.8, 13.5 Hz, 1H), 2.25 (dt, J = 2.0, 12.7 Hz, 1H), 2.09 (m, 1H), 1.67 (m, 1H), 1.46 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H).

[0651] Compound 15a: A mixture of compound 4 (43 mg, 0.13 mmol), (4-(trifluoromethyl)phenyl)hydrazine (47 mg, 0.27 mmol) and 12N aqueous HCl (22 μL, 0.26 mmol) in EtOH (1.2 mL) was heated at 100° C. for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc and washed with 1N aqueous HCl and water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexanes) to give compound 15a (37 mg, 60% yield) as a white solid. m / z=464 (M+1).

[0652] Compound 16a: Compound 15a (35 mg, 0.076 mmol) was dissolved in MeOH (1.5 mL). Sodium methoxide (25 wt % in methanol, 26 μL, 0.11 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. EtOAc was added, followed by a 10% aqueous solution of NaH2PO4 to adjust the pH <7. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 25% EtOAc in hexanes) to obtain compound 16a (26 mg, 74% yield) as a white solid. m / z=464 (M+1).

[0653] T6: Compound 16a (26 mg, 0.056 mmol) was dissolved in anhydrous DMF (0.36 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (8 mg, 0.028 mmol) in DMF (0.2 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (14 μL, 0.17 mmol) was added. The reaction was heated at 55 ° C for 2 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes) to give Compound T6 (12 mg, 46% yield) as a white solid. m / z=462 (M+1); 1H NMR (400MHz, CDCl3) δ7.88(d,J=8.2Hz,2H),7.70(m,4H),7.50(s,1H),7.42(m,2H),7.36(m,1H),2.98(m,1H),2.88(ddd,J=6.5,11.4,16.3Hz, 1H), 2.56 (qd, J=6.7, 13.4Hz, 1H), 2.27 (dt, J=2.0, 12.7Hz, 1H), 2.16 (dd, J=6.5, 13.8Hz, 1H), 1.81 (m, 1H), 1.60 (s, 3H), 1.34 (d, J=6.7Hz, 3H).

[0654] Compound 15b: Compound 4 (82 mg, 0.25 mmol) and 4-hydrazinopyridine hydrochloride (74 mg, 0.51 mmol) in EtOH (2 mL) were heated at 100 ° C for 1 h in a Biotage microwave and then cooled to room temperature. The mixture was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 40% acetone in hexanes) to obtain compound 15b (51 mg, 51% yield) as a white solid. m / z=397 (M+1).

[0655] Compound 16b: Compound 15b (48 mg, 0.12 mol) was dissolved in MeOH (1.2 mL). Sodium methoxide (25 wt % in methanol, 42 μL, 0.18 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. EtOAc was added, followed by a 10% aqueous solution of NaH2PO4 to adjust the pH to <7. The organic extract was dried over Na2SO4, filtered and concentrated to obtain crude compound 16b as a light yellow solid, which was used in the next step without purification. m / z=397 (M+1).

[0656] T7: Compound T7 was synthesized from compound 16b (56 mg, 0.14 mmol) using the same procedure reported for the synthesis of T6. The crude product was purified by column chromatography (silica gel, eluted with 0% to 60% EtOAc in hexanes) to give a partially purified product, which was further purified by column chromatography (C18, eluted with 10% to 80% acetonitrile in water) to give compound T7 (10 mg, 18% yield) as a white solid. m / z = 395 (M+1); 1H NMR (400MHz, CDCl3) δ8.89(m,2H),7.71(m,2H),7.56(s,1H),7.51(m,2H),7.43(m,2H),7.37(m,1H),2.98(ddd,J=1.5,6.4,16.4Hz,1 H), 2.88 (ddd, J=6.7, 11.5, 16.3Hz, 1H), 2.58 (qd, J=6.8, 13.5Hz, 1H), 2.22 (m, 2H), 1.83 (m, 1H), 1.68 (s, 3H), 1.34 (d, J=6.6Hz, 3H).

[0657] Compound 15c: Reaction A: A mixture of compound 4 (230 mg, 0.71 mmol), 4-hydrazinoquinoline (191 mg, 1.20 mmol) and 12N aqueous HCl solution (0.12 mL, 0.26 mmol) in EtOH (7 mL) was heated at 110° C. for 2 h in a Biotage microwave and then cooled to room temperature. Reaction B: A mixture of compound 4 (53 mg, 0.16 mmol), 4-hydrazinoquinoline (52 mg, 0.33 mmol) and 12N aqueous HCl solution (27 μL, 0.32 mmol) in EtOH (1.6 mL) was heated at 110° C. for 2 h in a Biotage microwave and then cooled to room temperature. The two reactants were combined and concentrated. The residue was diluted with EtOAc and washed with saturated NaHCO 3 aqueous solution and water. The organic extract was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0% to 70% EtOAc in hexanes) to give compound 15c (38 mg, 10% yield) as a white solid. m / z = 464 (M+1).

[0658] Compound 16c: Compound 16c was synthesized from compound 15c (65 mg, 0.16 mmol) using the same procedure as described for the synthesis of compound 16b. m / z = 447 (M+1).

[0659] T8: Compound 16c (35 mg, 0.078 mmol) was dissolved in benzene (0.8 mL). DDQ (21 mg, 0.093 mmol) was added. The mixture was heated at reflux for 2 h and cooled to room temperature. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3 and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 20% EtOAc in hexanes) to give Compound T8 (30 mg, 86% yield) as a light yellow solid. m / z=445 (M+1); 1 H NMR(400MHz,CDCl3)δ9.17(br s,1H),8.29(d,J=8.5Hz,1H),7.85(m,1H),7.74(m,2H),7.61(t,J=7.6 Hz,2H),7.43(m,2H),7.37(m,1H),7.30(m,1H),6.94(m,1H),3.02(m,2H ), 2.53(td,J=6.8,13.1Hz,1H),2.35(dd,J=11.7,13.7Hz,1H),2.20(dd,J=6.1,13.7Hz,1H),1.83(m,1H),1.59(s,3H),1.33(d,J=6.7Hz,3H).

[0660] Compound 15d: Compound 4 (129 mg, 0.40 mmol) and (2-fluorophenyl)hydrazine hydrochloride (130 mg, 0.80 mmol) in EtOH (4 mL) were heated at 100 ° C for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated and the residue was diluted with CH2Cl2. The mixture was washed with 1N aqueous HCl. The organic phase was separated. The aqueous phase was extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to obtain compound 15d (155 mg, 94% yield) as a white solid. m / z=414 (M+1).

[0661] Compound 16d: A mixture of compound 15d (153 mg, 0.37 mmol) and K2CO3 (153 mg, 0.37 mmol) in MeOH (3.6 mL) was stirred at room temperature for 16 h. 10% NaH2PO4 aqueous solution (20 mL) was added. The mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was triturated with refluxing MTBE and cooled to room temperature. The precipitated solid was collected by filtration, washed with MTBE, and dried in air to obtain compound 16d (87 mg, 57% yield) as a white solid. m / z=414 (M+1).

[0662] T9: Compound 16d (85 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.42 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (29 mg, 0.10 mmol) in DMF (0.58 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (50 μL, 0.62 mmol) was added. The reaction was heated at 55 ° C for 5.5 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give compound T9 (59 mg, 70% yield) as a white solid. m / z=412 (M+1); 1 H NMR (400MHz, CDCl3) δ7.71(m,2H),7.60(m,3H),7.38(m,5H),2.96(ddd,J=1.7,6.3,16.1Hz,1H),2.88(m,1H),2.55(qd,J=6.7,13.4Hz,1H),2.32(br t,J=12.7Hz,1H),2.15(dd,J=6.1,13.8Hz,1H),1.79(m,1H),1.47(s,3H),1.33(d,J=6.6Hz,3H).

[0663] Compound 15e: A mixture of compound 4 (100 mg, 0.309 mmol), phenylhydrazine (61 μL, 0.618 mmol) and 10.1 N aqueous HCl solution (61 μL, 0.618 mmol) in EtOH (2 mL) was heated at 100 ° C for 2 h in a microwave synthesizer and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc and washed with 1 N aqueous HCl solution. The organic extract was dried over Na2SO4, filtered and concentrated to obtain crude compound 15e (130 mg, quantitative yield) as a glass, which was used in the next step without further purification. m / z=396 (M+1).

[0664] Compound 16e: A mixture of compound 15e (125 mg, 0.316 mmol) and potassium carbonate (87 mg, 0.632 mmol) in MeOH (10 mL) was stirred at room temperature under nitrogen for 24 hours. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous KH2PO4. The organic extract was washed with brine; dried over Na2SO4; filtered; and concentrated. The residue was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes) to give compound 16e (69 mg, 55% yield) as a white solid. m / z=396 (M+1); 1 H NMR (400 MHz, CDCl3) δ

[0665] T11: A solution of compound 16e (63 mg, 0.159 mmol) in anhydrous DMF (3.0 mL) was cooled to 0°C under nitrogen. A solution of 1,3-dibromo-5,5-dimethylhydantoin (25 mg, 0.087 mmol) in anhydrous DMF (1.0 mL) was added. After the mixture was stirred at 0°C for 1 h, anhydrous pyridine (0.128 mL, 1.59 mmol) was added. The reaction mixture was heated at 60°C for 4 h and then cooled to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous KH2PO4. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine; dried over Na2SO4; filtered; and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes) to give compound T11 (33 mg, 53% yield) as a white solid. m / z=394(M+1); 1H NMR (400MHz, CDCl3) δ7.73(m,2H),7.59(m,3H),7.51(m,3H),7.41(m,2H),7.34(m,1H),2.98(ddd,J=1.6,6.3,16.2Hz,1H),2.88(ddd,J=6.5, 11.4,16.1Hz,1H),2.54(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2.1,12.7Hz,1H),2.14(m,1H),1.80(m,1H),1.57(s,3H),1.33(d,J=6.7Hz,3H).

[0666] Compound 15f: Compound 15f (orange glass, 133 mg, quantitative yield) was synthesized from compound 4 (100 mg, 0.309 mmol) and 4-chlorophenylhydrazine hydrochloride (111 mg, 0.618 mmol) using the same procedure as described for the synthesis of compound 15d. The reaction was heated at 100°C for 3 h in a microwave synthesizer. Compound 15f was purified by column chromatography (silica gel, eluted with 20% EtOAc in hexanes). m / z = 430 & 432 (M+1).

[0667] Compound 16f: Compound 16f (orange glass, 67 mg, 52% yield) was synthesized from compound 15f (130 mg, 0.302 mmol) using the same procedure as described for the synthesis of compound 16e. The reaction was stirred at room temperature for 27 h. Compound 16f was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes). m / z = 430 & 432 (M+1).

[0668] T13: Compound T13 (yellow solid, 44 mg, 68% yield) was synthesized from compound 16f (65 mg, 0.151 mmol) using the same procedure as described for the synthesis of compound T11. T13 was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes). m / z = 428 & 430 (M+1); 1H NMR (400MHz, CDCl3) δ7.70(m,2H),7.57(m,3H),7.44(m,4H),7.35(m,1H),2.96(ddd,J=1.6,6.3,16.2Hz,1H),2.87(ddd,J=6.4,11.4, 16.2Hz,1H),2.55(qd,J=6.8,13.4Hz,1H),2.27(dt,J=2.1,12.8Hz,1H),2.14(m,1H),1.79(m,1H),1.56(s,3H),1.33(d,J=6.7Hz,3H).

[0669] Compound 15g: Compound 15g (glass, 139 mg, 80% yield) was synthesized from compound 4 (121 mg, 0.374 mmol) and 3,4-dichlorophenylhydrazine hydrochloride (159 mg, 0.748 mmol) using the same procedure as described for the synthesis of compound 15d. The reaction was heated at 100°C for 3 h in a microwave synthesizer. Compound 15g was purified by column chromatography (silica gel, eluted with 10% EtOAc in hexanes). m / z = 464 & 466 (M+1).

[0670] Compound 16g: Compound 16g (glass, 105 mg, 76% yield) was synthesized from compound 15g (138 mg, 0.297 mmol) using the same procedure as described for the synthesis of compound 16e. The reaction was stirred at room temperature for 24 h. Compound 16g was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes). m / z = 464 & 466 (M+1).

[0671] T10: Compound T10 was synthesized from compound 16g (104 mg, 0.223 mmol) using the same procedure as described for the synthesis of compound T11. The crude product was purified by trituration with MeOH. The resulting solid was triturated with refluxing 50% aqueous MeOH solution. The precipitated solid was collected by filtration and dried under vacuum to give compound T10 (37 mg, 36% yield) as a white solid. m / z = 462 & 464 (M+1); 1H NMR (400MHz, CDCl3) δ7.69(m,3H),7.66(m,1H),7.58(s,1H),7.40(m,4H),2.96(ddd,J=1.5,6.3,16.1Hz,1H),2.87(m,1H),2.57(q d,J=6.7,13.4Hz,1H),2.26(dt,J=2.1,12.7Hz,1H),2.15(dd,J=6.4,13.8Hz,1H),1.80(m,1H),1.59(s,3H),1.34(d,J=6.7Hz,3H).

[0672] Compound 15h: Compound 15h (glass, 120 mg, 95% yield) was synthesized from compound 4 (100 mg, 0.309 mmol) and 4-methylphenylhydrazine hydrochloride (98 mg, 0.618 mmol) using the same procedure as described for the synthesis of compound 15d. The reaction was heated at 100°C for 3 h in a microwave synthesizer. Compound 15h was purified by column chromatography (silica gel, eluted with 20% EtOAc in hexanes). m / z = 410 (M+1).

[0673] Compound 16h: Compound 16h (glass, 94 mg, 79% yield) was synthesized from compound 15h (119 mg, 0.290 mmol) using the same procedure as described for the synthesis of compound 16e. The reaction was stirred at room temperature for 24 h. Compound 16h was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes). m / z = 410 (M+1).

[0674] T12: Compound T12 (yellow solid, 24 mg, 26% yield) was synthesized from compound 16h (94 mg, 0.229 mmol) using the same procedure as described for the synthesis of compound T11. T12 was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes). m / z = 408 (M+1); 1 H NMR (400MHz, CDCl3) δ7.72(m,2H),7.60(s,1H),7.39(m,7H),2.96(m,1H),2.88(m,1H),2.54(qd,J=6.7,13.4Hz,1H),2. 48(s,3H),2.27(td,J=2.1,12.7Hz,1H),2.14(dd,J=6.3,13.8Hz,1H),1.79(m,1H),1.56(s,3H),1.33(d,J=6.7Hz,3H).

[0675] Compound 15i: A mixture of compound 4 (100 mg, 0.309 mmol) and 4-methoxyphenylhydrazine hydrochloride (108 mg, 0.618 mmol) in EtOH (2.0 mL) was heated at 100° C. for 3 h in a microwave synthesizer, then at 130° C. for an additional 1 h. After cooling to room temperature, the residue was partitioned between EtOAc and 1.0 N aqueous HCl. The organic phase was dried over Na2SO4; filtered; and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes) to give partially purified compound 15i (40 mg, 30% yield) as a yellow glass, which was used in the next step without further purification. m / z=426 (M+1).

[0676] Compound 16i: Compound 16i (yellow glass, 60 mg, 61% yield) was synthesized from compound 15i (98 mg, 0.230 mmol) using the same procedure as described for the synthesis of compound 16e. The reaction was stirred at room temperature for 19 h. Compound 16i was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes). m / z = 426 (M+1).

[0677] T14: Compound T14 was synthesized from compound 16i (59 mg, 0.138 mmol) using the same procedure described for the synthesis of compound T11. The crude product was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes) and then triturated with MeOH to give compound T14 (14 mg, 24% yield) as a yellow solid. m / z = 424 (M+1); 1 H NMR (400MHz, CDCl3) δ7.72(m,2H),7.63(s,1H),7.41(m,4H),7.33(m,1H),7.06(m,2H),3.91(s,3H),2.96(m,1H),2.87(m,1H ), 2.54(qd,J=6.8,13.4Hz,1H),2.26(m,1H),2.14(dd,J=6.4,13.9Hz,1H),1.78(m,1H),1.55(s,3H),1.33(d,J=6.7Hz,3H).

[0678] Compound 19: To a stirred solution of compound 17 (Coltart and Danishefsky, 2003, 2.19 g, 9.77 mmol) in ethyl formate (23 mL, 285.95 mmol) was added sodium methoxide (25 wt% solution in MeOH, 35 mL, 152.95 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h and cooled to 0°C. Aqueous HCl (6N, 20 mL, 120 mmol) was added to adjust the pH to <7. The mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was mixed with hydroxylamine hydrochloride (910 mg, 13.10 mmol), EtOH (80 mL) and water (8 mL). The mixture was heated at 55°C for 2 h and then cooled to room temperature. After concentration, the residue was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes) to give compound 18 (453 mg, 19% yield) as a white solid. m / z = 250 (M+1). From the column, compound 19 (736 mg, 37% yield) was obtained as a colorless oil. m / z = 206 (M+1).

[0679] Compound 20: Compound 19 (520 mg, 2.53 mmol) was dissolved in CHCl (25 mL). Magnesium bromide ethyl etherate (1.60 g, 6.20 mmol) and N,N-diisopropylethylamine (1.32 mL, 7.56 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 5 min, and benzoyl chloride (0.382 mL, 3.29 mmol) was added. The mixture was stirred at room temperature for 3 h; refluxed overnight; and cooled to room temperature. Saturated aqueous NaHCO was added. The mixture was stirred at room temperature for 1 h. The organic phase was separated, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to give Compound 20 (560 mg, 71% yield) as an orange oil. m / z = 310 (M+1).

[0680] Compound 21a: A mixture of compound 20 (200 mg, 0.65 mmol), (4-cyanophenyl)hydrazine hydrochloride (219 mg, 1.29 mmol) and 12N HCl (60 μL, 0.72 mmol) in EtOH (3 mL) was heated at 100° C. for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated, and the residue was diluted with EtOAc and the mixture was washed with water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified twice by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give partially purified compound 21a (110 mg, 42% yield) as a light yellow solid. m / z=407 (M+1).

[0681] Compound 22a: Compound 21a (110 mg, 0.27 mmol) was dissolved in MeOH (4 mL). Sodium methoxide (25 wt % in methanol, 93 μL, 0.41 mmol) was added. The reaction mixture was stirred at 55 ° C for 2 h, cooled to room temperature, and concentrated. The residue was distributed between EtOAc and 10% NaH2PO4 aqueous solution to adjust the pH <7. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 65% EtOAc in hexanes) to obtain compound 22a (55 mg, 50% yield) as a yellow solid. m / z=407 (M+1).

[0682] T15: A solution of compound 22a (55 mg, 0.14 mmol) in anhydrous DMF (2 mL) was cooled to 0 ° C under nitrogen. A solution of 1,3-dibromo-5,5-dimethylhydantoin (19.3 mg, 0.067 mmol) in anhydrous DMF (1 mL) was added. After the mixture was stirred at 0 ° C for 1 hour, anhydrous pyridine (60 μL, 0.74 mmol) was added. The reaction mixture was heated at 55 ° C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified twice by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound T15 (21 mg, 38% yield) as a yellow solid. m / z=405 (M+1); 1 H NMR (400MHz, CDCl3) δ7.92(m,2H),7.69(m,4H),7.47(s,1H),7.41(m,3H),2.92(m,2H),2.65(m,3H),1.89(m,2H),1.59(s,3H).

[0683] Compound 21b: A mixture of compound 20 (117 mg, 0.38 mmol), (4-fluorophenyl)hydrazine hydrochloride (123 mg, 0.76 mmol) and 12N HCl (40 μL, 0.48 mmol) in EtOH (2.5 mL) was heated at 120° C. for 3 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated, and the residue was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to give a partially purified product, which was again purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to give partially purified compound 21b (35 mg, 23% yield) as a white solid. m / z=400 (M+1).

[0684] Compound 22b: Compound 21b (35 mg, 0.088 mol) was dissolved in MeOH (2 mL). Sodium methoxide (25 wt % in methanol, 30 μL, 0.13 mmol) was added. The reaction mixture was stirred at 55 ° C for 2 h and cooled to room temperature. EtOAc was added, followed by a 10% aqueous solution of NaH2PO4 to adjust the pH to <7. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified twice by column chromatography (silica gel, eluted with a solution of EtOAc in hexanes from 0% to 40%) to obtain compound 22b (12 mg, 34% yield). m / z=400 (M+1).

[0685] T16: A solution of compound 22b (12 mg, 0.030 mmol) in anhydrous DMF (1 mL) was cooled to 0°C under nitrogen. A solution of 1,3-dibromo-5,5-dimethylhydantoin (4.4 mg, 0.015 mmol) in anhydrous DMF (1 mL) was added. After the mixture was stirred at 0°C for 1 h, anhydrous pyridine (10 μL, 0.12 mmol) was added. The reaction mixture was heated at 55°C for 2 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound T16 (containing 11% of 1,2-epoxide, 4.9 mg, 41% yield) as a light yellow solid. m / z=398 (M+1); 1H NMR (400MHz, CDCl3) δ7.71(m,2H),7.55(s,1H),7.52(m,2H),7.36(m,5H),2.91(m,2H),2.64(m,3H),1.82(m,2H),1.53(s,3H).

[0686] Compounds 23a and 24a: Compound 4 (180 mg, 0.56 mmol) and o-tolylhydrazine hydrochloride (180 mg, 1.13 mmol) in EtOH (4 mL) were heated at 120 ° C for 1 h in a Biotage microwave and then cooled to room temperature. The mixture was diluted with MTBE. The mixture was washed with 1N aqueous HCl, 1N aqueous NaOH and water. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes) to obtain compound 23a (199 mg, 87% yield) as a beige solid. m / z=410 (M+1). From this column, compound 24a (13 mg, 6% yield) was also obtained. m / z=410 (M+1).

[0687] Compound 25a: A mixture of compound 23a (111 mg, 0.27 mmol) and KCO (112 mg, 0.81 mmol) in MeOH (2.8 mL) was stirred at room temperature for 16 h. 10% NaHPO aqueous solution (20 mL) was added. The mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The crude product was triturated with refluxing MTBE, cooled to room temperature, and kept at room temperature for 2 h. The precipitated solid was collected by filtration and dried in air to obtain compound 25a (80 mg, 72% yield) as a white solid. m / z=410 (M+1).

[0688] T17: Compound 25a (77 mg, 0.19 mmol) was dissolved in anhydrous DMF (0.5 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (27 mg, 0.094 mmol) in DMF (0.5 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (45 μL, 0.56 mmol) was added. The reaction was heated at 55 ° C for 5.5 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T17 (48 mg, 63% yield) as an off-white solid. m / z=408 (M+1); 1 H NMR (400 MHz, CDCl 3 ) δ: approximately a 3 / 1 mixture of atropisomers. Major isomer: 7.73 (m, 2H), 7.31-7.51 (m, 7H), 7.22 (s, 1H), 2.86-3.01 (m, 2H), 2.51 (qd, 1H, J = 6.4, 13.2 Hz), 2.30 (dt, 1H, J = 1.6, 12.8 Hz), 2.15 (dd, 1H, J = 6.4, 14.0 Hz), 2.03 (s, 3H), 1.80 (m, 1H), 1.51 (s, 3H), 1.32 (d, 3H, J = 6.8 Hz).

[0689] Compound 26a: Compound 24a (28 mg, 0.068 mmol) was dissolved in MeOH (0.7 mL). Sodium methoxide (25 wt % in methanol, 31 μL, 0.14 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. 10% NaH2PO4 aqueous solution (10 mL) was added to adjust the pH to <7. The mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes) to obtain compound 26a (24 mg, 86% yield) as a white solid. m / z=410 (M+1).

[0690] T18: Compound 26a (24 mg, 0.059 mmol) was dissolved in toluene (0.6 mL). DDQ (15 mg, 0.066 mmol) was added. The mixture was heated at 85 ° C for 2.5 h and cooled to room temperature. The mixture was diluted with CH2Cl2 (10 mL) and saturated aqueous NaHCO3 solution (10 mL) and stirred for 5 min. The organic phase was separated, and the aqueous phase was extracted three times with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes) to give Compound T18 (10.8 mg, 45% yield) as a yellow solid. m / z=408 (M+1); 1 H NMR (400MHz, CDCl3) δ8.56(s,1H),7.23(m,7H),7.08(m,2H),2.78(m,2H),2.60(m,1H),2.25(m,1H),2.10(d d,J=6.3,13.2Hz,1H),1.99(s,3H),1.81(qd,J=6.6,12.6Hz,1H),1.54(s,3H),1.34(dd,J=1.2,6.8Hz,3H).

[0691] Compounds 23b and 24b: Compounds 23b and 24b (131 mg, 67% yield) were synthesized from compound 4 (129 mg, 0.40 mmol) and 4-(trifluoromethoxy)phenylhydrazine hydrochloride (100 mg, 0.44 mmol) using the same procedure as described for the synthesis of compounds 23a and 24a. The crude product was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give a mixture of compounds 23b and 24b. m / z = 480 (M+1).

[0692] Compounds 25b and 26b: A mixture of compounds 23b and 24b (129 mg, 0.27 mmol) and K2CO3 (111 mg, 0.80 mmol) in MeOH (2.8 mL) was stirred at room temperature for 16 h. A 10% aqueous solution of NaH2PO4 was added. The mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes) to give compounds 25b (100 mg, 78% yield) and 26b (14 mg, 11% yield). Compound 25b: white solid; m / z = 480 (M+1); Compound 26b: white solid; m / z = 480 (M+1).

[0693] T19: Compound T19 was synthesized from compound 25b (98 mg, 0.20 mmol) using the same procedure described for the synthesis of compound T17. The crude product was purified twice by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound T19 (78 mg, 80% yield) as a white solid. m / z = 478 (M+1); 1 H NMR (400MHz, CDCl3) δ7.70(m,2H),7.57(m,2H),7.51(s,1H),7.43(m,4H),7. 36(m,1H),2.97(ddd,J=1.6,6.3,16.1Hz,1H),2.88(ddd,J=6.4,11.4,16.2H z,1H),2.56(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2.1,12.7Hz,1H),2.15(m,1 H), 1.80 (tdd, J=6.3, 12.1, 18.9Hz, 1H), 1.58 (s, 3H), 1.33 (d, J=6.7Hz, 3H).

[0694] T20: Compound 26b (14 mg, 0.029 mmol) was dissolved in anhydrous DMF (0.1 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (4.2 mg, 0.015 mmol) in DMF (0.21 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (10 μL, 0.12 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous HCl solution (10 mL) and water (3×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to give compound T20 (10.1 mg, 72% yield) as a white solid. m / z=478(M+1); 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),7.36(m,3H),7.28(m,2H),7.16(m,4H),2.77(m,1H),2.63(m, 2H), 2.18(dt,J=2.3,12.7Hz,1H),2.07(m,1H),1.79(m,1H),1.55(s,3H),1.32(d,J=6.7Hz,3H).

[0695] Compounds 23c and 24c: Compounds 23c and 24c were synthesized from compound 4 (129 mg, 0.40 mmol) and biphenyl-4-yl-hydrazine hydrochloride (176 mg, 0.80 mmol) using the same procedure described for the synthesis of compounds 23a and 24a. The reaction was heated at 100° C. for 2 h and then at 120° C. for 3 h in a microwave synthesizer. The crude product was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes) to give a 9 / 1 mixture of compounds 23c and 24c as a yellow solid (97 mg, 52% yield). Compound 23c: m / z = 472 (M+1); Compound 24c: m / z = 472 (M+1).

[0696] Compounds 25c and 26c: A mixture of compounds 23c and 24c (95 mg, 0.20 mmol) and K2CO3 (84 mg, 0.61 mmol) in MeOH (3 mL) was stirred at room temperature for 16 h. A 10% aqueous solution of NaH2PO4 was added. The mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes) to give compound 25c (56 mg, 59% yield) and compound 26c (10 mg, 11% yield). Compound 25c: white solid; m / z = 472 (M+1); Compound 26c: white solid; m / z = 472 (M+1).

[0697] T21: Compound 25c (54 mg, 0.11 mmol) was dissolved in anhydrous DMF (0.57 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (16 mg, 0.056 mmol) in DMF (0.57 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (28 μL, 0.35 mmol) was added. The reaction was heated at 55 ° C for 5.5 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes). The obtained product was recrystallized from EtOAc and hexanes to obtain compound T21 (34 mg, 63% yield) as a white solid. m / z=470 (M+1); 1H NMR(400MHz, CDCl3)δ7.80(m,2H),7.74(m,2H),7.67(m,3H),7.58(m,2H),7 .50(m,2H),7.42(m,3H),7.35(m,1H),2.99(ddd,J=1.6,6.3,16.4Hz,1H),2 .90(m,1H),2.56(qd,J=6.7,13.4Hz,1H),2.29(dt,J=2.0,12.9Hz,1H),2.1 6(dd,J=6.4,13.8Hz,1H),1.82(m,1H),1.61(s,3H),1.34(d,J=6.7Hz,3H).

[0698] T22: Compound 26c (10 mg, 0.021 mmol) was dissolved in anhydrous DMF (0.1 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (3.0 mg, 0.010 mmol) in DMF (0.1 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (10 μL, 0.12 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 18% EtOAc in hexanes) to give Compound T22 (8.4 mg, 84% yield) as a light yellow solid. m / z=470 (M+1); 1 H NMR (400MHz, CDCl3) δ8.61(s,1H),7.56(m,4H),7.43(m,2H),7.34(m,6H),7.21(m,2H),2.80(m,1H),2.65(m,2H ), 2.20 (dt, J = 2.3, 12.8Hz, 1H), 2.09 (dd, J = 7.1, 13.7Hz, 1H), 1.81 (m, 1H), 1.56 (s, 3H), 1.33 (d, J = 6.7Hz, 3H).

[0699] Compounds 23d and 24d: Compound 4 (200 mg, 0.62 mmol) and 1-naphthylhydrazine hydrochloride (240 mg, 1.23 mmol) in EtOH (4 mL) were heated at 120 ° C for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc (20 mL). The mixture was washed with 1N HCl aqueous solution (10 mL) and water (2×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain a mixture of compounds 23d and 24d as a pink solid (270 mg, 98% yield). Compounds 23d and 24d: m / z=446 (M+1).

[0700] Compound 25d and 26d: A mixture of compounds 23d and 24d (270 mg, 0.61 mmol) and K CO (418 mg, 3.02 mmol) in MeOH (6 mL) was stirred at room temperature for 16 h. 10% NaH PO aqueous solution (15 mL) was added. The mixture was stirred for 5 min and extracted with EtOAc (20 mL). The organic extract was dried with Na SO , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of 0% to 35% acetone in hexanes) to obtain compound 25d (110 mg, 41% yield) as a pink solid. The mixed fractions were merged and purified again by column chromatography (silica gel, eluted with a solution of 0% to 35% acetone in hexanes) to obtain compound 26d (15 mg, 6% yield) as a white solid. Compound 25d: m / z = 446 (M+1); Compound 26d: m / z = 446 (M+1).

[0701] T23: T23 (white solid, 80 mg, 73% yield) was synthesized from compound 25d (109 mg, 0.25 mmol) using the same procedure as described for the synthesis of T21. Compound T23 was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes). m / z = 444 (M+1); 1H NMR (400 MHz, DMSO-d6, 2:1 mixture of atropisomers) δ [8.28 (d, J = 8.4 Hz), 8.27 (d, J = 8.4 Hz); 2:1; 1H], [8.17 (d, J = 8.4 Hz), 8.14 (d, J = 8.4 Hz); 2:1; 1H], [8.02 (d, J = 7.2 Hz), 7.92 (d, J = 7.3 Hz); 1:2; 1H], 5.70 (m, 5H), 7.44 (m, 2H), 7.36 (m, 1H) ,[7.02(d,J=8.5Hz),6.99(d,J=8.4Hz);1:2;1H],6.66(s,1H),2.94(m,2H),2.67(tt,J=6.8,13.9Hz,1H),2.39( m,1H),2.06(m,1H),1.81(m,1H),[1.56(s),1.10(s);2:1;3H],[1.18(d,J=7.2Hz),1.16(d,J=6.8Hz);1:2;3H].

[0702] T24: T24 (white solid, 9 mg, 65% yield) was synthesized from compound 26d (14 mg, 0.31 mmol) using the same procedure as described for the synthesis of T21. Compound T24 was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes). m / z = 444 (M+1); 1 H NMR(400MHz, CDCl3)δ8.58(s,1H),7.89(m,2H),7.62(m,1H),7.52(m,2H) ,7.38(m,1H),7.24(m,1H),7.15(m,3H),7.04(m,2H),2.84(m,2H),2.64(q d,J=6.7,13.4Hz,1H),2.31(dt,J=2.2,12.7Hz,1H),2.15(dd,J=6.0,13.7 Hz, 1H), 1.87 (dq, J = 6.9, 12.6 Hz, 1H), 1.62 (s, 3H), 1.36 (d, J = 6.7 Hz, 3H).

[0703] Compounds 23e and 24e: Compounds 23e and 24e (approximately 6 / 1 mixture, brown solid, 256 mg, 95% yield) were synthesized from compound 4 (200 mg, 0.62 mmol) and 4-isopropylphenylhydrazine hydrochloride (230 mg, 1.18 mmol) using the same procedure described for the synthesis of compounds 23d and 24d. Compounds 23e and 24e were purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes). Compound 23e: m / z = 438 (M+1); Compound 24e: m / z = 438 (M+1).

[0704] Compounds 25e and 26e: Compounds 23e and 24e (256 mg, 0.59 mmol) were dissolved in MeOH (2.9 mL). Sodium methoxide (25% by weight in methanol, 267 μL, 1.17 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. A 10% aqueous solution of NaH2PO4 was added to adjust the pH to <7. The mixture was extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of 0% to 40% acetone in hexanes) to obtain compound 25e (176 mg, 69% yield) as a white solid. The mixed fractions were combined and purified again by column chromatography (silica gel, eluted with a solution of 0% to 40% acetone in hexanes) to obtain compound 26e (31 mg, 12% yield) as a white solid. Compound 25e: m / z = 438 (M+1); Compound 26e: m / z = 438 (M+1).

[0705] T25: Compound 25e (176 mg, 0.40 mmol) was dissolved in anhydrous DMF (1 mL), and the solution was cooled to 0°C. 1,3-Dibromo-5,5-dimethylhydantoin (57 mg, 0.20 mmol) in DMF (1 mL) was added. The reaction was stirred at 0°C for 1 h. Pyridine (162 μL, 2.01 mmol) was added. The reaction was heated at 55°C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in CH2Cl2 (1 mL). EtOAc (3 mL) was added. The mixture was heated to reflux to evaporate the solvent. When the volume was reduced by about 1 mL, the mixture was cooled to room temperature and maintained for 2 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to give compound T25 (110 mg, 63% yield) as a light yellow solid. m / z=436 (M+1); 1HNMR(400MHz, CDCl3)δ7.73(m,2H),7.55(s,1H),7.41(m,6H),7.34(m,1H),3.05(hep t,J=7.0Hz,1H),2.97(ddd,J=1.6,6.4,16.1Hz,1H),2.88(ddd,J=6.4,11.4,16.1Hz,1 H),2.53(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2.1,12.7Hz,1H),2.13(ddd,J=3.3,5.3 ,10.3Hz,1H),1.79(m,1H),1.57(m,3H),1.32(d,J=7.1Hz,6H),1.31(d,J=7.1Hz,3H).

[0706] T26: Compound 26e (31 mg, 0.071 mmol) was dissolved in anhydrous DMF (0.5 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (10 mg, 0.035 mmol) in DMF (0.2 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (29 μL, 0.36 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to give Compound T26 (25 mg, 81% yield) as a yellow solid. m / z=436 (M+1); 1 H NMR (400MHz, CDCl3) δ8.60 (s, 1H), 7.32 (m, 3H), 7.17 (m, 6H), 2.89 (hept, J = 6.9, 1H), 2.78 (ddd, J = 1.4, 6.6, 16.4Hz, 1H), 2.6 4(m,2H),2.19(dt,J=2.3,12.8Hz,1H),2.07(m,1H),1.79(m,1H),1.55(s,3H),1.32(d,J=6.7Hz,3H),1.22(d,J=6.9Hz,6H).

[0707] Compounds 23f and 24f: Reaction A: Compound 4 (100 mg, 0.31 mmol) and oxan-4-ylhydrazine dihydrochloride (117 mg, 0.63 mmol) in EtOH (2 mL) were heated at 120° C. for 2.5 h in a Biotage microwave and then cooled to room temperature. Reaction B: Compound 4 (100 mg, 0.31 mmol) and oxan-4-ylhydrazine dihydrochloride (117 mg, 1.13 mmol) in EtOH (2 mL) were heated at 120° C. for 5 h in a Biotage microwave and then cooled to room temperature. The two reactants were combined and distributed between CH2Cl2 (20 mL) and water (20 mL). The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound 23f (78 mg, 31% yield) and Compound 24f (81 mg, 32% yield). Compound 23f: white solid; m / z = 404 (M+1); Compound 24f: white solid; m / z = 404 (M+1).

[0708] Compound 25f: Compound 23f (76 mg, 0.19 mmol) and K2CO3 (78 mg, 0.56 mmol) in MeOH (2 mL) were stirred at room temperature for 14 h. 10% NaH2PO4 aqueous solution (20 mL) was added. The mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was ground with refluxed EtOAc (1 mL) and then cooled to room temperature. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to obtain compound 25f (52 mg, 68% yield) as a white solid. m / z=404 (M+1).

[0709] T27: Compound 25f (51 mg, 0.13 mmol) was dissolved in anhydrous DMF (0.6 mL), and the solution was cooled to 0 ° C. 1,3-Dibromo-5,5-dimethylhydantoin (18 mg, 0.063 mmol) in DMF (0.6 mL) was added. The reaction was stirred at 0 ° C for 1.5 h. Pyridine (51 μL, 0.62 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T27 (46 mg, 91% yield) as a white solid. m / z=402 (M+1); 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.68(m,2H),7.40(m,2H),7.32(m,1H),4.23(m,3H),3.63(dt,J=2.2,12.2Hz,1H),3.56(dt,J=2.2,12.2Hz,1 H),2.73(m,5H),2.26(dt,J=1.9,12.6Hz,1H),2.03(m,2H),1.83(ddd,J =2.2, 4.3, 13.3Hz, 1H), 1.63 (m, 1H), 1.56 (s, 3H), 1.37 (d, J = 6.8Hz, 3H).

[0710] Compound 26f: Compound 26f (white solid, 72 mg, 91% yield) was synthesized from compound 24f (79 mg, 0.20 mmol) using the same procedure as described for the synthesis of compound 25f. Compound 26f was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes). m / z = 404 (M+1).

[0711] T28: Compound T28 (white solid, 42 mg, 53% yield) was synthesized from compound 26f (79 mg, 0.20 mmol) using the same procedure as described for the synthesis of compound T27. Compound T28 was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes). m / z = 402 (M+1); 1H NMR (400MHz, CDCl3) δ8.55(s,1H),7.46(m,3H),7.27(m,2H),4.21(tt,J=4.2,11.4Hz,1H),4.05(m,2H),3.37(dtd,J=2.2,12.0,14.1Hz,2H),2.53 (m,3H),2.36(pd,J=4.7,12.0Hz,2H),2.12(dt,J=2.2,12.8Hz,1H),1.99 (dd,J=6.5,13.6Hz,1H),1.75(m,3H),1.46(s,3H),1.29(d,J=6.6Hz,3H)

[0712] Compounds 27 and 28: Reaction A: Compound 4 (100 mg, 0.31 mmol) and 3-hydrazinotetrahydrothiophene 1,1-dioxide dihydrochloride (115 mg, 1.62 mmol) in EtOH (2 mL) were heated at 120° C. for 3 h in a Biotage microwave and then cooled to room temperature. Reaction B: Compound 4 (100 mg, 0.31 mmol) and 3-hydrazinotetrahydrothiophene 1,1-dioxide dihydrochloride (115 mg, 1.62 mmol) in EtOH (2 mL) were heated at 120° C. for 5 h in a Biotage microwave and then cooled to room temperature. The two reactants were combined and partitioned between CH2Cl2 (20 mL) and water (20 mL). The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound 27 (94 mg, 35% yield) and Compound 28 (89 mg, 33% yield). Compound 27: white solid; m / z = 438 (M+1); Compound 28: white solid; m / z = 438 (M+1).

[0713] Compound 29: A mixture of compound 27 (92 mg, 0.21 mmol) and KCO (78 mg, 0.63 mmol) in MeOH (2 mL) and THF (1 mL) was stirred at room temperature for 14 h. A 10% aqueous solution of NaHPO (15 mL) was added. The mixture was extracted with EtOAc (20 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 29 (69 mg, 75% yield) as a white solid. m / z=438 (M+1).

[0714] T29: Compound 29 (69 mg, 0.16 mmol) was dissolved in anhydrous DMF (0.4 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (23 mg, 0.080 mmol) in DMF (0.4 mL) was added. The reaction was stirred at 0 ° C for 1.5 h. Pyridine (64 μL, 0.79 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 60% EtOAc in hexanes) to give compound T29 (34 mg, 50% yield) as a white solid. m / z=436 (M+1); 1 H NMR (400MHz, CDCN) δ8.33(s,1H),7.72(m,2H),7.44(m,2H),7.36(m,1H),5.38(qd,J=6.6,8.9Hz,1H),3.82(m,1H),3.62(m,2H),3.19(dddd,J=0 .9,7.0,7.9,13.0Hz,1H),2.75(m,3H),2.60(m,2H),2.28(dt,J=2.0,12 .6Hz,1H),2.04(m,1H),1.65(m,1H),1.54(s,3H),1.29(d,J=6.8Hz,3H).

[0715] Compound 30: A mixture of compound 28 (80 mg, 0.18 mmol) and KCO (80 mg, 0.58 mmol) in MeOH (2 mL) was stirred at room temperature for 18 h. 10% aqueous NaHPO (20 mL) was added. The mixture was extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 60% EtOAc in hexanes) to give compound 30 (65 mg, 81% yield) as a white solid. m / z = 438 (M+1).

[0716] T30: Compound 30 (65 mg, 0.15 mmol) was dissolved in anhydrous DMF (0.75 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (22 mg, 0.077 mmol) in DMF (0.75 mL) was added. The reaction was stirred at 0 ° C for 1.5 h. Pyridine (60 μL, 0.74 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc was added. The mixture was washed with 1N aqueous HCl solution and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 60% EtOAc in hexanes) to give Compound T30 (31 mg, 48% yield) as a white solid. m / z=436 (M+1); 1 H NMR (400MHz, CDCl3) δ8.05(s,1H),7.67(m,2H),7.43(m,2H),7.36(m,1H),5.15(pent,J=7.3Hz,1H),3.79(dt,J=7.8,14.0Hz,2H),3.50(dd ,J=7.7,13.5Hz,1H),3.34(m,1H),2.83(m,5H),2.27(dt,J=1.9,12.6Hz,1H),2.09(m,1H),1.64(m,1H),1.56(s,3H),1.37(d,J=6.8Hz,3H).

[0717] Compound 31a: Compound 4 (200 mg, 0.62 mmol) and 2-hydrazino-5-methyl-pyridine hydrochloride (198 mg, 1.24 mmol) in EtOH (4 mL) were heated at 120 ° C for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 31a (215 mg, 85% yield) as a white solid. m / z=411 (M+1).

[0718] Compound 32a: Compound 31a (215 mg, 0.52 mmol) was dissolved in MeOH (2.6 mL). Sodium methoxide (25 wt % in methanol, 239 μL, 1.04 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. The mixture was distributed between a 10% NaH2PO4 aqueous solution (10 mL) and EtOAc (20 mL). The organic extract was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of EtOAc in hexanes from 0% to 50%) to obtain compound 32a (187 mg, 87% yield) as a white solid. m / z=411 (M+1).

[0719] T31: Compound 32a (187 mg, 0.46 mmol) was dissolved in anhydrous DMF (1 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (65 mg, 0.23 mmol) in DMF (1.3 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (183 μL, 2.27 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with water (3×15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was diluted with toluene and concentrated to remove residual pyridine. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound T31 (145 mg, 78% yield) as a white solid. m / z=409(M+1); 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),8.27(td,J=0.8,2.5,1H),7.94(d,J=8.4Hz,1H),7.76(m ,2H),7.70(ddd,J=0.7,2.4,8.4Hz,1H),7.45(m,2H),7.38(m,1H),2.93(ddd,J=1.7,6.0,1 6.1Hz,1H),2.83(ddd,J=6.2,11.5,16.2,1H),2.65(td,J=6.8,13.6Hz,1H),2.42(s,3H),2 .21(dt,J=2.1,12.6Hz,1H),2.10(m,1H),1.94(s,3H),1.80(m,1H),1.35(d,J=6.8Hz,3H).

[0720] Compound 31b: Compound 4 (200 mg, 0.62 mmol) and 5-hydrazino-2-methylpyridine hydrochloride (198 mg, 1.24 mmol) in EtOH (4 mL) were heated at 120 ° C for 2 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc (20 mL) and washed with water (3×10 mL). The organic extract was dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes) to obtain compound 31b (205 mg, 81% yield) as a white solid. m / z=411 (M+1).

[0721] Compound 32b: A mixture of compound 31b (205 mg, 0.50 mmol) and KCO (345 mg, 2.50 mmol) in MeOH (5 mL) was stirred at room temperature for 15 h. 10% NaHPO aqueous solution (15 mL) was added. The mixture was stirred for 5 min and extracted with EtOAc (20 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes) to obtain compound 32b (185 mg, 90% yield) as a white solid. m / z=411 (M+1).

[0722] T32: Compound T32 (off-white solid, 150 mg, 82% yield) was synthesized from compound 32b (184 mg, 0.45 mmol) using the same procedure as described for the synthesis of T31. Compound T32 was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes). m / z = 409 (M+1); 1 H NMR (400 MHz, CDCl3, 1:1 mixture of atropisomers) δ [8.69 (s), 8.69 (s); 1:1; 1H], 7.74 (dd, J = 2.6, 8.2 Hz, 1H), 7.70 (m, 2H), 7.52 (s, 1H), 7.42 (m, 3H), 7.36 (m, 1H), 2.96 (ddd, J = 1.6, 6.3, 16.2 Hz, 1H), 2. 87(ddd,J=6.4,11.4,16.1Hz,1H),2.72(s,3H),2.56(qd,J=6.7,13.5Hz,1H),2.28(dt,J=2.1 ,12.7Hz,1H),2.15(dd,J=6.0,14.4Hz,1H),1.80(m,1H),1.59(s,3H),1.34(d,J=6.7Hz,3H).

[0723] Compound 33: Compound 4 (200 mg, 0.62 mmol) and (3-bromophenyl)hydrazine hydrochloride (276 mg, 1.23 mmol) in EtOH (4 mL) were heated at 120 ° C for 4 h in a Biotage microwave and then cooled to room temperature. The mixture was diluted with EtOAc and washed with 1N aqueous HCl and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to obtain compound 33 (250 mg, 85% yield) as a white solid. m / z=474 & 476 (M+1).

[0724] Compound 34: Compound 33 (247 mg, 0.52 mmol) was dissolved in MeOH (2.6 mL). Sodium methoxide (25 wt % in methanol, 240 μL, 1.05 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. The mixture was treated with 10% NaH2PO4 aqueous solution (10 mL) to adjust the pH to <7 and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 34 (257 mg, quantitative yield) as a white solid. m / z=474 & 476 (M+1).

[0725] T33: Compound 34 (157 mg, 0.33 mmol) was dissolved in anhydrous DMF (0.8 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (47 mg, 0.16 mmol) in DMF (0.8 mL) was added. The reaction was stirred at 0 ° C for 1.5 h. Pyridine (134 μL, 1.66 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous HCl solution (10 mL) and water (3×15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give compound T33 (123 mg, 78% yield) as a yellow solid. m / z=472&474(M+1); 1H NMR (400MHz, CDCl3) δ7.72(m,4H),7.53(s,1H),7.48(m,2H),7.42(m,2H),7.36(m,1H),2.96(ddd,J=1.5,6.3,16.2Hz,1H),2.87(m,1H),2 .56(qd,J=6.7,13.4Hz,1H),2.26(dt,J=2.1,12.7Hz,1H),2.15(dd,J=6.5,13.8Hz,1H),1.80(m,1H),1.59(s,3H),1.33(d,J=6.7Hz,3H).

[0726] T34: A mixture of compound T33 (73 mg, 0.15 mmol), 3-pyridylboronic acid (29 mg, 0.24 mmol) and K3PO4 (99 mg, 0.47 mmol) in 1,4-dioxane (0.72 mL) and DMF (0.36 mL) in a bottle was bubbled with N2 for 5 min. Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) was added. The bottle was sealed and heated at 90°C for 3 h. The mixture was cooled to room temperature and diluted with EtOAc (20 mL). The mixture was washed with water (4×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% acetone in hexanes) to give a partially purified product, which was again purified by column chromatography (silica gel, eluted with 0% to 30% acetone in CH2Cl2) to give Compound T34 (22 mg, 30% yield) as a white solid. m / z = 471 (M+1); 1 H NMR(400MHz, CDCl3) δ8.90(dd,J=0.8,2.5Hz,1H),8.66(dd,J=1.6,4.8Hz,1H),7.93(ddd,J=1.6,2.4,7.9Hz ,1H),7.81(ddd,J=1.1,1.8,7.8Hz,1H),7.73(m,4H),7.62(s,1H),7.57(ddd,J=1.1,2.1,7.8Hz,1H),7.42( m,3H),7.36(m,1H),2.98(m,1H),2.90(ddd,J=6.5,11.4,16.2Hz,1H),2.55(qd,J=6.7,13.4Hz,1H),2.29(d t,J=2.1,12.7Hz,1H),2.17(m,1H),1.82(tdd,J=6.2,12.2,18.6Hz,1H),1.61(s,3H),1.33(d,J=6.7Hz,3H).

[0727] Compound 35: A mixture of compound 34 (50 mg, 0.11 mmol), phenylboronic acid (19 mg, 0.16 mmol) and K3PO4 (67 mg, 0.32 mmol) in 1,4-dioxane (0.5 mL) and DMF (0.25 mL) in a bottle was bubbled with N2 for 3 min. Tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) was added. The bottle was sealed and heated at 90°C for 4.5 h. The mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and 10% aqueous NaH2PO4 solution (15 mL). The organic extract was separated and washed with water (3×15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give compound 35 (39 mg, 78% yield) as a white solid. m / z = 472 (M+1); 1 H NMR (400 MHz, CDCl3)

[0728] T35: Compound 35 (39 mg, 0.083 mmol) was dissolved in anhydrous DMF (0.4 mL), and the solution was cooled to 0 ° C. 1,3-Dibromo-5,5-dimethylhydantoin (12 mg, 0.041 mmol) in DMF (0.4 mL) was added. The reaction was stirred at 0 ° C for 1.5 h. Pyridine (34 μL, 0.42 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous HCl solution (10 mL) and water (3×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T35 (28 mg, 72% yield) as a yellow solid. m / z=470 (M+1); 1 HNMR(400MHz, CDCl3)δ7.80(m,1H),7.73(m,3H),7.64(m,4H),7.45(m,7H),2.98(m,1H),2.90(m,1H),2.55(qd,J=6.7,1 3.4Hz, 1H), 2.29 (dt, J = 2.1, 12.7Hz, 1H), 2.15 (dd, J = 6.4, 13.7Hz, 1H), 1.81 (m, 1H), 1.59 (s, 3H), 1.33 (d, J = 6.7Hz, 3H).

[0729] Compound 36: Compound 4 (1.00 g, 3.09 mmol) and (4-bromophenyl)hydrazine hydrochloride (1.38 g, 6.17 mmol) in EtOH (17 mL) were heated at 120 ° C for 4 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc (80 mL) and washed with 1N aqueous HCl (2×30 mL) and water (30 mL). The organic extract was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to obtain compound 36 (1.367 g, 93% yield) as a yellow solid. By HPLC, compound 36 was found to contain 11% of pyrazole position isomers. m / z=474 / 476 (M+1).

[0730] Compound 37: Compound 36 (1.365 g, 2.88 mmol) was dissolved in MeOH (14 mL). Sodium methoxide (25 wt % in methanol, 1.32 mL, 5.77 mmol) was added. The reaction mixture was stirred at 55 ° C for 1 h and cooled to room temperature. The mixture was treated with 10% NaH2PO4 aqueous solution (50 mL) to adjust the pH <7 and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes) to obtain compound 37 (1.120 g, 82% yield) as a white solid. m / z=474 / 476 (M+1).

[0731] Compound 38a: A mixture of compound 37 (90 mg, 0.19 mmol), 2-fluorophenylboronic acid (40 mg, 0.29 mmol), K3PO4 (121 mg, 0.57 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.010 mmol) in a bottle was purged with N2. 1,4-dioxane (1 mL) and DMF (0.5 mL) were degassed with N2 and added to the bottle. The bottle was filled with N2 and sealed. The mixture was heated at 90°C for 4 h and then cooled to room temperature. EtOAc (10 mL) and 10% NaH2PO4 aqueous solution (6 mL) were added. The mixture was passed through The mixture was filtered through a pad of 4-nitro-2-nitropropene (5% HCl) and eluted with EtOAc (15 mL). The filtrate was washed with water (3 × 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to obtain compound 38a (78 mg, 87% yield) as a white solid. m / z=490 (M+1).

[0732] T36: Compound 38a (78 mg, 0.16 mmol) was dissolved in anhydrous DMF (0.6 mL), and the solution was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (23 mg, 0.080 mmol) in DMF (0.2 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (64 μL, 0.79 mmol) was added. The reaction was heated at 55 ° C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous HCl solution (10 mL) and water (3×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes) to give Compound T36 (57 mg, 73% yield) as a light yellow solid. m / z=488 (M+1); 1 H NMR (400MHz, CDCl3) δ8.93 (d, J=2.4Hz, 1H), 8.68 (dd, J=1.6, 4.8Hz, 1H), 7.97 (td, J=2.1,8.0Hz,1H),7.81(m,2H),7.74(m,2H),7.65(m,3H),7.43(m,3H),7.36(m,1H) ,2.98(m,1H),2.90(m,1H),2.57(qd,J=6.7,13.4Hz,1H),2.30(dt,J=2.0,12.8Hz, 1H), 2.16 (dd, J = 6.2, 14.0Hz, 1H), 1.82 (m, 1H), 1.62 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0733] Compound 38b: Compound 38b (white solid, 66 mg, 74% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 3-pyridylboronic acid (35 mg, 0.28 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 38b was purified by column chromatography (silica gel, eluted with 0% to 40% acetone in hexanes). m / z = 473 (M+1).

[0734] T37: Compound 38b (66 mg, 0.14 mmol) was dissolved in anhydrous DMF (0.5 mL) and the solution was cooled to 0°C. 1,3-Dibromo-5,5-dimethylhydantoin (20 mg, 0.070 mmol) in DMF (0.2 mL) was added. The reaction was stirred at 0°C for 1.5 h. Pyridine (56 μL, 0.69 mmol) was added. The reaction was heated at 55°C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with water (4×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 20% acetone in CH2Cl2) to give compound T37 (52 mg, 79% yield) as a yellow solid. m / z=471 (M+1); 1 H NMR(400MHz, CDCl3)8.93(d,J=2.4Hz,1H),8.68(dd,J=1.6,4.8Hz,1H),7.97(td,J =2.1,8.0Hz,1H),7.81(m,2H),7.74(m,2H),7.65(m,3H),7.43(m,3H),7.36(m,1H) ,2.98(m,1H),2.90(m,1H),2.57(qd,J=6.7,13.4Hz,1H),2.30(dt,J=2.0,12.8Hz, 1H), 2.16 (dd, J = 6.2, 14.0Hz, 1H), 1.82 (m, 1H), 1.62 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0735] Compound 38c: Compound 38c (white solid, 58 mg, 62% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 3,5-dimethylisoxazole-4-boronic acid (40 mg, 0.28 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 38c was purified by column chromatography (silica gel, eluted with 0% to 25% EtOAc in CH2Cl2). m / z = 491 (M+1).

[0736] T38: Compound T38 (white solid, 49 mg, 85% yield) was synthesized from compound 38c (58 mg, 0.12 mmol) using the same procedure as described for the synthesis of compound T36. Compound T38 was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes). m / z = 489 (M+1); 1H NMR (400MHz, CDCl3) δ7.73(m,2H),7.60(m,2H),7.54(s,1H),7.49(m,2H),7.43(m,2H),7.36(m,1H),2.99(m,1H),2.90(m,1H),2.56(qd,J=6.7,1 3.4Hz,1H),2.48(s,3H),2.34(s,3H),2.29(dt,J=2.2,12.8Hz,1H),2.17 (dd,J=6.7,13.7Hz,1H),1.83(m,1H),1.61s,3H),1.34(d,J=6.7Hz,3H).

[0737] Compound 38d: Compound 38d (light yellow solid, 65 mg, 72% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 4-pyridylboronic acid (35 mg, 0.28 mmol) using the same procedure as described for the synthesis of compound 38a. The reaction mixture was heated at 90°C for 5 h. Compound 38d was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes). m / z = 473 (M+1).

[0738] T39: Compound 38d (65 mg, 0.14 mmol) was dissolved in anhydrous DMF (0.5 mL) and the solution was cooled to 0°C. 1,3-Dibromo-5,5-dimethylhydantoin (20 mg, 0.070 mmol) in DMF (0.2 mL) was added. The reaction was stirred at 0°C for 1 h. Pyridine (55 μL, 0.68 mmol) was added. The reaction was heated at 55°C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with water (4×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 55% acetone in hexanes) to give a partially purified product. The product was dissolved in CH2Cl2 (1 mL) and EtOAc (2 mL). The mixture was heated to reflux to evaporate the solvent. When the volume was reduced by about 0.5 mL, the mixture was cooled to room temperature. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to give compound T39 (40 mg, 62% yield) as a light yellow solid. m / z = 471 (M+1); 1H NMR(400MHz, CDCl3)δ8.74(m,2H),7.86(m,2H),7.73(m,2H),7.65(m,3H),7 .58(m,2H),7.42(m,2H),7.36(m,1H),2.99(ddd,J=1.6,6.3,16.2Hz,1H),2 .90(m,1H),2.57(qd,J=6.7,13.3Hz,1H),2.29(dt,J=2.1,12.8Hz,1H),2.1 7(dd,J=6.8,13.3Hz,1H),1.82(m,1H),1.62(s,3H),1.34(d,J=6.7Hz,3H).

[0739] Compound 38e: Compound 38e (white solid, 73 mg, 79% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and (3-fluorophenyl)boronic acid (40 mg, 0.29 mmol) using the same procedure as described for the synthesis of compound 38a. The reaction mixture was heated at 90° C. for 3.5 h. Compound 38e was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes). m / z=490 (M+1).

[0740] Compound T40: Compound T40 (white solid, 57 mg, 79% yield) was synthesized from compound 38e (72 mg, 0.15 mmol) using the same procedure as described for the synthesis of compound T36. Compound T40 was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes). m / z = 488 (M+1); 1 H NMR (400MHz, CDCl3) δ7.78(m,2H),7.74(m,2H),7.66(s,1H),7.60(m,2H),7.41(m,6H),7.12(m,1H),2.98(m,1H),2.90(m,1H ), 2.56 (qd, J = 6.7, 13.4Hz, 1H), 2.29 (dt, J = 2.0, 12.7Hz, 1H), 2.16 (m, 1H), 1.82 (m, 1H), 1.61 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0741] Compound 38f: Compound 38f (white solid, 79 mg, 86% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and p-tolylboronic acid (39 mg, 0.29 mmol) using the same procedure as described for the synthesis of compound 38a. The reaction mixture was heated at 90° C. for 3.5 h. Compound 38f was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes). m / z=486 (M+1).

[0742] Compound T41: Compound T41 (white solid, 59 mg, 76% yield) was synthesized from compound 38f (78 mg, 0.16 mmol) using the same procedure as described for the synthesis of compound T36. Compound T41 was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes). m / z = 484 (M+1); 1 H NMR(400MHz, CDCl3)δ7.76(m,4H),7.70(s,1H),7.56(m,4H),7.42(m,2H),7.33(m,3H),2.98(m,1H),2.90(m,1H),2.56(qd,J =6.7,13.4Hz,1H),2.43(s,3H),2.29(dt,J=2.0,12.7Hz,1H),2.15(m,1H),1.81(m,1H),1.60(s,3H),1.34(d,J=6.7Hz,3H).

[0743] Compound 38g: Using the same procedure as described for the synthesis of compound 38a, compound 38g (white solid, 78 mg, 82% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 4-hydroxymethylphenylboronic acid (43 mg, 0.28 mmol). The reaction mixture was heated at 90°C for 3.5 h. The crude product was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes) to obtain partially purified compound 38g. The product was dissolved in CH2Cl2 (1 mL) and EtOAc (2 mL). The mixture was heated to reflux to evaporate the solvent. When the volume was reduced by about 0.5 mL, the mixture was cooled to room temperature and maintained for 2 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to obtain compound 38g. m / z=502 (M+1).

[0744] Compound T42: Compound T42 (yellow solid, 24 mg, 31% yield) was synthesized from compound 38 g (78 mg, 0.16 mmol) using the same procedure as described for the synthesis of compound T36. Compound T42 was purified by column chromatography (silica gel, eluted with 0% to 30% acetone in CH2Cl2). m / z = 500 (M+1); 1 H NMR (400MHz, CDCl3) δ7.80(m,2H),7.74(m,2H),7.69(s,1H),7.66(m,2H),7.58(m,2H),7. 50(m,2H),7.42(m,2H),7.35(m,1H),4.79(d,J=5.9Hz,2H),2.99(ddd,J=1.6,6.5,16.6Hz ,1H),2.90(m,1H),2.56(qd,J=6.7,13.4Hz,1H),2.29(dt,J=2.0,12.6Hz,1H),2.15(m,1H ), 1.82 (tt, J = 6.3, 12.6 Hz, 1H), 1.74 (t, J = 6.0 Hz, 1H), 1.61 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H).

[0745] Compound 38h: Compound 38h (white solid, 67 mg, 70% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 2-(hydroxymethyl)phenylboronic acid (43 mg, 0.28 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 38h was purified by column chromatography (silica gel, eluted with 0% to 90% EtOAc in hexanes). m / z = 502 (M+1).

[0746] Compound T43: Compound T43 (off-white solid, 56 mg, 84% yield) was synthesized from compound 38h (67 mg, 0.13 mmol) using the same procedure as described for the synthesis of compound T36. Compound T43 was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes). m / z = 500 (M+1); 1H NMR(400MHz, CDCl3)δ7.76(m,2H),7.62(m,3H),7.57(m,2H),7.50(s,1H),7.43(m, 4H),7.36(m,2H),4.65(d,J=4.6Hz,2H),3.01(ddd,J=1.5,6.7,16.5Hz,1H),2.91(m ,1H),2.55(qd,J=6.7,13.4Hz,1H),2.30(dt,J=2.1,12.7Hz,1H),2.17(dd,J=6.7,1 3.8Hz, 1H), 1.91 (t, J = 4.9Hz, 1H), 1.83 (m, 1H), 1.63 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0747] Compound 38i: Compound 38i (white solid, 82 mg, 89% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and o-tolylboronic acid (39 mg, 0.29 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 38i was purified by column chromatography (silica gel, eluted with 0% to 25% acetone in hexanes). m / z = 486 (M+1).

[0748] Compound T44: Compound T44 (off-white solid, 48 mg, 59% yield) was synthesized from compound 38i (82 mg, 0.17 mmol) using the same procedure as described for the synthesis of compound T36. Compound T44 was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes). m / z = 484 (M+1); 1 H NMR (400MHz, CDCl3) δ7.75(m,2H),7.59(s,1H),7.55(m,4H),7.43(m,2H),7.32(m,5H),3.00(ddd,J=1.3,6.2,16.1Hz,1H),2.91(m,1H),2.56(q d,J=6.7,13.4Hz,1H),2.33(s,3H),2.30(dt,J=2.1,12.7Hz,1H),2.17( dd,J=6.5,13.9Hz,1H),1.83(m,1H),1.63(s,3H),1.34(d,J=6.7Hz,3H).

[0749] Compound 38j: Compound 38j (white solid, 62 mg, 65% yield) was synthesized from compound 37 (90 mg, 0.19 mmol) and 3-hydroxymethylphenylboronic acid (43 mg, 0.28 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 38j was purified by column chromatography (silica gel, eluted with 0% to 70% EtOAc in hexanes). m / z = 502 (M+1).

[0750] T45: Compound 38j (62 mg, 0.12 mmol) was dissolved in anhydrous DMF (0.6 mL), and the solution was cooled to 0 ° C. 1,3-Dibromo-5,5-dimethylhydantoin (18 mg, 0.063 mmol) in DMF (0.6 mL) was added. The reaction was stirred at 0 ° C for 1 h. Pyridine (50 μL, 0.62 mmol) was added. The reaction was heated at 55 ° C for 4 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous HCl solution and water (3×10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes) to give compound T45 (52 mg, 84% yield) as a white solid. m / z=500 (M+1); 1 H NMR(400MHz, CDCl3)δ7.81(m,2H),7.74(m,2H),7.68(m,2H),7.58(m,3H),7.50 (t,J=7.6Hz,1H),7.42(m,3H),7.35(m,1H),4.81(d,J=5.9Hz,2H),2.99(m,1H) ,2.90(m,1H),2.56(qd,J=6.7,13.4Hz,1H),2.29(dt,J=2.0,12.7Hz,1H),2.16 (m,1H),1.83(m,1H),1.79(t,J=6.0Hz,1H),1.61(s,3H),1.34(d,J=6.7Hz,3H).

[0751] Compound 38k: Compound 38k (white semisolid, 51 mg, 75% yield) was synthesized from compound 37 (64 mg, 0.13 mmol) and (4-methoxyphenyl)boronic acid (31 mg, 0.20 mmol) using the same procedure as described for the synthesis of compound 38a. The reaction was heated at 90°C for 3 h. Compound 38k was purified by column chromatography (silica gel, eluted with 0% to 30% EtOAc in hexanes). m / z = 502 (M+1).

[0752] T46: Compound T46 (off-white solid, 39 mg, 76% yield) was synthesized from compound 38k (51 mg, 0.10 mmol) using the same procedure as described for the synthesis of compound T45. Compound T46 was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes). m / z = 500 (M+1); 1 H NMR(400MHz, CDCl3)δ7.74(m,4H),7.70(s,1H),7.60(m,2H),7.55(m,2H) ,7.42(m,2H),7.35(m,1H),7.03(m,2H),3.88(s,3H),2.98(m,1H),2.90( m,1H),2.56(qd,J=6.7,13.4Hz,1H),2.29(dt,J=2.0,12.7Hz,1H),2.15( dd,J=6.5,13.9Hz,1H),1.81(m,1H),1.59(s,3H),1.34(d,J=6.7Hz,3H).

[0753] Compound 381: Compound 381 (white solid, 27 mg, 78% yield) was synthesized from compound 37 (32 mg, 0.067 mmol) and (4-(dimethylamino)phenyl)boronic acid (17 mg, 0.10 mmol) using the same procedure as described for the synthesis of compound 38a. Compound 381 was purified by column chromatography (silica gel, eluted with 0% to 35% acetone in hexanes). m / z = 515 (M+1).

[0754] T47: Compound 381 (26 mg, 0.051 mmol) was dissolved in anhydrous DMF (0.25 mL) and the solution was cooled to 0°C. 1,3-Dibromo-5,5-dimethylhydantoin (7.2 mg, 0.025 mmol) in DMF (0.25 mL) was added. The reaction was stirred at 0°C for 1 h. Pyridine (20 μL, 0.25 mmol) was added. The reaction was heated at 55°C for 3 h and cooled to room temperature. EtOAc (20 mL) was added. The mixture was washed with 1N aqueous NaOH solution (10 mL), water (3×10 mL) and brine (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 40% EtOAc in hexanes) to give a partially purified product, and again purified by column chromatography (silica gel, eluted with 0% to 30% acetone in hexanes) to give compound T47 (6 mg, 23% yield) as a yellow solid. m / z=513 (M+1); 1H NMR (400MHz, CDCl3) δ7.74(m,5H),7.57(m,2H),7.51(m,2H),7.41(m,2H),7.34(m,1H),6.83(m,2H),3.03(s,6H),2.98(dd,J=5.6,16.0Hz, 1H), 2.89 (m, 1H), 2.55 (qd, J = 6.7, 13.3Hz, 1H), 2.29 (dt, J = 2.0, 12.7Hz, 1H), 2.15 (m, 1H), 1.81 (m, 1H), 1.59 (s, 3H), 1.33 (d, J = 6.7Hz, 3H).

[0755] Compound 39: Under N2, a stirred solution of pyrimidine-4-carboxylic acid (500 mg, 4.02 mmol) and pentafluorophenol (815 mg, 4.43 mmol) in 1,4-dioxane (20 mL) was treated with N,N′-dicyclohexylcarbodiimide (914 mg, 4.43 mmol). The reaction mixture was stirred at room temperature for 19 h. The precipitated urea was removed by filtration. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes) to give compound 39 (880 mg, 69% yield) as a yellow oil, which crystallized after standing. m / z=291 (M+1).

[0756] Compound 40: At room temperature, to a stirred suspension of compound 3 (200 mg, 0.912 mmol) and magnesium bromide etherate (588 mg, 2.28 mmol) in CHCl (12 mL), N,N-diisopropylethylamine (0.45 mL, 2.58 mmol) was added dropwise. The mixture was stirred at room temperature for 2 min, and a solution of 39 (396 mg, 1.36 mmol) in CHCl (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h. A saturated KHPO aqueous solution (30 mL) was added. The mixture was extracted with EtOAc (100 mL). The organic extract was washed with water and brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to obtain compound 40 (145 mg, 49% yield) as a yellow viscous oil. m / z=326(M+1).

[0757] Compound 41: A mixture of compound 40 (145 mg, 0.445 mmol), biphenyl-4-ylhydrazine hydrochloride (196 mg, 0.897 mmol) and EtOH (3 mL) was heated at 120° C. for 2 h in a Biotage microwave and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The mixture was washed with saturated aqueous KH2PO4 and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound 41 (142 mg, 67% yield) as an orange glass. m / z=474 (M+1).

[0758] Compound 42: A solution of 41 (138 mg, 0.291 mmol) in MeOH (10 mL) was treated with potassium carbonate (80 mg, 0.582 mmol). The reaction mixture was stirred at room temperature for 24 h and then concentrated. The residue was partitioned between EtOAc and a saturated aqueous KH2PO4 solution. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to obtain compound 42 (113 mg, 82% yield) as a yellow glass. m / z=474 (M+1).

[0759] T48: Under nitrogen, a solution of 42 (112 mg, 0.236 mmol) in anhydrous DMF (3 mL) was cooled to 0 ° C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (37 mg, 0.129 mmol) in anhydrous DMF (1 mL) was added. The mixture was stirred at 0 ° C for 40 min, and then anhydrous pyridine (0.19 mL, 2.36 mmol) was added. The reaction mixture was heated at 60 ° C for 4 h and then cooled to room temperature. The reaction mixture was distributed between EtOAc and saturated KH2PO4 aqueous solution. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 3% MeOH in CHCl 3 ) to give a partially purified product, and again purified by column chromatography (silica gel, eluted with 30% EtOAc in CHCl 2 ) and then again purified using a third column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give Compound T48 (74 mg, 66% yield) as a white solid. m / z = 472 (M + 1); 1H NMR (400MHz, CDCl3) δ9.23(d,J=1.4Hz,1H),8.71(d,J=5.4Hz,1H),7.95(dd,J=1.4,5.4Hz,1H) ,7.83(m,2H),7.67(m,2H),7.62(s,1H),7.58(m,2H),7.52(m,2H),7.45(m,1H),3.42(dd,J=5.3 ,18.0Hz,1H),2.99(ddd,J=6.9,11.8,17.3Hz,1H),2.56(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2 .1,12.7Hz,1H),2.17(dd,J=6.8,14.0Hz,1H),1.82(m,1H),1.61(s,3H),1.34(d,J=6.7Hz,3H).

[0760] Compound 43: A mixture of 40 (200 mg, 0.614 mmol), (4-bromophenyl)hydrazine hydrochloride (274 mg, 1.23 mmol) and EtOH (3 mL) was heated at 100 ° C for 2 h in a Biotage microwave and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The mixture was washed with saturated aqueous KH2PO4 and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 40% EtOAc in hexanes) to give compound 43 (261 mg, 89% yield) as a yellow glass. m / z=476 & 478 (M+1).

[0761] Compound 44: A solution of 43 (257 mg, 0.539 mmol) in MeOH (15 mL) was treated with potassium carbonate (149 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h and then concentrated. The residue was partitioned between EtOAc and a saturated aqueous KH2PO4 solution. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to obtain compound 44 (205 mg, 80% yield) as a white glass. m / z=476 & 478 (M+1).

[0762] Compound 45a (T185): A thick-walled glass container was charged with 44 (204 mg, 0.428 mmol), tripotassium phosphate (272 mg, 1.28 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.021 mmol), 5-fluoropyridine-3-boronic acid (91 mg, 0.642 mmol), anhydrous 1,4-dioxane (2 mL) and anhydrous DMF (1 mL). The mixture was bubbled with N2. The container was sealed. The reaction mixture was heated at 90 ° C for 21 h and then cooled to room temperature. The mixture was diluted with EtOAc and passed through The product was filtered through a pad of 4% paraffin wax. The filtrate was washed with a saturated aqueous KH2PO4 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% EtOAc in hexanes) to give compound 45a (149 mg, 71% yield). Compound 45a was contaminated with triphenylphosphine oxide and was used in the next step without further purification. m / z=493 (M+1); 1 H NMR(400MHz, CDCl3)δ9.22(m,1H),8.75(br s,1H),8.69(m,1H),8.54(m,1H),7.92(dd,J=1.4,5.4Hz,1H),7.76(m,2H),7.68(m,1H),7.57(m,2H),3.54(dd,J=5.7,13.5Hz ,1H),3.37(m,1H),2.93(ddd,J=6.7,12.0,17.7Hz,1H),2.53(qd,J=6.4,12.8Hz,1H),1.98(m,5H),1.59(s,3H),1.26(m,3H).

[0763] T49: Under nitrogen, a solution of 45a (148 mg, 0.300 mmol) in anhydrous DMF (3 mL) was cooled to 0°C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (47 mg, 0.165 mmol) in anhydrous DMF (1 mL) was added. The mixture was stirred at 0°C for 60 min, then anhydrous pyridine (0.24 mL, 2.97 mmol) was added. The reaction mixture was heated at 60°C for 4 h and then cooled to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous KH2PO4. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give a partially purified product, which was dissolved in a minimum amount of 1,4-dioxane and kept at 5°C for 1 h. The precipitated solid was collected by filtration and dried in vacuo to give compound T49 (38 mg, 26% yield) as a yellow solid. m / z = 491 (M+1); 1 H NMR (400MHz, CDCl3) δ9.23(d,J=1.4Hz,1H),8.77(t,J=1.7Hz,1H),8.71(d,J=5.3Hz,1H), 8.56(d,J=2.7Hz,1H),7.93(dd,J=1.5,5.4Hz,1H),7.84(m,2H),7.67(m,3H),7.57(s,1H) ,3.42(m,1H),2.99(ddd,J=6.9,11.8,18.1Hz,1H),2.57(m,1H),2.27(dt,J=2.1,12.7Hz, 1H), 2.18 (m, 1H), 1.83 (tdd, J = 6.2, 12.6, 18.7Hz, 1H), 1.63 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0764] Compound 45b: Compound 44 (200 mg, 0.42 mmol) was dissolved in 1,4-dioxane (2 mL) and DMF (1 mL). K 3 PO 4 (270 mg, 1.27 mmol), Pd(PPh 3 ) 4 (25 mg, 0.021 mmol) and pyrimidin-5-ylboronic acid (80 mg, 0.65 mmol) were added. The mixture was bubbled with N 2 for 10 min and then stirred at 90 ° C for 4 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes) to obtain compound 45b (150 mg, 75% yield) as a solid. m / z=476 (M+1).

[0765] T50: A solution of compound 45b (150 mg, 0.32 mmol) in dry DMF (2 mL) was cooled to 0 ° C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (47 mg, 0.16 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 0 ° C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The reactants were heated at 60 ° C for 4 h and then concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes) to give T50 (90 mg, 60% yield) as a light yellow solid. m / z=474 (M+1); 1 H NMR (400MHz, CDCl3) δ9.31(d,J=0.7Hz,1H),9.23(d,J=1.2Hz,1H),9.07(m,2H),8.71(dd,J =0.7,5.3Hz,1H),7.93(td,J=1.1,5.4Hz,1H),7.86(m,2H),7.69(m,2H),7.57(s,1H),3.42( m,1H),2.99(ddd,J=6.9,11.8,18.0Hz,1H),2.57(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2.1, 12.8Hz, 1H), 2.18 (dd, J = 6.9, 13.9Hz, 1H), 1.84 (m, 1H), 1.63 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0766] Compound 45c: Compound 45c (solid, 110 mg, 55% yield) was synthesized from compound 44 (200 mg, 0.42 mmol) and pyridin-3-ylboronic acid (80 mg, 0.65 mmol) using the same procedure as described for the synthesis of compound 45b. The reaction was heated at 90° C. for 5 h. Compound 45c was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes). m / z=475 (M+1).

[0767] T51: A solution of compound 45c (110 mg, 0.23 mmol) in dry DMF (2 mL) was cooled to 0 ° C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (35 mg, 0.12 mmol) in DMF (1 mL) was added. The reaction was stirred at 0 ° C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The reaction was stirred at 60 ° C for 4 h and then concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes) to give T51 (75 mg, 68% yield) as an off-white solid. m / z=473 (M+1); 1 H NMR (400MHz, CDCl3) δ9.23(d,J=1.4Hz,1H),8.94(dd,J=0.8,2.5Hz,1H),8.71(d,J=5.5Hz,1H),8.69(m,1H),7.98(dd d,J=1.7,2.4,7.9Hz,1H),7.94(dd,J=1.5,5.4Hz,1H),7.84(m,2H),7.63(m,2H),7.59(s,1H),7.45(ddd,J=0.8,4.8, 7.9Hz,1H),3.42(dd,J=5.9,17.6Hz,1H),2.99(ddd,J=6.9,11.8,18.0Hz,1H),2.56(qd,J=6.7,13.4Hz,1H),2.27(dt ,J=2.1,12.8Hz,1H),2.18(dd,J=6.9,14.0Hz,1H),1.83(tt,J=6.4,12.7Hz,1H),1.62(s,3H),1.34(d,J=6.7Hz,3H).

[0768] Compound 46: Compound 4 (82 mg, 0.62 mmol) and 4-hydrazinobenzoic acid hydrochloride (232 mg, 1.23 mmol) in EtOH (4 mL) were heated at 120° C. for 4 h in a Biotage microwave and then cooled to room temperature. The mixture was concentrated. The residue was diluted with EtOAc (20 mL) and washed with water (2×15 mL). The organic extract was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0% to 100% acetone in hexanes) to give compound 46 (82 mg, 30% yield) and compound 47 (192 mg, 66% yield). Compound 46: light yellow solid; m / z=440 (M+1); Compound 47: light yellow solid; m / z=468 (M+1).

[0769] Compound 48: Compound 47 (80 mg, 0.18 mol) was dissolved in MeOH (1.8 mL). Sodium methoxide (25 wt % in methanol, 104 μL, 0.45 mmol) was added. The reaction mixture was stirred at 55 ° C for 2 h and cooled to room temperature. A 10% aqueous solution of NaH2PO4 (15 mL) was added. The mixture was extracted with EtOAc (2×20 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0% to 100% acetone in hexanes) to obtain compound 48 (49 mg, 61% yield) as a light yellow solid. m / z=440 (M+1).

[0770] T52: Compound T52 (brown solid, 41 mg, 85% yield) was synthesized from compound 48 (48 mg, 0.11 mmol) using the same procedure as described for the synthesis of compound T45. Compound T52 was purified by column chromatography (silica gel, eluted with 0% to 50% acetone in hexanes). m / z = 438 (M+1); 1 H NMR (400MHz, CDCl3) δ8.34(m,2H),7.72(m,2H),7.66(m,2H),7.52(s,1H),7.43(m,2H),7.36(m,1H),2.99(dd,J=5.6,16.6Hz,1H),2. 89(m,1H),2.57(qd,J=6.6,13.4Hz,1H),2.27(dt,J=2.0,12.7Hz,1H),2.16(m,1H),1.82(m,1H),1.62(s,3H),1.34(d,J=6.7Hz,3H).

[0771] Compound 49: A thick-walled glass container was charged with compound 40 (100 mg, 0.307 mmol), 4-bromo-2-fluorophenylhydrazine hydrochloride (148 mg, 0.614 mmol) and EtOH (3 mL). The container was sealed and the reaction mixture was heated at 100° C. for 21 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and a saturated aqueous KH PO solution. The organic extract was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography (silica gel, 40% EtOAc in hexanes) to obtain compound 49 (161 mg, quantitative yield) as a yellow glass. m / z=494 / 496 (M+1).

[0772] Compound 50: A mixture of 49 (155 mg, 0.313 mmol) and potassium carbonate (87 mg, 0.626 mmol) in MeOH (10 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and a saturated aqueous KH2PO4 solution. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 40% EtOAc in hexanes) to obtain compound 50 (103 mg, 66% yield) as a white glass. m / z=494 / 496 (M+1).

[0773] Compound 51: A mixture of compound 50 (102 mg, 0.206 mmol), tripotassium phosphate (131 mg, 0.618 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.0103 mmol) and pyridine-3-boronic acid (38 mg, 0.309 mmol) in anhydrous 1,4-dioxane (2 mL) and anhydrous DMF (1 mL) was purged with N2. The reactor was sealed and the mixture was irradiated in a Biotage microwave at 90 ° C for 4 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc and passed through The product was filtered through a pad of 4% paraffin wax. The filtrate was washed with a saturated aqueous KH2PO4 solution and brine. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 60% to 100% EtOAc in hexanes) to give compound 51 (69.5 mg, 68% yield) as a white glass. m / z=493 (M+1).

[0774] T53: Under nitrogen, a solution of 51 (69 mg, 0.140 mmol) in anhydrous DMF (3 mL) was cooled to 0 ° C. 1,3-dibromo-5,5-dimethylhydantoin (22 mg, 0.077 mmol) in anhydrous DMF (1 mL) was added. The mixture was stirred at 0 ° C for 1 h, and then anhydrous pyridine (0.11 mL, 1.36 mmol) was added. The mixture was heated at 60 ° C for 4 h and then cooled to room temperature. The mixture was partitioned between EtOAc and saturated KH2PO4 aqueous solution. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 40% EtOAc in hexanes) to give compound T53 (52 mg, 76% yield) as a yellow solid. m / z=491 (M+1); 1H NMR (400MHz, CDCl3) δ9.23(d,J=1.5Hz,1H),8.94(d,J=2.4Hz,1H),8.72(m,2H),7.97(td,J=2.0,8 .0Hz,1H),7.92(dd,J=1.4,5.3Hz,1H),7.63(m,4H),7.47(dd,J=4.8,7.9Hz,1H),3.43(dd,J=5.8,1 7.5Hz,1H),2.98(ddd,J=6.8,11.8,18.0Hz,1H),2.57(qd,J=6.7,13.4Hz,1H),2.32(t,J=12.7Hz,1 H), 2.18 (dd, J=6.8, 13.8Hz, 1H), 1.81 (qd, J=6.0, 12.5Hz, 1H), 1.52 (s, 3H), 1.35 (d, J=6.7Hz, 3H).

[0775] Compound 52: In a sealable bottle, a mixture of compound 44 (0.51 g, 1.07 mmol), bisvaleryl diboron (0.41 g, 1.61 mmol) and potassium acetate (0.32 g, 3.26 mmol) in 1,4-dioxane (11 mL) was degassed and treated with [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (78 mg, 0.11 mmol). The mixture was degassed, sealed, and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with saturated KH2PO4 aqueous solution. The organic extract was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 50% EtOAc in hexanes) to give compound 52 (0.41 g, 73% yield) as a light yellow solid. m / z=524(M+1).

[0776] Compound 53a: In a sealable bottle, a mixture of compound 52 (0.30 g, 0.57 mmol), 4-bromo-2-(fluoromethyl)pyridine (0.11 g, 0.58 mmol) and K3PO4 (0.36 g, 1.70 mmol) in 1,4-dioxane (4.8 mL) and DMF (1.2 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.057 mmol) was added. The mixture was degassed again. The bottle was sealed. The mixture was heated at 100°C for 16 h, cooled to room temperature, diluted with EtOAc (50 mL), and washed with saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL); dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl 3 ) to give Compound 53a (0.17 g, 59% yield) as a light yellow solid. m / z=507 (M+1).

[0777] T54: To a stirred solution of compound 53a (0.17 g, 0.34 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (47 mg, 0.16 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.27 mL, 3.34 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl3) to give compound T54 (90 mg, 53% yield) as a light yellow solid. m / z=505 (M+1); 1H NMR(400MHz, CDCl3)δ9.23(d,J=1,4Hz,1H),8.71(m,2H),7.93(m,3H),7.77(m,1H),7.66(m,2H),7 .57(s,1H),7.55(dd,J=1.8,5.1Hz,1H),5.60(d,J=46.8Hz,2H),3.42(dd,J=5.9,17.6Hz,1H),3.0 0(ddd,J=6.9,11.8,18.1Hz,1H),2.57(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2.1,12.7Hz,1H),2.18 (dd, J=7.2, 14.2Hz, 1H), 1.83 (tdd, J=6.4, 13.2, 19.3Hz, 1H), 1.63 (s, 3H), 1.34 (d, J=6.7Hz, 3H).

[0778] Compound 53b: In a sealable bottle, a mixture of compound 52 (0.22 g, 0.42 mmol), (4-bromopyridin-2-yl)methanol (59 mg, 0.31 mmol) and K3PO4 (0.20 g, 0.94 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added. The mixture was degassed again. The bottle was sealed. The mixture was heated at 100°C for 16 h and then cooled to room temperature. The mixture was diluted with a 10% solution of MeOH in CHCl3 (25 mL) and washed with a saturated aqueous KH2PO4 solution (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl 3 ) to give Compound 53b (0.10 g, 63% yield) as a light yellow solid. m / z=505 (M+1).

[0779] T55: At 0 ° C, under N2, to a stirred solution of compound 53b (0.10 g, 0.20 mmol) in degassed DMF (3 mL), a solution of 1,3-dibromo-5,5-dimethylhydantoin (31 mg, 0.11 mmol) in degassed DMF (1 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 min, and then pyridine (0.16 mL, 1.98 mmol) was added. The mixture was heated at 60 ° C for 4 h and then concentrated. The residue was partitioned between a saturated KH2PO4 aqueous solution (25 mL) and a 10% MeOH solution in CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH solution in CHCl3) to obtain compound T55 (26 mg, 26% yield) as a light yellow solid. m / z=503(M+1); 1 H NMR (400MHz, CDCl3) δ9.23 (d, J=1.4Hz, 1H), 8.71 (m, 2H), 7.93 (dd, J=1.5, 5.3Hz, 1H),7.89(m,2H),7.65(m,2H),7.56(m,2H),7.51(dd,J=1.7,5.2Hz,1H),4.89(br s,2H),3.64(br s,1H),3.42(dd,J=5.7,17.7Hz,1H),2.99(ddd,J=6.9,11.8,18.1Hz,1H),2.57(qd,J=6.7,13.4Hz,1H),2.27(dt,J=2. 0,12.7Hz,1H),2.18(dd,J=6.9,13.8Hz,1H),1.84(ddd,J=6.4,12.6,19.8Hz,1H),1.62(s,3H),1.34(d,J=6.7Hz,3H).

[0780] Compound 54: Compound 40 (1.31 g, 4.05 mmol) and 5-bromo-2-hydrazinepyridine hydrochloride (1.52 g, 6.77 mmol) in EtOH (10 mL) were heated at 100 ° C for 2 h in a Biotage microwave synthesizer. The reaction mixture was concentrated. The residue was diluted with a saturated aqueous solution of NaHCO and extracted with EtOAc. The organic extract was dried over MgSO , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of EtOAc in hexanes from 0% to 50%) to obtain compound 54 (1.4 g, 73% yield) as a solid. m / z=477 / 479 (M+1).

[0781] Compound 55: Compound 54 (1.4 g, 2.93 mmol) was dissolved in MeOH (30 mL) and KCO (2.05 g, 14.8 mmol) was added. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was neutralized by adding a saturated aqueous KHPO solution and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain Compound 55 (1.29 g, 92% yield) as a solid. m / z=477 / 479 (M+1).

[0782] Compound 56a: Compound 55 (260 mg, 0.55 mmol) was dissolved in 1,4-dioxane (2 mL) and DMF (1 mL). K 3 PO 4 (350 mg, 1.65 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) and 4-fluorophenylboric acid (115 mg, 0.82 mmol) were added. The mixture was bubbled with N 2 for 10 min and then stirred at 90 ° C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 56a (265 mg, 98% yield) as a solid. m / z=493 (M+1).

[0783] T56: Compound 56a (265 mg, 0.54 mmol) was dissolved in dry DMF (3 mL) and cooled to 0°C. Bromine (95 mg, 0.59 mmol) in CH2Cl2 (1 mL) was added. The reaction was stirred at 0°C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T56 (30 mg, 11% yield) as a light orange solid. m / z=491 (M+1); 1H NMR (400MHz, CDCl3) δ9.25(d,J=1.4Hz,1H),8.77(d,J=5.3Hz,1H),8.67(dd,J=0.8,2.4Hz,1H) ,8.49(s,1H),8.15(dd,J=0.8,8.6Hz,1H),8.10(dd,J=2.4,8.6Hz,1H),8.06(dd,J=1.4,5.3Hz, 1H),7.63(m,2H),7.23(m,2H),3.41(dd,J=5.6,17.6Hz,1H),2.96(ddd,J=6.6,11.9,17.9Hz,1 H), 2.68 (td, J = 6.7, 13.5Hz, 1H), 2.20 (m, 2H), 2.00 (s, 3H), 1.84 (m, 1H), 1.37 (d, J = 6.8Hz, 3H).

[0784] Compound 56b: Compound 55 (250 mg, 0.52 mmol) was dissolved in 1,4-dioxane (2 mL) and DMF (1 mL). K 3 PO 4 (350 mg, 1.65 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) and pyridin-3-ylboronic acid (115 mg, 0.94 mmol) were added. The mixture was bubbled with N 2 for 10 min and stirred at 90 ° C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 56b (170 mg, 68% yield) as a solid. m / z=476 (M+1).

[0785] T57: Compound 56b (170 mg, 0.36 mmol) was dissolved in dry DMF (3 mL) and cooled to 0°C. Bromine (60 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added. The reaction was stirred at 0°C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The reaction mixture was heated at 60°C for 4 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 100% EtOAc in hexanes) to give compound T57 (60 mg, 35% yield) as a white solid. m / z=474 (M+1); 1H NMR (400MHz, CDCl3) δ9.25(d,J=1.4Hz,1H),8.94(dd,J=0.8,2.5Hz,1H),8.78(d,J=5.3Hz,1H),8.72(m,2H),8.51(s,1H) ,8.23(dd,J=0.8,8.5Hz,1H),8.16(dd,J=2.4,8.6Hz,1H),8.07(dd,J=1.4,5.3Hz,1H),7.99(ddd,J=1.6,2.4,7.9Hz,1H) ,7.48(ddd,J=0.9,4.8,7.8Hz,1H),3.42(m,1H),2.97(ddd,J=6.6,11.9,17.3Hz,1H),2.70(qd,J=6.8,13.6Hz,1H),2.22 (dt,J=2.1,12.6Hz,1H),2.15(dd,J=6.6,13.7Hz,1H),2.01(s,3H),1.85(qt,J=5.8,12.7Hz,1H),1.38(d,J=6.8Hz,3H).

[0786] Compound 56c: Compound 55 (250 mg, 0.52 mmol) was dissolved in 1,4-dioxane (2 mL) and DMF (1 mL). K 3 PO 4 (350 mg, 1.65 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) and 3-fluorophenylboric acid (115 mg, 0.82 mmol) were added. The mixture was bubbled with N 2 for 10 min and then stirred at 90 ° C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 56c (126 mg, 49% yield) as a solid. m / z=493 (M+1).

[0787] T58: Compound 56c (125 mg, 0.25 mmol) was dissolved in dry DMF (3 mL) and cooled to 0°C. Bromine (41 mg, 0.26 mmol) in CH2Cl2 (1 mL) was added. The reaction was stirred at 0°C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The reaction mixture was stirred at 60°C for 4 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T58 (80 mg, 64% yield) as an off-white solid. m / z=491 (M+1); 1H NMR (400MHz, CDCl3) δ9.25(d,J=1.4Hz,1H),8.78(d,J=5.3Hz,1H),8.71(dd,J=0.8,2.4Hz,1H),8.51(s,1H),8.18(dd, J=0.8,8.6Hz,1H),8.12(dd,J=2.4,8.6Hz,1H),8.06(dd,J=1.5,5.3Hz,1H),7.48(m,2H),7.37(td,J=2.1,9.6Hz,1H),7 .16(ddt,J=1.1,2.6,8.2Hz,1H),3.42(dd,J=5.5,17.6Hz,1H),2.96(ddd,J=6.6,11.9,17.9Hz,1H),2.68(td,J=6.7,13 .5Hz,1H),2.22(td,J=2.0,12.6Hz,1H),2.14(m,1H),2.00(s,3H),1.84(qd,J=5.9,13.0Hz,1H),1.37(d,J=6.8Hz,3H).

[0788] Compound 56d: Compound 55 (260 mg, 0.55 mmol) was dissolved in 1,4-dioxane (2 mL) and DMF (1 mL). K 3 PO 4 (350 mg, 1.65 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) and phenylboronic acid (100 mg, 0.82 mmol) were added. The mixture was bubbled with N 2 for 10 min and then stirred at 90 ° C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to obtain compound 56d (250 mg, 97% yield) as a solid. m / z=475 (M+1).

[0789] T59: Compound 56d (250 mg, 0.53 mmol) was dissolved in dry DMF (3 mL) and cooled to 0°C. Bromine (90 mg, 0.56 mmol) in CH2Cl2 (1 mL) was added. The reaction was stirred at 0°C for 2 h. Pyridine (2 mL, 24.73 mmol) was added. The reaction mixture was stirred at 60°C for 4 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexanes) to give Compound T59 (27 mg, 11% yield) as an off-white solid. m / z=473 (M+1); 1H NMR (400MHz, CDCl3) δ9.25(d,J=1.4Hz,1H),8.77(d,J=5.3Hz,1H),8.72(t,J=1.6Hz,1H),8 .51(s,1H),8.15(d,J=1.6Hz,2H),8.07(dd,J=1.5,5.3Hz,1H),7.66(m,2H),7.53(m,2H),7. 47(m,1H),3.42(dd,J=5.5,17.5Hz,1H),2.96(ddd,J=6.6,12.0,18.0Hz,1H),2.69(qd,J=6 .8,13.5Hz,1H),2.22(m,1H),2.14(m,1H),2.01(s,3H),1.85(m,1H),1.37(d,J=6.8Hz,3H).

[0790] Compound 56e: In a sealable bottle, a mixture of compound 55 (0.20 g, 0.42 mmol), 3-(hydroxymethyl)phenylboronic acid (0.13 g, 0.86 mmol) and K3PO4 (0.27 g, 1.27 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) was added. The mixture was degassed again. The bottle was sealed. The mixture was heated at 90 ° C for 6 h and then at room temperature overnight. The mixture was diluted with EtOAc (50 mL) and washed with KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl3) to obtain compound 56e (0.14 g, 66%) as a light yellow solid. m / z=505 (M+1).

[0791] T60: At 0 ° C, under N2, to a stirred solution of compound 56e (0.14 g, 0.28 mmol) in degassed DMF (4 mL), a solution of 1,3-dibromo-5,5-dimethylhydantoin (44 mg, 0.15 mmol) in degassed DMF (1 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 min, and then pyridine (0.23 mL, 2.84 mmol) was added. The mixture was heated at 60 ° C for 4 h and then concentrated. The residue was distributed between saturated KH2PO4 aqueous solution (25 mL) and 5% MeOH in CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl3). The obtained product was triturated with Et2O. The solid was collected by filtration and dried under vacuum to give compound T60 (34 mg, 24% yield) as a light yellow solid. m / z=503 (M+1); 1 H NMR (400MHz, DMSO-d6) δ9.26(d,J=1.4Hz,1H),8.93(d,J=2.4Hz,1H),8.87(d,J=5.3Hz,1H),8.45(dd,J =2.5,8.6Hz,1H),8.37(s,1H),8.11(m,2H),7.80(s,1H),7.74(td,J=1.5,7.9Hz,1H),7.51(t,J=7.6Hz, 1H),7.43(d,J=7.6Hz,1H),5.31(t,J=5.7Hz,1H),4.62(t,J=5.7Hz,2H),3.28(m,1H),2.85(m,2H),2.29 (m, 1H), 2.04 (dd, J = 6.5, 13.3Hz, 1H), 1.96 (s, 3H), 1.80 (dq, J = 5.7, 12.7Hz, 1H), 1.23 (d, J = 6.7Hz, 3H).

[0792] T61: To a stirred solution of compound T60 (30 mg, 0.059 mmol) in CHCl (2 mL) at -78°C under N2 was added a solution of diethylaminosulfur trifluoride (14 mg, 0.087 mmol) in CHCl (1 mL) dropwise. After stirring for 2 h, the cold solution was poured into a cold saturated aqueous NaHCO3 solution (25 mL). The mixture was warmed to room temperature and extracted with CHCl (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound T61 (12 mg, 40% yield) as an off-white solid. m / z=505 (M+1); 1 H NMR (400MHz, CDCl3) δ9.25(d,J=1.4Hz,1H),8.78(d,J=5.3Hz,1H),8.73(dd,J=1.3,2.0Hz,1H),8.52(s,1H ),8.16(m,2H),8.07(dd,J=1.4,5.3Hz,1H),7.67(m,2H),7.57(t,J=7.6Hz,1H),7.47(dd,J=1.6,7.7Hz,1H) ,5.50(d,J=47.6Hz,2H),3.42(dd,J=5.5,17.5Hz,1H),2.96(ddd,J=6.6,11.9,18.0Hz,1H),2.68(m,1H),2 .22(dt,J=2.1,12.6Hz,1H),2.14(dd,J=6.5,13.6Hz,1H),2.01(s,3H),1.84(m,1H),1.37(d,J=6.8Hz,3H).

[0793] Compound 57: In a sealable bottle, a mixture of compound 55 (0.25 g, 0.52 mmol), potassium cyclopropyltrifluoroborate (0.23 g, 1.55 mmol), K 3 PO 4 (0.33 g, 1.55 mmol) and RuPhos (24 mg, 0.051 mmol) in toluene (3.2 mL) and water (0.8 mL) was degassed. Palladium (II) acetate (6 mg, 0.027 mmol) was added. The mixture was degassed again. The bottle was sealed. The mixture was heated at 95° C. for 16 h and then cooled to room temperature. The mixture was concentrated. The residue was distributed between a 5% solution of MeOH in CHCl 3 (25 mL) and a saturated KH 2 PO 4 aqueous solution (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 70% EtOAc in hexanes) to give compound 57 (82 mg, 36% yield) as a light blue solid. m / z = 439 (M+1).

[0794] T62: To a stirred solution of compound 57 (82 mg, 0.19 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (30 mg, 0.10 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.15 mL, 1.85 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 70% EtOAc in hexanes) to give compound T62 (52 mg, 63% yield) as a tan solid. m / z=437 (M+1); 1H NMR (400MHz, CDCl3) δ9.22(d,J=1.4Hz,1H),8.74(d,J=5.3Hz,1H),8.33(s,1H),8.30(d,J= 2.4Hz,1H),8.02(dd,J=1.4,5.3Hz,1H),7.88(d,J=8.4Hz,1H),7.53(dd,J=2.5,8.5Hz,1H) ,3.39(dd,J=5.8,17.6Hz,1H),2.94(ddd,J=6.6,12.0,18.0Hz,1H),2.65(m,1H),2.17(m,2 H), 2.00 (m, 1H), 1.95 (s, 3H), 1.84 (m, 1H), 1.35 (d, J = 6.8Hz, 3H), 1.14 (m, 2H), 0.83 (m, 2H).

[0795] Compound 58: Compound 40 (0.25 g, 0.77 mmol) and 2-hydrazino-5-(trifluoromethyl)pyridine (275 mg, 1.55 mmol) in EtOH (2 mL) and a 4N solution of HCl in 1,4-dioxane (0.4 mL) were heated at 100 ° C for 2 h in a Biotage microwave synthesizer. The reaction mixture was concentrated. The residue was treated with an aqueous solution of NaHCO 3 and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to obtain compound 58 (350 mg, 97% yield) as a solid. m / z=467 (M+1).

[0796] Compound 59: Compound 58 (0.34 g, 0.73 mmol) in MeOH (10 mL) was treated with KCO (0.5 g, 3.62 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was neutralized by adding a saturated KHPO aqueous solution and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of EtOAc in hexanes from 0% to 35%) to obtain compound 59 (175 mg, 51% yield) as a solid. m / z=467 (M+1).

[0797] T63: Compound 59 (175 mg, 0.37 mmol) was dissolved in dry DMF (2 mL) and cooled to 0 ° C. 1,3-Dibromo-5,5-dimethylhydantoin (58 mg, 0.20 mmol) in DMF (1 mL) was added. The reactants were stirred at 0 ° C for 2 h, and then pyridine (2 mL, 24.73 mmol) was added. The mixture was stirred at 60 ° C for 4 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0% to 35% EtOAc in hexanes) to give Compound T63 (150 mg, 86% yield) as a white solid. m / z=465 (M+1); 1 H NMR(400MHz, CDCl3) δ9.26(d,J=1.4Hz,1H),8.80(d,J=5.3Hz,1H),8.77(m,1H),8 .50(s,1H),8.33(d,J=8.7Hz,1H),8.16(dd,J=2.4,8.8Hz,1H),8.06(dd,J=1.5,5. 3Hz,1H),3.41(m,1H),2.95(ddd,J=6.6,12.0,18.1Hz,1H),2.69(m,1H),2.21(dt, J=2.1,12.5Hz,1H),2.13(m,1H),1.95(s,3H),1.82(m,1H),1.37(d,J=6.8Hz,3H).

[0798] Compound 61: A mixture of compound 40 (55 mg, 0.169 mmol) and 5-hydrazino-2-phenylpyridine hydrochloride (75 mg, 0.338 mmol) in EtOH (3 mL) was heated at 100 ° C for 5 h in a Biotage microwave synthesizer. The mixture was cooled to room temperature and concentrated. The residue was partitioned between EtOAc and saturated KH2PO4 aqueous solution. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to obtain compound 61 (64 mg, 80% yield) as a yellow glass. m / z=475 (M+1).

[0799] Compound 62: A mixture of 61 (63 mg, 0.132 mmol) and potassium carbonate (36 mg, 0.265 mmol) in MeOH (7 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and a saturated aqueous KH2PO4 solution. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with MeOH to obtain compound 62 (35 mg, 56% yield) as an orange solid. m / z=475 (M+1).

[0800] T64: Under nitrogen, a solution of 62 (35 mg, 0.074 mmol) in anhydrous DMF (3 mL) was cooled to 0 ° C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (11.5 mg, 0.040 mmol) in anhydrous DMF (1 mL) was added. The mixture was stirred at 0 ° C for 1 h. Anhydrous pyridine (0.06 mL, 0.742 mmol) was added. The reaction mixture was heated at 60 ° C for 4 h and then cooled to room temperature. The mixture was partitioned between EtOAc and saturated KH2PO4 aqueous solution. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with MeOH to give compound T64 (21 mg, 60% yield) as an off-white solid. m / z=473 (M+1); 1 H NMR (400MHz, CDCl3) δ9.24 (s, 1H), 8.86 (d, J = 2.6Hz, 1H), 8.73 (d, J = 5.3Hz, 1H), 8.1 1(d,J=7.2Hz,2H),8.02(d,J=8.4Hz,1H),7.92(m,2H),7.54(m,4H),3.42(dd,J=5.9 ,17.6Hz,1H),2.99(ddd,J=6.8,11.6,17.9Hz,1H),2.57(m,1H),2.27(t,J=12.8Hz, 1H), 2.18 (dd, J=6.8, 14.1Hz, 1H), 1.84 (m, 1H), 1.64 (s, 3H), 1.34 (d, J=6.7Hz, 3H).

[0801] Compound 64: At room temperature, under N2, a solution of compound 63 (4.31 g, 18.08 mmol) in ethyl formate (50 mL, 0.61 mol) and benzene (50 mL) was treated dropwise with sodium methoxide (30 wt% MeOH, 17 mL, 91 mmol). The mixture was stirred at room temperature for 16 h and then concentrated. The residue was distributed between saturated KH2PO4 aqueous solution (100 mL) and Et2O (100 mL). The organic extract was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain compound 64 (4.69 g, 97% yield) as a light pink solid. m / z=267 (M+1, 100%).

[0802] Compounds 65 and 66: A solution of compound 64 (0.66 g, 2.48 mmol) and acetic acid (1.4 mL, 24.4 mmol) in EtOH (25 mL) was degassed and cooled to 0°C. Biphenyl-4-ylhydrazine (0.55 g, 2.99 mmol) was added. Under N2, the mixture was warmed to room temperature overnight and then concentrated. The residue was partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL). The organic extract was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound 65 (0.49 g, 47% yield) and compound 66 (0.46 g, 45% yield). Compound 65: orange-yellow solid; m / z=415 (M+1). Compound 66: yellow solid; m / z=415 (M+1).

[0803] Compound 67: at -10 ℃, under N2, to compound 66 (1.31 g, 3.16 mmol) and sodium carbonate (1.67 g, 15.76 mmol) in CH2Cl2 (30 mL) in a stirred suspension, a solution of bromine (1.5 g, 9.4 mmol) in CH2Cl2 (10 mL) was added dropwise. After stirring for 4 h, the cold reaction mixture was quenched by dropwise addition of saturated aqueous sodium thiosulfate solution (50 mL). The ice bath was removed. The mixture was stirred at room temperature for 1 h and then concentrated. The residue was extracted with EtOAc (50 mL). The organic extract was washed with brine (50 mL), dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to obtain compound 67 (1.32 g, 85% yield) as a light orange solid. m / z=493&495(M+1).

[0804] Compound 68a: In a sealable bottle, a mixture of compound 67 (0.25 g, 0.51 mmol), 4-fluorophenylboronic acid (0.14 g, 1.00 mmol) and potassium phosphate (0.32 g, 1.51 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL) was degassed and treated with tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol). The mixture was degassed again. The bottle was sealed and the mixture was heated at 100 ° C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with a 1N NaOH aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1 / 5 / 5 EtOAc / CH2Cl2 / hexanes) to give compound 68a (0.22 g, 85% yield) as a yellow oil. m / z = 509 (M+1).

[0805] Compound 69a: A solution of compound 68a (0.22 g, 0.43 mmol) and 3N aqueous HCl (1.4 mL, 4.2 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 69a (0.22 g, quantitative yield) as a yellow oil. m / z=465 (M+1).

[0806] Compound 70a: A solution of compound 69a (0.22 g, ≤ 0.43 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 % by weight in MeOH, 0.40 mL, 2.13 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with salt water (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70a (0.17 g, 80% yield) as an orange solid. m / z=493 (M+1).

[0807] Compound 71a: A solution of compound 70a (0.17 g, 0.34 mmol), acetic acid (0.20 mL, 3.50 mmol) and hydroxylamine hydrochloride (35 mg, 0.50 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71a (0.17 g, quantitative yield) as a tan solid. m / z=490 (M+1).

[0808] Compound 72a: A mixture of compound 71a (0.17 g, ≤ 0.34 mmol) and potassium carbonate (0.24 g, 1.74 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated, and the residue was distributed between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with salt water (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to obtain compound 72a (0.10 g, 60% yield) as a yellow solid. m / z=490 (M+1).

[0809] T65: To a stirred solution of compound 72a (93 mg, 0.19 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (30 mg, 0.10 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.15 mL, 1.86 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound T65 (48 mg, 52% yield) as a light yellow solid. m / z=488 (M+1); 1H NMR(400MHz, CDCl3)δ7.80(m,2H),7.72(m,2H),7.66(m,3H),7.57(m,2H),7.50(m,2H),7.43(m,1H),7.11(m,2H),2.94(m,1H),2.87(m,1H) ,2.56(qd,J=6.7,13.4Hz,1H),2.28(dt,J=2.0,12.7Hz,1H),2.16(dd,J=6.3,13.9Hz,1H),1.82(m,1H),1.61(s,3H),1.34(d,J=6.7Hz,3H).

[0810] Compound 68b: Compound 68b (yellow gummy solid, 0.20 g, 78% yield) was synthesized from compound 67 (0.25 g, 0.51 mmol) and 2-fluorophenylboronic acid (0.14 g, 1.00 mmol) using the same procedure as for compound 68a. Compound 68b was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes). m / z = 509 (M+1).

[0811] Compound 69b: A solution of compound 69b (0.20 g, 0.39 mmol) and 3N aqueous HCl (1.4 mL, 4.2 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give compound 69b (0.17 g, 94% yield) as a light yellow solid. m / z=465 (M+1).

[0812] Compound 70b: A solution of compound 69b (0.17 g, 0.37 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % in MeOH, 0.34 mL, 1.81 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70b (0.17 g, 94% yield) as a dark yellow solid. m / z=493 (M+1).

[0813] Compound 71b: A solution of compound 70b (0.17 g, 0.34 mmol), acetic acid (0.20 mL, 3.50 mmol) and hydroxylamine hydrochloride (35 mg, 0.50 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71b (0.16 g, 94% yield) as a dark yellow solid. m / z=490 (M+1).

[0814] Compound 72b: A mixture of compound 71b (0.16 g, 0.33 mmol) and potassium carbonate (0.23 g, 1.66 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated and the residue was distributed between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 72b (0.15 g, 94% yield) as a tan foamy solid. m / z=490 (M+1).

[0815] T66: To a stirred solution of compound 72b (0.15 g, 0.31 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (44 mg, 0.15 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.25 mL, 3.10 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound T66 (87 mg, 58% yield) as a light yellow solid. m / z=488 (M+1); 1H NMR (400MHz, CDCl3) δ7.80(m,2H),7.70(s,1H),7.66(m,2H),7.59(m,3H),7.50(m,2H),7.38(m,2H),7.18(m,2H),2.74(m,2H ), 2.56 (qd, J = 6.7, 13.4Hz, 1H), 2.31 (dt, J = 2.1, 12.7Hz, 1H), 2.09 (m, 1H), 1.79 (m, 1H), 1.62 (s, 3H), 1.33 (d, J = 6.7Hz, 3H).

[0816] Compound 68c: Compound 68c (yellow solid, 0.18 g, 72% yield) was synthesized from compound 67 (0.25 g, 0.51 mmol) and pyridine-4-boronic acid (0.12 g, 0.98 mmol) using the same procedure as for compound 68a. The reaction was heated at 110°C for 16 h. Compound 68c was purified by column chromatography (silica gel, eluted with 100% EtOAc). m / z = 492 (M+1).

[0817] Compound 69c: A solution of compound 68c (0.18 g, 0.37 mmol) and 3N aqueous HCl (1.3 mL, 3.9 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give compound 69c (0.19 g, quantitative yield) as a yellow oil. m / z=448 (M+1).

[0818] Compound 70c: A solution of compound 69c (0.19 g, ≤ 0.37 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % MeOH, 0.35 mL, 1.86 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70c (0.16 g, 91% yield) as a dark yellow solid. m / z=476 (M+1).

[0819] Compound 71c: A solution of compound 70c (0.16 g, 0.34 mmol), acetic acid (0.20 mL, 3.50 mmol) and hydroxylamine hydrochloride (35 mg, 0.50 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 75% EtOAc in hexanes) to obtain compound 71c (90 mg, 56% yield) as a light yellow foamy solid. m / z=473 (M+1).

[0820] Compound 72c: A mixture of compound 71c (90 mg, 0.19 mmol) and potassium carbonate (0.13 g, 0.94 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated and the residue was distributed between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 72c (70 mg, 78% yield) as an off-white solid. m / z=473 (M+1).

[0821] T67: To a stirred solution of compound 72c (70 mg, 0.15 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (23 mg, 0.080 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.12 mL, 1.48 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated aqueous KH2PO4 solution (25 mL) and CHCl3 (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 100% EtOAc in hexanes) to give compound T67 (40 mg, 57% yield) as a light yellow solid. m / z=471 (M+1); 1H NMR (400MHz, CDCl3) δ8.66 (br s,2H),7.83(m,2H),7.67(m,5H),7.57(m,2H),7.51(m,2H),7.44(m,1H),3.04(m,1H),2.93(m,1H),2.57(qd,J=6.7,13 .3Hz,1H),2.29(dt,J=2.1,12.7Hz,1H),2.20(dd,J=6.5,13.7Hz,1H),1.84(m,1H),1.61(s,3H),1.35(d,J=6.7Hz,3H).

[0822] Compound 68d: Using the same procedure as compound 68a, compound 68d (light yellow solid, 0.19 g, 76% yield) was synthesized from compound 67 (0.25 g, 0.51 mmol) and pyridine-3-boronic acid (0.13 g, 1.06 mmol). The reaction was heated at 110°C for 16 h. Compound 68d was purified by column chromatography (silica gel, eluted with 75% EtOAc in hexanes). m / z = 492 (M+1).

[0823] Compound 69d: A solution of compound 68d (0.19 g, 0.39 mmol) and 3N aqueous HCl (1.3 mL, 3.9 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give compound 69d (0.23 g, quantitative yield) as a yellow oil. m / z=448 (M+1).

[0824] Compound 70d: A solution of compound 69d (0.23 g, ≤ 0.39 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % in MeOH, 0.37 mL, 1.97 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and a saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70d (0.17 g, 92% yield) as a tan foamy solid. m / z=476 (M+1).

[0825] Compound 71d: A solution of compound 70d (0.17 g, 0.36 mmol), acetic acid (0.21 mL, 3.67 mmol) and hydroxylamine hydrochloride (38 mg, 0.55 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71d (0.15 g, 88% yield) as a yellow-brown foamy solid. m / z=473 (M+1).

[0826] Compound 72d: A mixture of compound 71d (0.15 g, 0.32 mmol) and potassium carbonate (0.22 g, 1.59 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated, and the residue was distributed between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 75% EtOAc in hexanes) to obtain compound 72d (99 mg, 66% yield) as a light yellow solid. m / z=473 (M+1).

[0827] T68: To a stirred solution of compound 72d (99 mg, 0.21 mmol) in degassed DMF (4 mL) at 0°C under N2 was added dropwise a solution of 1,3-dibromo-5,5-dimethylhydantoin (33 mg, 0.12 mmol) in degassed DMF (1 mL). The mixture was stirred at 0°C for 30 min, and then pyridine (0.17 mL, 2.11 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between a saturated aqueous KH2PO4 solution (25 mL) and CHCl3 (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl3) to give compound T68 (57 mg, 58% yield) as a light yellow solid. m / z=471 (M+1); 1H NMR (400MHz, CDCl3) δ8.98(d,J=2.0Hz,1H),8.59(d,J=4.0Hz,1H),8.08(td,J=1.9,8.0H z,1H),7.82(m,2H),7.67(m,3H),7.58(m,2H),7.51(m,2H),7.44(m,1H),7.35(dd,J=4.5 ,7.8Hz,1H),2.99(m,1H),2.91(m,1H),2.57(qd,J=6.7,13.3Hz,1H),2.30(dt,J=2.0,12 .7Hz, 1H), 2.19 (dd, J = 6.4, 13.8Hz, 1H), 1.84 (m, 1H), 1.62 (s, 3H), 1.34 (d, J = 6.7Hz, 3H).

[0828] Compound 68e: In a sealable bottle, a mixture of compound 67 (0.21 g, 0.42 mmol), 4-methylphenylboronic acid (0.11 g, 0.81 mmol) and potassium phosphate (0.27 g, 1.27 mmol) in 1,4-dioxane (2.6 mL) and DMF (1.3 mL) was degassed and treated with tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.051 mmol). The mixture was degassed again. The bottle was sealed and the mixture was heated at 100 ° C for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with 1N NaOH aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1 / 10 / 10 EtOAc / CH2Cl2 / hexanes) to give compound 68e (0.13 g, 61% yield) as a tan solid. m / z = 505 (M+1).

[0829] Compound 69e: A solution of compound 68e (0.13 g, 0.26 mmol) and 3N aqueous HCl (1.0 mL, 3.0 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give compound 69e (0.11 g, 93%) as an off-white solid. m / z=461 (M+1).

[0830] Compound 70e: A solution of compound 69e (0.11 g, 0.24 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % in MeOH, 0.22 mL, 1.17 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with salt water (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70e (0.15 g, quantitative yield) as a tan solid. m / z=489 (M+1).

[0831] Compound 71e: A solution of compound 70e (0.15 g, ≤ 0.24 mmol), acetic acid (0.14 mL, 2.44 mmol) and hydroxylamine hydrochloride (25 mg, 0.36 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71e (0.12 g, quantitative yield) as a light yellow solid. m / z=486 (M+1).

[0832] Compound 72e: A mixture of compound 71e (0.12 g, ≤ 0.24 mmol) and potassium carbonate (0.17 g, 1.23 mmol) in MeOH (10 mL) was stirred overnight at room temperature under N2. The mixture was concentrated and the residue was partitioned between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to afford compound 72e (0.11 g, 94% yield) as a tan solid. m / z=486 (M+1).

[0833] T69: To a stirred solution of compound 72e (0.11 g, 0.23 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (32 mg, 0.11 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.19 mL, 2.35 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated aqueous KH2PO4 solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound T69 (40 mg, 37% yield) as a light yellow solid. m / z=484 (M+1); 1 H NMR(400MHz, CDCl3)δ7.79(m,2H),7.69(s,1H),7.65(m,4H),7.58(m,2H),7 .50(m,2H),7.43(m,1H),7.23(d,J=7.9Hz,2H),2.96(m,1H),2.88(m,1H),2 .56(qd,J=6.7,13.4Hz,1H),2.38(s,3H),2.28(dt,J=2.0,12.7Hz,1H),2.1 5(dd,J=6.4,13.8Hz,1H),1.81(m,1H),1.60(s,3H),1.33(d,J=6.7Hz,3H).

[0834] Compound 68f: In a sealable bottle, a mixture of compound 67 (0.30 g, 0.61 mmol), pyrimidine-5-boric acid (0.15 g, 1.21 mmol) and potassium phosphate (0.39 g, 1.84 mmol) in 1,4-dioxane (4 mL) and DMF (2 mL) was degassed and treated with tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.060 mmol). The mixture was degassed again. The bottle was sealed and the mixture was heated at 100 ° C for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with a 1N NaOH aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes) to give compound 68f (0.11 g, 37% yield) as a tan solid. m / z = 493 (M+1).

[0835] Compound 69f: A solution of compound 68f (0.11 g, 0.22 mmol) and 3N aqueous HCl (0.75 mL, 2.25 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 69f (94 mg, 94% yield) as a tan solid. m / z=449 (M+1).

[0836] Compound 70f: A solution of compound 69f (94 mg, 0.21 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 % by weight in MeOH, 0.20 mL, 1.07 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with salt water (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70f (96 mg, 96% yield) as a tan solid. m / z=477 (M+1).

[0837] Compound 71f: A solution of compound 70f (96 mg, 0.20 mmol), acetic acid (0.15 mL, 2.62 mmol) and hydroxylamine hydrochloride (21 mg, 0.30 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71f (86 mg, 90% yield) as a dark yellow solid. m / z=474 (M+1).

[0838] Compound 72f: A mixture of compound 71f (86 mg, 0.18 mmol) and potassium carbonate (0.13 g, 0.94 mmol) in MeOH (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and the residue was distributed between a saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 72f (77 mg, 90% yield) as a tan solid. m / z=474 (M+1).

[0839] T70: At 0 ° C, under N2, to a stirred solution of compound 72f (77 mg, 0.16 mmol) in degassed DMF (4 mL), a solution of 1,3-dibromo-5,5-dimethylhydantoin (23 mg, 0.080 mmol) in degassed DMF (1 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 min, and then pyridine (0.13 mL, 1.61 mmol) was added. The mixture was heated at 60 ° C for 4 h and then concentrated. The residue was distributed between saturated KH2PO4 aqueous solution (25 mL) and CHCl3 (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% MeOH in CHCl 3 ) to give a partially purified product, and again purified by column chromatography (silica gel, eluted with 75% EtOAc in hexanes) to give Compound T70 (35 mg, 46% yield) as an off-white solid. m / z = 472 (M + 1); 1 H NMR(400MHz, CDCl3)δ9.19(s,1H),9.12(s,2H),7.83(m,2H),7.67(m,2H) ,7.64(s,1H),7.57(m,2H),7.51(m,2H),7.44(m,1H),2.98(m,1H),2.91( m,1H),2.57(qd,J=6.7,13.3Hz,1H),2.29(dt,J=2.1,12.7Hz,1H),2.21( dd,J=6.3,14.0Hz,1H),1.86(m,1H),1.62(s,3H),1.35(d,J=6.7Hz,3H).

[0840] Compound 68g: In a sealable bottle, a mixture of compound 67 (0.25g, 0.51mmol), 3-isopropylphenylboronic acid (0.17g, 1.04mmol) and potassium phosphate (0.32g, 1.51mmol) in 1,4-dioxane (4mL) and DMF (2mL) was degassed and treated with tetrakis(triphenylphosphine)palladium(0) (59mg, 0.051mmol). The mixture was degassed again. The bottle was sealed and the mixture was heated at 100°C for 48h. After cooling to room temperature, the mixture was diluted with EtOAc (50mL) and washed with a 1N NaOH aqueous solution (50mL). The organic extract was washed with brine (50mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 1 / 20 / 20 EtOAc / CH2Cl2 / hexanes) to afford Compound 68g (0.10 g, 37% yield) as an off-white solid. m / z = 533 (M+1).

[0841] Compound 69g: A solution of compound 68g (0.10 g, 0.19 mmol) and 3N aqueous HCl (0.60 mL, 1.80 mmol) in MeOH (10 mL) was stirred at room temperature under N2 for 48 h. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give compound 69g (90 mg, 98% yield) as an off-white solid. m / z=489 (M+1).

[0842] Compound 70g: A solution of compound 69g (90 mg, 0.18 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % MeOH, 0.17 mL, 0.91 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with salt water (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70g (90 mg, 95% yield) as a yellow-brown foamy solid. m / z=517 (M+1).

[0843] Compound 71g: A solution of compound 70g (90 mg, 0.17 mmol), acetic acid (0.10 mL, 1.75 mmol) and hydroxylamine hydrochloride (18 mg, 0.26 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71g (89 mg, quantitative yield) as a light yellow solid. m / z=514 (M+1).

[0844] Compound 72g: A mixture of compound 71g (89 mg, 0.17 mmol) and potassium carbonate (0.12 g, 0.87 mmol) in MeOH (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and the residue was distributed between a saturated KHPO aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO, filtered, and concentrated to obtain compound 72g (91 mg, quantitative yield) as a light yellow solid. m / z=514 (M+1).

[0845] T71: At 0 ° C, under N2, to a stirred solution of compound 72g (91 mg, ≤0.17 mmol) in degassed DMF (4 mL), a solution of 1,3-dibromo-5,5-dimethylhydantoin (24 mg, 0.084 mmol) in degassed DMF (1 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 min, and then pyridine (0.14 mL, 1.73 mmol) was added. The mixture was heated at 60 ° C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound T71 (54 mg, 62% yield) as a light yellow solid. m / z=512 (M+1); 1 H NMR(400MHz, CDCl3)δ7.80(m,2H),7.67(m,3H),7.60(m,3H),7.51(m,3H), 7.43(m,1H),7.35(t,J=7.7Hz,1H),7.23(m,1H),2.95(m,3H),2.56(qd,J= 6.7,13.4Hz,1H),2.29(dt,J=2.0,12.7Hz,1H),2.16(dd,J=6.2,13.8Hz,1 H), 1.81 (m, 1H), 1.60 (s, 3H), 1.34 (d, J = 6.7Hz, 3H), 1.28 (d, J = 6.9Hz 6H).

[0846] Compound 68h: Using the same procedure as compound 68g, compound 68h (light yellow solid, 0.15 g, 67% yield) was synthesized from compound 67 (0.22 g, 0.44 mmol) and 2-methylphenylboronic acid (0.12 g, 0.88 mmol). Compound 68h was purified by column chromatography (silica gel, eluting with 1 / 20 / 20 EtOAc / CH2Cl2 / hexanes). m / z = 505 (M+1).

[0847] Compound 69h: A solution of compound 68h (0.15 g, 0.30 mmol) and 3N aqueous HCl (1.0 mL, 3.0 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 69h (0.15 g, quantitative yield) as a dark yellow oil. m / z=461 (M+1).

[0848] Compound 70h: A solution of compound 69h (0.15 g, ≤ 0.30 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % in MeOH, 0.28 mL, 1.49 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and a saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with brine (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70h (0.15 g, quantitative yield) as a light yellow solid. m / z=489 (M+1).

[0849] Compound 71h: A solution of compound 70h (0.15 g, ≤ 0.30 mmol), acetic acid (0.17 mL, 2.97 mmol) and hydroxylamine hydrochloride (31 mg, 0.45 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71h (0.15 g, quantitative yield) as a light yellow foamy solid. m / a=486 (M+1).

[0850] Compound 72h: A mixture of compound 11h (0.15 g, ≤ 0.30 mmol) and potassium carbonate (0.21 g, 1.52 mmol) in MeOH (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and the residue was partitioned between a saturated KHPO aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO, filtered, and concentrated to afford compound 72h (0.14 g, 96% yield) as a tan solid. m / z=486 (M+1).

[0851] T72: To a stirred solution of compound 72h (0.14 g, 0.29 mmol) in degassed DMF (4 mL) at 0°C under N2 was added a solution of 1,3-dibromo-5,5-dimethylhydantoin (43 mg, 0.15 mmol) in degassed DMF (1 mL) dropwise. The mixture was stirred at 0°C for 30 min, and then pyridine (0.25 mL, 3.09 mmol) was added. The mixture was heated at 60°C for 4 h and then concentrated. The residue was partitioned between saturated KH2PO4 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 25% EtOAc in hexanes) to give compound T72 (91 mg, 65% yield) as a light yellow solid. m / z=484 (M+1); 1 H NMR (400MHz, CDCl3) δ7.78(m,2H),7.73(s,1H),7.66(m,2H),7.58(m,2H),7.50(m,2H),7.42(m,1H),7.32(m,1H),7.28(m,2H),7. 22(m,1H),2.59(m,3H),2.36(s,3H),2.29(dt,J=2.1,12.7Hz,1H),2.07(m,1H),1.80(m,1H),1.63(s,3H),1.32(d,J=6.7Hz,3H).

[0852] Compound 68i: Using the same procedure as for compound 68g, compound 68i (light yellow solid, 0.28 g, 78% yield) was synthesized from compound 67 (0.34 g, 0.69 mmol) and 4-(hydroxymethyl)phenylboronic acid (0.21 g, 1.38 mmol). Compound 68i was purified by column chromatography (silica gel, eluted with 50% EtOAc in hexanes). m / z = 521 (M+1).

[0853] Compound 69i: A solution of compound 68i (0.28 g, 0.54 mmol) and 3N aqueous HCl (1.8 mL, 5.4 mmol) in MeOH (10 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated. The residue was cooled and basified to pH 9-10 with 10% aqueous NH4OH. The mixture was extracted with CHCl3 (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 69i (0.27 g, quantitative yield) as a light yellow solid. m / z=477 (M+1).

[0854] Compound 70i: A solution of compound 69i (0.27 g, ≤0.54 mmol) in ethyl formate (10 mL, 0.12 mol) was treated with sodium methoxide (30 wt % in MeOH, 0.53 mL, 2.82 mmol). The mixture was stirred overnight at room temperature under N2 and then concentrated. The residue was distributed between EtOAc (50 mL) and saturated KH2PO4 aqueous solution (50 mL). The organic extract was washed with salt water (50 mL), dried with MgSO4, filtered, and concentrated to obtain compound 70i (0.28 g, quantitative yield) as a yellow-brown-orange solid. m / z=505 (M+1).

[0855] Compound 71i: A solution of compound 70i (0.28 g, ≤ 0.54 mmol), acetic acid (0.33 mL, 5.76 mmol) and hydroxylamine hydrochloride (0.10 g, 1.44 mmol) in EtOH (10 mL) was stirred at 60 ° C for 2 h, then stirred at room temperature overnight. The mixture was concentrated. The residue was distributed between saturated NaHCO3 aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to obtain compound 71i (0.29 g, quantitative yield) as a yellow-brown foamy solid. m / z=502 (M+1).

[0856] Compound 72i: A mixture of compound 71i (70 mg, 0.14 mmol) and potassium carbonate (0.10 g, 0.72 mmol) in MeOH (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and the residue was distributed between a saturated KHPO aqueous solution (25 mL) and EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried over MgSO, filtered, and concentrated to obtain compound 72i (59 mg, 84% yield) as a yellow solid. m / z=502 (M+1).

[0857] T73: To a stirred solution of compound 72i (59 mg, 0.1...

Claims

1. A compound of the formula: in: n is 0, 1, or 2; R1 is cyano, fluorine, -CF3 or -C(O)R a ,in: R a is hydroxy or amino; or Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups; R2 is hydrogen; or alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , Heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; R2′ is hydrogen; R3 is an alkyl group (C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups; R4 and R5 are each independently absent; or Cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) , -Arene diyl (C≤12) -alkyl (C≤12) , -Arene diyl (C≤12) -Aryl (C≤12) , -Arene diyl (C≤12) -Heteroaryl (C≤12) , -Arene diyl (C≤12) -Heterocycloalkyl (C≤12) , -Arene diyl (C≤12) -Cycloalkyl (C≤12) , -Heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -Heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -Cycloalkyl (C≤12) , -Heterocycloalkanediyl (C≤12) -Aryl (C≤12) , -Heterocycloalkanediyl (C≤12) -Heteroaryl (C≤12) or a substituted form of any of these groups; or A group of the formula: Wherein l and m are each 0, 1, 2 or 3; R6 is absent or is amino; or Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , Alkyl(cycloalkyl)amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) , -alkanediyl (C≤12) -Cycloalkyl (C≤12) , -alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) , -Arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) , -Arene diyl (C≤18) -Heterocycloalkyl (C≤12) , Heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When , X2 is C; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further defined as: in: n is 0, 1, or 2; R1 is cyano, fluorine, -CF3 or -C(O)R a ,in R a is hydroxy or amino; or Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups; R2 is hydrogen; or alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , Heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; R2′ is hydrogen; R3 is an alkyl group (C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups; R4 and R5 are each independently absent; or Cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) , -Arene diyl (C≤12) -alkyl (C≤12) , -Arene diyl (C≤12) -Aryl (C≤12) , -Arene diyl (C≤12) -Heteroaryl (C≤12) , -Arene diyl (C≤12) -Heterocycloalkyl (C≤12) , -Arene diyl (C≤12) -Cycloalkyl (C≤12) , -Heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -Heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -Cycloalkyl (C≤12) , -Heterocycloalkanediyl (C≤12) -Aryl (C≤12) , -Heterocycloalkanediyl (C≤12) -Heteroaryl (C≤12) or a substituted form of any of these groups; or A group of the formula: Wherein l and m are each 0, 1, 2 or 3; R6 is absent or is amino; or Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , Alkyl(cycloalkyl)amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) , -alkanediyl (C≤12) -Cycloalkyl (C≤12) , -alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) , -Arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) , -Arene diyl (C≤18) -Heterocycloalkyl (C≤12) , Heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When X2 is C; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, further defined as: in: R1 is cyano, fluorine, -CF3 or -C(O)R a ,in R a is hydroxy or amino; or Alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) or a substituted form of any of these groups; R2 is hydrogen; or alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aromatic (C≤18) , arylalkyl (C≤18) , Heteroaryl (C≤18) , heteroarylalkyl (C≤18) or a substituted form of any of these groups; R2′ is hydrogen; R3 is an alkyl group (C≤12) , alkenyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) or a substituted form of any of these groups; R4 and R5 are each independently absent; or Cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aromatic (C≤12) , arylalkyl (C≤12) , heteroaryl (C≤12) , heteroarylalkyl (C≤12) , -Arene diyl (C≤12) -alkyl (C≤12) , -Arene diyl (C≤12) -Aryl (C≤12) , -Arene diyl (C≤12) -Heteroaryl (C≤12) , -Arene diyl (C≤12) -Heterocycloalkyl (C≤12) , -Arene diyl (C≤12) -Cycloalkyl (C≤12) , -Heteroarene diyl (C≤12) -alkyl (C≤12) ,-heteroarene diyl (C≤12) -Aryl (C≤12) ,-heteroarene diyl (C≤12) -Heteroaryl (C≤12) ,-heteroarene diyl (C≤12) -Heterocycloalkyl (C≤12) ,-heteroarene diyl (C≤12) -Cycloalkyl (C≤12) , -Heterocycloalkanediyl (C≤12) -Aryl (C≤12) , -Heterocycloalkanediyl (C≤12) -Heteroaryl (C≤12) or a substituted form of any of these groups; or A group of the formula: Wherein l and m are each 0, 1, 2 or 3; R6 is absent or is amino; or Alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , Alkyl(cycloalkyl)amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) ,alkyl (C≤12) , cycloalkyl (C≤12) , -alkanediyl (C≤12) -Cycloalkyl (C≤12) , -alkanediyl (C≤18) -Aralkyloxy (C≤18) , heterocycloalkyl (C≤12) , aromatic (C≤18) , -Arene diyl (C≤12) -alkyl (C≤12) , arylalkyl (C≤18) , -Arene diyl (C≤18) -Heterocycloalkyl (C≤12) , Heteroaryl (C≤18) ,-heteroarene diyl (C≤12) -alkyl (C≤12) , heteroarylalkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) or a substituted form of any of these groups; and X1 and X2 are each independently C or N, provided that when R6 is amino, alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl (cycloalkyl) amino (C≤12) , arylamino (C≤12) or diarylamino (C≤12) When , X2 is C; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, further defined as: or a pharmaceutically acceptable salt of any one of the above formulae.

5. A pharmaceutical composition comprising: (a) the compound according to any one of claims 1 to 4; and (b) Excipients.

6. Use of a compound or composition according to any one of claims 1 to 5 in the preparation of a medicament for treating or preventing a disease or disorder in a patient in need thereof.

7. The use according to claim 6, wherein the disease or disorder is associated with increased production of the cytokine IL-17.

8. The use according to claim 6 or 7, wherein the disease or disorder is associated with dysregulated angiogenesis.

9. Use according to any one of claims 6 to 8, wherein the disease or disorder is an autoimmune disease, organ rejection, asthma, cancer, a neurological disorder, a psychiatric disorder, a neuropsychiatric disorder, a chronic pain syndrome, an inflammatory disorder, a retinal disorder or a cardiovascular disease.

10. The use according to claim 6, wherein the disease or disorder is associated with inflammation.

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